U.S. patent application number 17/522249 was filed with the patent office on 2022-03-03 for substituted organofluoroborates as imaging agents.
The applicant listed for this patent is THE UNIVERSITY OF BRITISH COLUMBIA. Invention is credited to Zhibo LIU, David PERRIN.
Application Number | 20220062445 17/522249 |
Document ID | / |
Family ID | |
Filed Date | 2022-03-03 |
United States Patent
Application |
20220062445 |
Kind Code |
A1 |
PERRIN; David ; et
al. |
March 3, 2022 |
SUBSTITUTED ORGANOFLUOROBORATES AS IMAGING AGENTS
Abstract
Fluoridated organofluoroborates comprising at least one .sup.18F
atom and precursors thereto, for use in PET scanning.
Inventors: |
PERRIN; David; (Vancouver,
CA) ; LIU; Zhibo; (Vancouver, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
THE UNIVERSITY OF BRITISH COLUMBIA |
Vancouver |
|
CA |
|
|
Appl. No.: |
17/522249 |
Filed: |
November 9, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16746458 |
Jan 17, 2020 |
11207432 |
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17522249 |
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14773743 |
Sep 8, 2015 |
10556023 |
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PCT/CA2014/000200 |
Mar 7, 2014 |
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16746458 |
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61775280 |
Mar 8, 2013 |
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International
Class: |
A61K 51/04 20060101
A61K051/04; C07F 5/02 20060101 C07F005/02; A61K 51/08 20060101
A61K051/08; C07B 59/00 20060101 C07B059/00 |
Claims
1. A positron emitting compound or salt thereof, wherein the
compound is of the formula I: ##STR00074## wherein: B is boron; A
is a linear or branched C.sub.1-C.sub.15 alkyl group, a linear or
branched C.sub.1-C.sub.15 alkenyl, group, a linear or branched
C.sub.1-C.sub.15 alkynyl group, or a C.sub.3-C.sub.18 non-aromatic
cycloalkyl group, wherein each of the C.sub.1-C.sub.15 alkyl group,
the C.sub.1-C.sub.15 alkenyl, group, the C.sub.1-C.sub.15 alkynyl,
group, and the C.sub.3-C.sub.18 non-aromatic cycloalkyl group is
unsubstituted or substituted and optionally includes at least one
heteroatom interposed between two carbon atoms of the carbon chain
of the group, wherein each of the at least one heteroatom is
independently selected from the group consisting of O, S, N and P;
A is joined to B through a carbon atom; each Y.sup.1 is
independently selected from the group consisting of R.sup.1,
.sup.18F and .sup.19F; n=1 or 2; Y.sup.2 is selected from the group
consisting of R.sup.2, .sup.18F and .sup.19F; R.sup.1 is a
non-interfering substituent with regard to fluoridation of B;
R.sup.2 is a non-interfering substituent with regard to
fluoridation of B; and at least one of (Y.sup.1).sub.n and Y.sup.2
is .sup.18F; providing that A is selected such that the pK.sub.a of
H.sup.a of an acid of the formula II: ##STR00075## is less than or
equal to about 2.8.
2. The positron emitting compound or salt of claim 1, wherein when
A is substituted at the carbon alpha to the ##STR00076## group with
a group that has a dissociable proton, the dissociable proton has a
pKa greater than about 9 and contributes to a net positive charge
on the group that has the dissociable proton.
3. The positron emitting compound or salt of claim 1 or 2, wherein
A is selected such that the pK.sub.a of H.sup.a of the acid of the
formula II is less than or equal to about 2.4.
4. The positron emitting compound or salt of claim 1 or 2, wherein
A is selected such that the pK.sub.a of H.sup.a of the acid of the
formula II is less than or equal to about 2.0.
5. The positron emitting compound or salt of claim 1 or 2, wherein
A is selected such that the pK.sub.a of H.sup.a of the acid of
formula II is less than or equal to about 1.5.
6. The positron emitting compound or salt of claim 1 or 2, wherein
A is selected such that the pK.sub.a of H.sup.a of the acid of
formula II is less than or equal to about 1.0.
7. The positron emitting compound or salt of any one of claims 1 to
6, wherein A is substituted with one or more substituents
independently selected from the group consisting of F, Cl, Br, I,
--N.sup.+(C.sub.1-15alkyl).sub.3,
--N.sup.+(C.sub.2-15alkenyl).sub.3,
--N.sup.+(C.sub.2-15alkynyl).sub.3,
--N.sup.+H(C.sub.1-15alkyl).sub.2,
--N.sup.+H(C.sub.2-15alkenyl).sub.2,
--N.sup.+H(C.sub.2-15alkynyl).sub.2,
P.sup.+(C.sub.1-15alkyl).sub.3, P.sup.+(C.sub.2-15alkenyl).sub.3,
P.sup.+(C.sub.2-15alkynyl).sub.3, S.sup.+(C.sub.1-15alkyl).sub.2,
S.sup.+(C.sub.2-15alkenyl).sub.2, S.sup.+(C.sub.2-15alkynyl).sub.2,
oxo (i.e., .dbd.O), OH, --OC.sub.1-15alkyl, unsubstituted or
substituted aromatic C.sub.3-C.sub.18 cycloalkyl, unsubstituted or
substituted non-aromatic C.sub.3-C.sub.18 heterocyclic group,
unsubstituted or substituted aromatic C.sub.3-C.sub.18 heterocyclic
group, .dbd.NH, --C.sub.1-C.sub.15alkyl, non-aromatic
C.sub.3-C.sub.18 cycloalkyl, --N(C.sub.1-15alkyl).sub.2,
--N(C.sub.2-15alkenyl).sub.2, --N(C.sub.2-15alkynyl).sub.2, --COOH,
--NH.sub.2, --SH, a biomolecule, and a linking group optionally
joined to a biomolecule.
8. The positron emitting compound or salt of any one of claims 1 to
7, wherein A is substituted with at least one substituent that is a
biomolecule or a linking group optionally joined to a
biomolecule.
9. The positron emitting compound or salt as defined in any one of
claims 1 to 8, wherein the compound is of the formula (IV):
##STR00077## wherein: Q.sup.1 is --CR.sup.3R.sup.4R.sup.5,
--C.ident.CR.sup.8, ##STR00078## or
--R.sup.10C.dbd.CR.sup.11R.sup.12; each of R.sup.3, R.sup.4, and
R.sup.5 is independently H, D, F, Cl, Br, I, CX.sub.3,
--N.sup.+R.sup.15R.sup.16R.sup.17,
--P.sup.+R.sup.18R.sup.19R.sup.20, --S.sup.+R.sup.21R.sup.22,
--NR.sup.23R.sup.24, NHR.sup.23, a biomolecule, a linking group
optionally joined to a biomolecule, a linear or branched
C.sub.1-C.sub.15 alkyl group, or a C.sub.3-C.sub.18 cycloalkyl
group, wherein each of the C.sub.1-C.sub.15 alkyl group and the
C.sub.3-C.sub.18 cycloalkyl group is unsubstituted or substituted
and is optionally includes at least one heteroatom interposed
between two carbon atoms of the carbon chain of the group, wherein
each of the at least one heteroatom is independently selected from
the group consisting of O, S, N and P, each of the C.sub.1-C.sub.15
alkyl group and the C.sub.3-C.sub.18 cycloalkyl group is joined to
the carbon atom of --CR.sup.3R.sup.4R.sup.5 through a carbon atom,
and each X is the same or different and is F, Cl, Br, or I; each of
R.sup.15, R.sup.16 and R.sup.17 is independently H, D, a
biomolecule, a linking group optionally joined to a biomolecule, a
linear or branched C.sub.1-C.sub.15 alkyl group, or a
C.sub.3-C.sub.18 cycloalkyl group, wherein each of the
C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18 cycloalkyl
group is unsubstituted or substituted and optionally includes at
least one heteroatom interposed between two carbon atoms of the
carbon chain of the group, wherein each of the at least one
heteroatom is independently selected from the group consisting of
O, S, N and P, and each of the C.sub.1-C.sub.15 alkyl group and the
C.sub.3-C.sub.18 cycloalkyl group is joined to the nitrogen atom of
--N.sup.+R.sup.15R.sup.16R.sup.17 through a carbon atom, or
R.sup.15 is absent and R.sup.16 and R.sup.17 are joined so that
--N.sup.+R.sup.15R.sup.16R.sup.17 forms a positively charged
nitrogen containing heterocyclic group which is substituted or
unsubstituted; each of R.sup.18, R.sup.19, and R.sup.20 is
independently H, D, a biomolecule, a linking group optionally
joined to a biomolecule, a linear or branched C.sub.1-C.sub.15
alkyl group, or a C.sub.3-C.sub.18 cycloalkyl group, wherein each
of the C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18
cycloalkyl group is unsubstituted or substituted and includes at
least one heteroatom interposed between two carbon atoms of the
carbon chain of the group, wherein each of the at least one
heteroatom is independently selected from the group consisting of
O, S, N and P, and each of the C.sub.1-C.sub.15 alkyl group and the
C.sub.3-C.sub.18 cycloalkyl group is joined to the phosphorus atom
of --P.sup.+R.sup.18R.sup.19R.sup.20 through a carbon atom; each of
R.sup.21 and R.sup.22 is independently H, D, a biomolecule, a
linking group optionally joined to a biomolecule, a linear or
branched C.sub.1-C.sub.15 alkyl group, or a C.sub.3-C.sub.18
cycloalkyl group, wherein each of the C.sub.1-C.sub.15 alkyl group
and the C.sub.3-C.sub.18 cycloalkyl group is unsubstituted or
substituted and optionally includes at least one heteroatom
interposed between two carbon atoms of the carbon chain of the
group, wherein each of the at least one heteroatom is independently
selected from the group consisting of O, S, N and P, and each of
the C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18
cycloalkyl group is joined to the sulfur atom of
--S.sup.+R.sup.21R.sup.22 through a carbon atom; each of R.sup.23
and R.sup.24 is independently H, D, a biomolecule, a linking group
optionally joined to a biomolecule, a linear or branched
C.sub.1-C.sub.15 alkyl group, or a C.sub.3-C.sub.18 cycloalkyl
group, wherein each of the C.sub.1-C.sub.15 alkyl group and the
C.sub.3-C.sub.18 cycloalkyl group is unsubstituted or substituted
and optionally includes at least one heteroatom interposed between
two carbon atoms of the carbon chain of the group, wherein each of
the at least one heteroatom is independently selected from the
group consisting of O, S, N and P, and each of the C.sub.1-C.sub.15
alkyl group and the C.sub.3-C.sub.18 cycloalkyl group is joined to
the nitrogen atom of --NR.sup.23R.sup.24 through a carbon atom;
R.sup.8 is --NR.sup.25R.sup.26R.sup.27,
--P.sup.+R.sup.28R.sup.29R.sup.30, --SR.sup.31R.sup.32,
--NR.sup.33R.sup.34, ##STR00079## a biomolecule, a linking group
optionally joined to a biomolecule, a linear or branched
C.sub.1-C.sub.15 alkyl group, or a C.sub.3-C.sub.18 cycloalkyl
group, wherein each of the C.sub.1-C.sub.15 alkyl group and the
C.sub.3-C.sub.18 cycloalkyl group is substituted with at least one
substituent that is a biomolecule and optionally includes at least
one heteroatom interposed between two carbon atoms of the carbon
chain of the group, wherein each of the at least one heteroatom is
independently selected from the group consisting of O, S, N and P,
and each of the C.sub.1-C.sub.15 alkyl group and the
C.sub.3-C.sub.18 cycloalkyl group is joined to the carbon atom of
--C.ident.CR.sup.8 through a carbon atom; each of R.sup.25,
R.sup.26 and R.sup.27 is independently H, D, a biomolecule, a
linking group optionally joined to a biomolecule, a linear or
branched C.sub.1-C.sub.15 alkyl group, or a C.sub.3-C.sub.18
cycloalkyl group, wherein each of the C.sub.1-C.sub.15 alkyl group
and the C.sub.3-C.sub.18 cycloalkyl group is unsubstituted or
substituted and optionally includes at least one heteroatom
interposed between two carbon atoms of the carbon chain of the
group, wherein each of the at least one heteroatom is independently
selected from the group consisting of O, S, N and P, and each of
the C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18
cycloalkyl group is joined to the nitrogen atom of
--N.sup.+R.sup.25R.sup.26R.sup.27 through a carbon atom, or
R.sup.25 is absent and R.sup.26 and R.sup.27 are joined so that
--N.sup.+R.sup.25R.sup.26R.sup.27 forms a positively charged
nitrogen containing heterocyclic group which is unsubstituted or
substituted; each of R.sup.28, R.sup.29, and R.sup.30 is
independently H, D, a biomolecule, a linking group optionally
joined to a biomolecule, a linear or branched C.sub.1-C.sub.15
alkyl group, or a C.sub.3-C.sub.18 cycloalkyl group, wherein each
of the C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18
cycloalkyl group is unsubstituted or substituted and optionally
includes at least one heteroatom interposed between two carbon
atoms of the carbon chain of the group, wherein each of the at
least one heteroatom is independently selected from the group
consisting of O, S, N and P, and each of the C.sub.1-C.sub.15 alkyl
group and the C.sub.3-C.sub.18 cycloalkyl group is joined to the
phosphorus atom of --P.sup.+R.sup.28R.sup.29R.sup.30 through a
carbon atom; each of R.sup.31 and R.sup.32 is independently H, D, a
biomolecule, a linking group optionally joined to a biomolecule, a
linear or branched C.sub.1-C.sub.15 alkyl group, or a
C.sub.3-C.sub.18 cycloalkyl group, wherein each of the
C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18 cycloalkyl
group is unsubstituted or substituted and optionally includes at
least one heteroatom interposed between two carbon atoms of the
carbon chain of the group, wherein each of the at least one
heteroatom is independently selected from the group consisting of
O, S, N and P, and each of the C.sub.1-C.sub.15 alkyl group and the
C.sub.3-C.sub.18 cycloalkyl group is joined to the sulfur atom of
--S.sup.+R.sup.31R.sup.32 through a carbon atom; each of R.sup.33
and R.sup.34 is independently H, D, a biomolecule, a linking group
optionally joined to a biomolecule, a linear or branched
C.sub.1-C.sub.15 alkyl group, or a C.sub.3-C.sub.18 cycloalkyl
group, wherein each of the C.sub.1-C.sub.15 alkyl group and the
C.sub.3-C.sub.18 cycloalkyl group is unsubstituted or substituted
and optionally includes at least one heteroatom interposed between
two carbon atoms of the carbon chain of the group, wherein each of
the at least one heteroatom is independently selected from the
group consisting of O, S, N and P, and each of the C.sub.1-C.sub.15
alkyl group and the C.sub.3-C.sub.18 cycloalkyl group is joined to
the nitrogen atom of --NR.sup.33R.sup.34 through a carbon atom;
R.sup.35 is a biomolecule, a linking group optionally joined to a
biomolecule, a linear or branched C.sub.1-C.sub.15 alkyl group, or
a C.sub.3-C.sub.18 cycloalkyl group, wherein each of the
C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18 cycloalkyl
group is substituted with at least one substituent that is a
biomolecule and optionally includes at least one heteroatom
interposed between two carbon atoms of the carbon chain of the
group, wherein each of the at least one heteroatom is independently
selected from the group consisting of O, S, N and P, and each of
the C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18
cycloalkyl group is joined to the carbon atom of ##STR00080##
through a carbon atom; R.sup.9 is --NR.sup.38R.sup.39, ##STR00081##
a biomolecule, a linking group optionally joined to a biomolecule,
a linear or branched C.sub.1-C.sub.15 alkyl group, or a
C.sub.3-C.sub.18 cycloalkyl group, wherein each of the
C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18 cycloalkyl
group is substituted with at least one substituent that is a
biomolecule and optionally includes at least one heteroatom
interposed between two carbon atoms of the carbon chain of the
group, wherein each of the at least one heteroatom is independently
selected from the group consisting of O, S, N and P, and each of
the C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18
cycloalkyl group is joined to the carbon atom of ##STR00082##
through a carbon atom; each of R.sup.38 and R.sup.39 is
independently H, D, a biomolecule, a linking group optionally
joined to a biomolecule, a linear or branched C.sub.1-C.sub.15
alkyl group, or a C.sub.3-C.sub.18 cycloalkyl group, wherein each
of the C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18
cycloalkyl group is unsubstituted or substituted and optionally
includes at least one heteroatom interposed between two carbon
atoms of the carbon chain of the group, wherein each of the at
least one heteroatom is independently selected from the group
consisting of O, S, N and P, and each of the C.sub.1-C.sub.15 alkyl
group and the C.sub.3-C.sub.18 cycloalkyl group is joined to the
nitrogen atom of --NR.sup.38R.sup.39 through a carbon atom;
R.sup.40 is a biomolecule, a linking group optionally joined to a
biomolecule, a linear or branched C.sub.1-C.sub.15 alkyl group, or
a C.sub.3-C.sub.18 cycloalkyl group, wherein each of the
C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18 cycloalkyl
group is substituted with at least one substituent that is a
biomolecule and optionally includes at least one heteroatom
interposed between two carbon atoms of the carbon chain of the
group, wherein each of the at least one heteroatom is independently
selected from the group consisting of O, S, N and P, and each of
the C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18
cycloalkyl group is joined to the carbon atom of ##STR00083##
through a carbon atom; each of R.sup.10, R.sup.11, and R.sup.12 is
independently H, D, F, Cl, Br, I, CX.sub.3,
--N.sup.+R.sup.41R.sup.42R.sup.43,
--P.sup.+R.sup.44R.sup.45R.sup.46, --S.sup.+R.sup.47R.sup.48, a
biomolecule, a linking group optionally joined to a biomolecule, a
linear or branched C.sub.1-C.sub.15 alkyl group, or a
C.sub.3-C.sub.18 cycloalkyl group, wherein each of the
C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18 cycloalkyl
group is unsubstituted or substituted and optionally includes at
least one heteroatom interposed between two carbon atoms of the
carbon chain of the group, wherein each of the at least one
heteroatom is independently selected from the group consisting of
O, S, N and P, each of the C.sub.1-C.sub.15 alkyl group and the
C.sub.3-C.sub.18 cycloalkyl group is joined to the carbon atom of
--R.sup.10C.dbd.CR.sup.11R.sup.12 through a carbon atom, and each X
is the same or different and is F, Cl, Br, or I; each of R.sup.41,
R.sup.42 and R.sup.43 is independently H, D, a biomolecule, a
linking group optionally joined to a biomolecule, a linear or
branched C.sub.1-C.sub.15 alkyl group, or a C.sub.3-C.sub.18
cycloalkyl group, wherein each of the C.sub.1-C.sub.15 alkyl group
and the C.sub.3-C.sub.18 cycloalkyl group is unsubstituted or
substituted and optionally includes at least one heteroatom
interposed between two carbon atoms of the carbon chain of the
group, wherein each of the at least one heteroatom is independently
selected from the group consisting of O, S, N and P, and each of
the C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18
cycloalkyl group is joined to the nitrogen atom of
--NR.sup.41R.sup.42R.sup.43 through a carbon atom, or R.sup.41 is
absent and R.sup.42 and R.sup.43 are joined so that
--N.sup.+R.sup.41R.sup.42R.sup.43 forms a positively charged
nitrogen containing heterocyclic group which is substituted or
unsubstituted; each of R.sup.44, R.sup.45, and R.sup.46 is
independently H, D, a biomolecule, a linking group optionally
joined to a biomolecule, a linear or branched C.sub.1-C.sub.15
alkyl group, or a C.sub.3-C.sub.18 cycloalkyl group, wherein each
of the C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18
cycloalkyl group is unsubstituted or substituted and optionally
includes at least one heteroatom interposed between two carbon
atoms of the carbon chain of the group, wherein each of the at
least one heteroatom is independently selected from the group
consisting of O, S, N and P, and each of the C.sub.1-C.sub.15 alkyl
group and the C.sub.3-C.sub.18 cycloalkyl group is joined to the
phosphorus atom of --P.sup.+R.sup.44R.sup.45R.sup.46 through a
carbon atom; each of R.sup.47 and R.sup.48 is independently H, D, a
biomolecule, a linking group optionally joined to a biomolecule, a
linear or branched C.sub.1-C.sub.15 alkyl group, or a
C.sub.3-C.sub.18 cycloalkyl group, wherein each of the
C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18 cycloalkyl
group is unsubstituted or substituted and optionally includes at
least one heteroatom interposed between two carbon atoms of the
carbon chain of the group, wherein each of the at least one
heteroatom is independently selected from the group consisting of
O, S, N and P, and each of the C.sub.1-C.sub.15 alkyl group and the
C.sub.3-C.sub.18 cycloalkyl group is joined to the sulfur atom of
--S.sup.+R.sup.47R.sup.48 through a carbon atom; at least one of
R.sup.3, R.sup.4, R.sup.5, R.sup.8, R.sup.9, R.sup.10, R.sup.11,
R.sup.12, R.sup.15, R.sup.16, R.sup.17, R.sup.18, R.sup.19,
R.sup.20, R.sup.21, R.sup.22, R.sup.23, R.sup.24 R.sup.25,
R.sup.26, R.sup.27, R.sup.28, R.sup.29, R.sup.30, R.sup.31,
R.sup.32, R.sup.33, R.sup.34, R.sup.35, R
.sup.38, R.sup.39, R.sup.40, R.sup.41, R.sup.42, R.sup.43,
R.sup.44, R.sup.45, R.sup.46, R.sup.47, and R.sup.48 is a
biomolecule, a linking group optionally joined to a biomolecule, or
a group that is substituted with at least one substituent that is a
biomolecule, or forms a group that is substituted with at least one
substituent that is a biomolecule; and B, Y.sup.1, n and Y.sup.2
are as defined in claim 1, provided that when Q.sup.1 is
--CR.sup.3R.sup.4R.sup.5, at least one of R.sup.3, R.sup.4 and
R.sup.5 is F, Cl, Br, I, CX.sub.3,
--N.sup.+R.sup.15R.sup.16R.sup.17,
--P.sup.+R.sup.18R.sup.19R.sup.20, --S.sup.+R.sup.21R.sup.22 or
--NR.sup.23R.sup.24.
10. The positron emitting compound or salt of claim 9, wherein
Q.sup.1 is --CR.sup.3R.sup.4R.sup.5, ##STR00084## or
--R.sup.10C.dbd.CR.sup.11R.sup.12; and each R.sup.3, R.sup.4,
R.sup.5, R.sup.9, R.sup.10, R.sup.11, and R.sup.12 is as defined in
claim 9.
11. The positron emitting compound or salt of claim 9, wherein
Q.sup.1 is --CR.sup.3R.sup.4R.sup.5, --C.ident.CR.sup.8, or
##STR00085## and each of R.sup.3, R.sup.4, R.sup.5, R.sup.8, and
R.sup.9 is as defined in claim 9.
12. The positron emitting compound or salt of claim 9, wherein
Q.sup.1 is --CR.sup.3R.sup.4R.sup.5 or --C.ident.CR.sup.8; and each
of R.sup.3, R.sup.4, R.sup.5, and R.sup.8 is as defined in claim
9.
13. The positron emitting compound or salt of claim 9, wherein
Q.sup.1 is --CR.sup.3R.sup.4R.sup.5; and each of R.sup.3, R.sup.4,
and R.sup.5 is as defined in claim 9.
14. The positron emitting compound or salt of claim 9, wherein:
Q.sup.1 is --CR.sup.3R.sup.4R.sup.5; each of R.sup.3, R.sup.4, and
R.sup.5 is as defined in claim 9; at least two of R.sup.3, R.sup.4
and R.sup.5 are independently F, Cl, Br, I, or CX.sub.3, or at
least one of R.sup.3, R.sup.4 and R.sup.5 is
--N.sup.+R.sup.15R.sup.16R.sup.17,
--P.sup.+R.sup.18R.sup.19R.sup.20, --S.sup.+R.sup.21R.sup.22, or
--NR.sup.23R.sup.24; each of R.sup.15, R.sup.16, R.sup.17,
R.sup.18, R.sup.19, R.sup.20, R.sup.21, R.sup.22, R.sup.23, and
R.sup.24 is as defined in claim 9; and at least one of R.sup.3,
R.sup.4, R.sup.5, R.sup.15, R.sup.16, R.sup.17, R.sup.18, R.sup.19,
R.sup.20, R.sup.21, R.sup.22, R.sup.23, and R.sup.24 is a
biomolecule, a linking group optionally joined to a biomolecule, or
a group that is substituted with at least one substituent that is a
biomolecule, or forms a group that is substituted with at least one
substituent that is a biomolecule.
15. The positron emitting compound or salt of claim 9, wherein:
Q.sup.1 is --CR.sup.3R.sup.4R.sup.5; each of R.sup.3, R.sup.4, and
R.sup.5 are selected from H, D, F, Cl, Br, I, CX.sub.3,
--N.sup.+R.sup.15R.sup.16R.sup.17, a biomolecule, a linking group
optionally joined to a biomolecule, a linear or branched
C.sub.1-C.sub.15 alkyl group, and a C.sub.3-C.sub.18 cycloalkyl
group, wherein each of the C.sub.1-C.sub.15 alkyl group and the
C.sub.3-C.sub.18 cycloalkyl group is unsubstituted or substituted
and optionally includes at least one heteroatom interposed between
two carbon atoms of the carbon chain of the group, wherein each of
the at least one heteroatom is independently selected from the
group consisting of O, S, N and P, each of the C.sub.1-C.sub.15
alkyl group and the C.sub.3-C.sub.18 cycloalkyl group is joined to
the carbon atom of --CR.sup.3R.sup.4R.sup.5 through a carbon atom,
and each X is the same or different and is F, Cl, Br, or I; each of
R.sup.15, R.sup.16 and R.sup.17 is as defined in claim 9; at least
two of R.sup.3, R.sup.4 and R.sup.5 are independently F, Cl, Br, I,
or CX.sub.3, or at least one of R.sup.3, R.sup.4 and R.sup.5 is
--N.sup.+R.sup.15R.sup.16R.sup.17; and at least one of R.sup.3,
R.sup.4, R.sup.5, R.sup.15, R.sup.16 and R.sup.17 is a biomolecule,
a linking group optionally joined to a biomolecule, or a group that
is substituted with at least one substituent that is a biomolecule,
or forms a group that is substituted with at least one substituent
that is a biomolecule.
16. The positron emitting compound or salt of claim 9, wherein:
Q.sup.1 is --CR.sup.3R.sup.4R.sup.5; each of R.sup.3, R.sup.4, and
R.sup.5 are selected from F, Cl, Br, I, CX.sub.3, a biomolecule, a
linking group optionally joined to a biomolecule, a linear or
branched C.sub.1-C.sub.15 alkyl group, and a C.sub.3-C.sub.18
cycloalkyl group, wherein each of the C.sub.1-C.sub.15 alkyl group
and the C.sub.3-C.sub.18 cycloalkyl group is unsubstituted or
substituted and optionally includes at least one heteroatom
interposed between two carbon atoms of the carbon chain of the
group, wherein each of the at least one heteroatom is independently
selected from the group consisting of O, S, N and P, each of the
C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18 cycloalkyl
group is joined to the carbon atom of --CR.sup.3R.sup.4R.sup.5
through a carbon atom, and each X is the same or different and is
F, Cl, Br, or I; two of R.sup.3, R.sup.4 and R.sup.5 are
independently F, Cl, Br, I, or CX.sub.3; and one of R.sup.3,
R.sup.4 and R.sup.5 is a biomolecule, a linking group optionally
joined to a biomolecule, or is a group that is substituted with at
least one substituent that is a biomolecule.
17. The positron emitting compound or salt of claim 9, wherein:
Q.sup.1 is --CR.sup.3R.sup.4R.sup.5; each of R.sup.3 and R.sup.4 is
independently F or C.sub.1; R.sup.5 a biomolecule, a linking group
optionally joined to a biomolecule, a linear or branched
C.sub.1-C.sub.15 alkyl group, or a C.sub.3-C.sub.18 cycloalkyl
group, wherein each of the C.sub.1-C.sub.15 alkyl group and the
C.sub.3-C.sub.18 cycloalkyl group is substituted with at least one
substituent that is a biomolecule and optionally includes at least
one heteroatom interposed between two carbon atoms of the carbon
chain of the group, wherein each of the at least one heteroatom is
independently selected from the group consisting of O, S, N and P,
and each of the C.sub.1-C.sub.15 alkyl group and the
C.sub.3-C.sub.18 cycloalkyl group is joined to the carbon atom of
--CR.sup.3R.sup.4R.sup.5 through a carbon atom.
18. The positron emitting compound or salt of claim 9, wherein:
Q.sup.1 is --CR.sup.3R.sup.4R.sup.5; R.sup.3 is
--N.sup.+R.sup.15R.sup.16R.sup.17; each of each of R.sup.4 and
R.sup.5 is independently are selected from H, D, a biomolecule, a
linking group optionally joined to a biomolecule, a linear or
branched C.sub.1-C.sub.15 alkyl group, or a C.sub.3-C.sub.18
cycloalkyl group, wherein each of the C.sub.1-C.sub.15 alkyl group
and the C.sub.3-C.sub.18 cycloalkyl group is unsubstituted or
substituted and optionally includes at least one heteroatom
interposed between two carbon atoms of the carbon chain of the
group, wherein each of the at least one heteroatom is independently
selected from the group consisting of O, S, N and P, and each of
the C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18
cycloalkyl group is joined to the carbon atom of
--CR.sup.3R.sup.4R.sup.5 through a carbon atom; each of R.sup.15,
R.sup.16 and R.sup.17 is independently H, D, a biomolecule, a
linking group optionally joined to a biomolecule, a linear or
branched C.sub.1-C.sub.15 alkyl group, or a C.sub.3-C.sub.18
cycloalkyl group, wherein each of the C.sub.1-C.sub.15 alkyl group
and the C.sub.3-C.sub.18 cycloalkyl group is unsubstituted or
substituted and optionally includes at least one heteroatom
interposed between two carbon atoms of the carbon chain of the
group, wherein each of the at least one heteroatom is independently
selected from the group consisting of O, S, N and P, and each of
the C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18
cycloalkyl group is joined to the nitrogen atom of
--N.sup.+R.sup.15R.sup.16R.sup.17 through a carbon atom, or
R.sup.15 is absent and R.sup.16 and R.sup.17 are joined so that
--N.sup.+R.sup.15R.sup.16R.sup.17 forms a positively charged
nitrogen containing heterocyclic group which is substituted or
unsubstituted; and at least one of R.sup.4, R.sup.5, R.sup.15,
R.sup.16 and R.sup.17 is a biomolecule, a linking group optionally
joined to a biomolecule, or a group that is substituted with at
least one substituent that is a biomolecule, or forms a group that
is substituted with at least one substituent that is a
biomolecule.
19. The positron emitting compound or salt of claim 9, wherein:
Q.sup.1 is --CR.sup.3R.sup.4R.sup.5; R.sup.3 is
--N.sup.+R.sup.15R.sup.16R.sup.17; each of R.sup.4 and R.sup.5 is
independently H, D, a biomolecule, or a linking group optionally
joined to a biomolecule; each of R.sup.15, R.sup.16 and R.sup.17 is
independently H, D, a biomolecule, a linking group optionally
joined to a biomolecule, or a linear or branched C.sub.1-C.sub.6
alkyl group which is unsubstituted or substituted, or R.sup.15 is
absent and R.sup.16 and R.sup.17 are joined so that
--N.sup.+R.sup.15R.sup.16R.sup.17 forms a positively charged
nitrogen containing C.sub.4-C.sub.6 heterocyclic group which is
substituted or unsubstituted; and at least one of R.sup.4, R.sup.5,
R.sup.15, R.sup.16 and R.sup.17 is a biomolecule, a linking group
optionally joined to a biomolecule, or a group that is substituted
with at least one substituent that is a biomolecule, or forms a
group that is substituted with at least one substituent that is a
biomolecule.
20. The positron emitting compound or salt of claim 9, wherein
Q.sup.1 is --C.ident.CR.sup.8; and R.sup.8 is as defined in claim
9.
21. The positron emitting compound or salt of claim 9, wherein:
Q.sup.1 is --C.ident.CR.sup.8; R.sup.8 is a biomolecule, a linking
group optionally joined to a biomolecule, a linear or branched
C.sub.1-C.sub.15 alkyl group, or a C.sub.3-C.sub.18 cycloalkyl
group, wherein each of the C.sub.1-C.sub.15 alkyl group and the
C.sub.3-C.sub.18 cycloalkyl group is substituted with at least one
substituent that is a biomolecule and is optionally intercepted
with at least one heteroatom selected from the group consisting of
O, S, N and P, and each of the C.sub.1-C.sub.15 alkyl group and the
C.sub.3-C.sub.18 cycloalkyl group is joined to the carbon atom of
--C.ident.CR.sup.8 through a carbon atom.
22. The positron emitting compound or salt of claim 9, wherein
Q.sup.1 is ##STR00086## and R.sup.9 is as defined in claim 8.
23. The positron emitting compound or salt of claim 8, wherein
Q.sup.1 is --R.sup.10C.dbd.CR.sup.11R.sup.12; and each of R.sup.10,
R.sup.11, and R.sup.12 is as defined in claim 9.
24. The positron emitting compound or salt of claim 1 or 2, wherein
A is: ##STR00087## ##STR00088##
25. The positron emitting compound or salt of any one of claims 1
to 23, wherein each of R.sup.1 and R.sup.2 is independently a
linear or branched C.sub.1-C.sub.15 alkyl group or a non-aromatic
C.sub.3-C.sub.18 cycloalkyl group, wherein each of the
C.sub.1-C.sub.15 alkyl group and the non-aromatic C.sub.3-C.sub.18
cycloalkyl group is unsubstituted or substituted and is optionally
intercepted with at least one heteroatom selected from the group
consisting of O, S, N and P.
26. A positron emitting compound or salt of any one of claims 1 to
25, wherein n is 2, each Y.sup.1 is F and Y.sup.2 is F.
27. A positron emitting compound or salt as defined in any one of
claims 1 to 25, wherein at least one of (Y.sup.1).sub.n and Y.sup.2
is .sup.18F.
28. A positron emitting compound or salt as defined in any one of
claims 1 to 27, having a solvolytic de-18F-fluoridation half-life
at physiological pH of about 1000 minutes or more.
29. A positron emitting compound or salt as defined in any one of
claims 1 to 27, having a solvolytic de-18F-fluoridation half-life
at physiological pH of about 5000 minutes or more.
30. A positron emitting compound or salt as defined in any one of
claims 1 to 26, having a solvolytic de-18F-fluoridation half-life
at physiological pH of about 10000 minutes or more.
31. A positron emitting compound or salt as defined in any one of
claims 1 to 27, having a solvolytic de-18F-fluoridation half-life
at physiological pH of about 15000 minutes or more.
32. A positron emitting compound or salt as defined in any one of
claims 1 to 27, having a solvolytic de-18F-fluoridation half-life
at physiological pH of about 20000 minutes or more.
33. A positron emitting compound or salt as defined in any one of
claims 1 to 27, having a solvolytic de-18F-fluoridation half-life
at physiological pH of about 25000 minutes or more.
34. A positron emitting compound or salt as defined in any one of
claims 1 to 27, having a solvolytic de-18F-fluoridation half-life
at physiological pH of about 50000 minutes or more.
35. A positron emitting compound or salt as defined in any one of
claims 1 to 27, having a solvolytic de-18F-fluoridation half-life
at physiological pH of about 100000 minutes or more.
36. A positron emitting compound or salt as defined in any one of
claims 1 to 27, having a solvolytic de-18F-fluoridation half-life
at physiological pH of about 125000 minutes or more.
37. A positron emitting compound or salt as defined in any one of
claims 1 to 27, having a solvolytic de-18F-fluoridation half-life
at physiological pH of about 150000 minutes or more.
38. A method of making a positron emitting compound or salt as
defined in claim 1, comprising contacting an .sup.18F source with a
compound or salt thereof, wherein the compound is of the formula I:
##STR00089## wherein: B is boron; A is a linear or branched
C.sub.1-C.sub.15 alkyl group, a linear or branched C.sub.1-C.sub.15
alkenyl, group, a linear or branched C.sub.1-C.sub.15 alkynyl
group, or a C.sub.3-C.sub.18 non-aromatic cycloalkyl group, wherein
each of the C.sub.1-C.sub.15 alkyl group, the linear or branched
C.sub.1-C.sub.15 alkenyl group, the linear or branched
C.sub.1-C.sub.15 alkynyl group, and the C.sub.3-C.sub.18
non-aromatic cycloalkyl group is unsubstituted or substituted and
optionally includes at least one heteroatom interposed between two
carbon atoms of the carbon chain of the group, wherein each of the
at least one heteroatom is independently selected from the group
consisting of O, S, N and P; A is joined to B through a carbon
atom; n=1 or 2; each Y.sup.1 is independently selected from the
group consisting of R.sup.1 and a leaving group that can be
displaced by fluoride; Y.sup.2 is selected from the group
consisting of R.sup.2 and a leaving group that can be displaced by
fluoride; at least one of (Y.sup.1).sub.n and Y.sup.2 is said
leaving group when n is 2; R.sup.1 is a non-interfering substituent
with regard to fluoridation of B; R.sup.2 is a non-interfering
substituent with regard to fluoridation of B; and providing that A
is selected such that the pK.sub.a of H.sup.a of an acid of the
formula II: ##STR00090## is less than or equal to about 2.8.
39. The method claim 38, wherein when A is substituted at a carbon
alpha to the ##STR00091## group with a group that has a dissociable
proton, the dissociable proton has a pKa greater than about 9 and
contributes to a net positive charge on the group that has the
dissociable proton.
40. The method of claim 38 or 39, comprising, prior to contacting
the compound or salt thereof with the .sup.18F source, selecting
the compound on the basis that the pK.sub.a of H.sup.a of an acid
of the formula II: ##STR00092## is less than or equal to about
2.8.
41. The method of claim 38, 39, or 40 wherein said .sup.18F source
is a fluoride.
42. The method of any one of claims 38 to 41, wherein A is further
substituted by a biomolecule, or a linking group optionally joined
to a biomolecule.
43. A method of performing PET imaging comprising administering an
imaging effective amount of a positron emitting compound or salt
according to any one of claims 1 to 35 to a subject or object to be
subjected to PET.
44. A method of selecting a PET imaging agent or precursor thereof
having resistance to solvolytic
fluoridationde-18F-fluoridationde-18F-fluoridation at physiological
pH, the method comprising: (i) providing one or more compounds or
salt thereof wherein the compound is of the formula I: ##STR00093##
wherein: B is boron; A is a linear or branched C.sub.1-C.sub.15
alkyl group, a linear or branched C.sub.1-C.sub.15 alkenyl, group,
a linear or branched C.sub.1-C.sub.15 alkynyl group, or a
C.sub.3-C.sub.18 non-aromatic cycloalkyl group, wherein each of the
C.sub.1-C.sub.15 alkyl group, the linear or branched
C.sub.1-C.sub.15 alkenyl group, the linear or branched
C.sub.1-C.sub.15 alkynyl group, and the C.sub.3-C.sub.18
non-aromatic cycloalkyl group is unsubstituted or substituted and
optionally includes at least one heteroatom interposed between two
carbon atoms of the carbon chain of the group, wherein each of the
at least one heteroatom is independently selected from the group
consisting of O, S, N and P; A is joined to B through a carbon
atom; each Y.sup.1 is independently selected from the group
consisting of R.sup.1, .sup.18F and .sup.19F; n=1 or 2; Y.sup.2 is
selected from the group consisting of R.sup.2, .sup.18F and
.sup.19F; R.sup.1 is a non-interfering substituent with regard to
fluoridation of B; R.sup.2 is a non-interfering substituent with
regard to fluoridation of B; and at least one of (Y.sup.1).sub.n
and Y.sup.2 is .sup.18F; providing that A is selected such that the
pK.sub.a of H.sup.a of an acid of the formula II: ##STR00094## is
less than or equal to about 2.8; (ii) assessing the half-life of
the presence of the fluorine bound to B; and (iii) selecting a
compound or compounds having said half-life of about 1000 minutes
or more as said imaging agent or precursor thereof.
45. The method of claim 45, wherein when A is substituted at the
carbon alpha to the ##STR00095## group with a group that has a
dissociable proton, the dissociable proton has a pKa greater than
about 9 and contributes to a net positive charge on the group that
has the dissociable proton.
46. The method of claim 44 or 45, wherein the solvolytic
de-18F-fluoridation half-life at physiological pH is about 1000
minutes or more.
47. The method of claim 44 or 45, wherein the solvolytic
de-18F-fluoridation half-life at physiological pH is about 5000
minutes or more.
48. The method of claim 44 or 45, wherein the solvolytic
de-18F-fluoridation half-life at physiological pH is about 10000
minutes or more.
49. The method of claim 44 or 45, wherein the solvolytic
de-18F-fluoridation half-life at physiological pH is about 15000
minutes or more.
50. The method of claim 44 or 45, wherein the solvolytic
de-18F-fluoridation half-life at physiological pH is about 20000
minutes or more.
51. The method of claim 44 or 45, wherein the solvolytic
de-18F-fluoridation half-life at physiological pH is about 25000
minutes or more.
52. The method of claim 44 or 45, wherein the solvolytic
de-18F-fluoridation half-life at physiological pH is about 50000
minutes or more.
53. The method of claim 44 or 45, wherein the solvolytic
de-18F-fluoridation half-life at physiological pH is about 100000
minutes or more.
54. The method of claim 44 or 45, wherein the solvolytic
de-18F-fluoridation half-life at physiological pH is about 125000
minutes or more.
55. The method of claim 44 or 45, wherein the solvolytic
de-18F-fluoridation half-life at physiological pH of about 150000
minutes or more.
56. The method of any one of claims 44 to 55, wherein said fluorine
comprises .sup.18F.
57. The method of any one of claims 44 to 56, wherein said selected
compound or compounds are for use as a whole body PET imaging agent
or precursor thereof.
58. A positron emitting compound or salt thereof as defined in any
one of claims 1 to 37 for use as a whole body PET imaging agent or
precursor thereof.
59. Use of a compound or salt thereof as a precursor in the
manufacture of an .sup.18F containing PET imaging agent, wherein
the compound is of the formula I: ##STR00096## wherein: B is boron;
A is a linear or branched C.sub.1-C.sub.15 alkyl, a linear or
branched C.sub.1-C.sub.15 alkenyl group, a linear or branched
C.sub.1-C.sub.15 alkynyl group, or a C.sub.3-C.sub.18 non-aromatic
cycloalkyl group, wherein each of the C.sub.1-C.sub.15 alkyl group,
the linear or branched C.sub.1-C.sub.15 alkenyl group, the linear
or branched C.sub.1-C.sub.15 alkynyl group, and the
C.sub.3-C.sub.18 non-aromatic cycloalkyl group is unsubstituted or
substituted and optionally includes at least one heteroatom
interposed between two carbon atoms of the carbon chain of the
group, wherein each of the at least one heteroatom is independently
selected from the group consisting of O, S, N and P; A is joined to
B through a carbon atom; n=1 or 2; each Y.sup.1 is independently
selected from the group consisting of R.sup.1 and a leaving group
that can be displaced by .sup.18F-fluoride; Y.sup.2 is selected
from the group consisting of R.sup.2 and a leaving group that can
be displaced by .sup.18F-fluoride; at least one of (Y.sup.1).sub.n
and Y.sup.2 is said leaving group when n is 2; R.sup.1 is a
non-interfering substituent with regard to fluoridation of B;
R.sup.2 is a non-interfering substituent with regard to
fluoridation of B; and providing that A is selected such that the
pK.sub.a of H.sup.a of an acid of the formula II: ##STR00097## is
less than or equal to about 2.8.
60. The use of claim 59, wherein when A is substituted at a carbon
alpha to the ##STR00098## group with a group that has a dissociable
proton, the dissociable proton has a pKa greater than about 9 and
contributes to a net positive charge on the group that has the
dissociable proton.
61. The use of claim 59 or 60, wherein at least one leaving group
is 19F.
62. A conjugate or a salt thereof, wherein the conjugate comprises
a peptide conjugated to a positron-emitting compound as defined in
any one of claims 1 to 37.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 16/746,458, filed Jan. 17, 2020, which is a continuation of
U.S. application Ser. No. 14/773,743, filed Sep. 8, 2015 (issued as
U.S. Pat. No. 10,556,023), which is a national stage entry of
International Patent Application No. PCT/CA2014/000200, filed Mar.
7, 2014, which claims the benefit of U.S. Provisional Application
No. 61/775,280, filed Mar. 8, 2013, each of which are hereby
incorporated herein by reference in their entireties.
TECHNICAL FIELD
[0002] This invention relates to the field of .sup.18F radiolabeled
reagents for use in positron emission tomography (PET) imaging.
BACKGROUND
[0003] .sup.18F is the isotope of choice for many PET cancer
imaging applications.
[0004] PET imaging agents are often based on a labeled biomolecule.
Examples include fluorodeoxyglucose (FDG); Octreotate, an
octapeptide that is used to image cancer; and folate, which has
been used to image cancer. Since the high energy particle
bombardment used to produce .sup.18F destroys complex organic
molecules, .sup.18F is first made as fluoride ion in a cyclotron
and subsequently attached to the biomolecule used as the imaging
agent. Also, conditions used to incorporate .sup.18F are often too
harsh for direct labeling of many biomolecules. Therefore, .sup.18F
is usually introduced into a precursor (such as an aryl fluoride)
that is then subsequently appended to a larger molecule. Such
multi-step procedures result in delays, with consequent loss in
specific radioactivity.
[0005] Some methodologies for incorporating .sup.18F into imaging
agents have been reported, including a new approach which makes use
of boron as an acceptor capable of binding several .sup.18F atoms,
thus increasing the density of positron emitters in the resulting
imaging agent (see, for example, PCT publication WO 2005/0077967).
In addition, the use of arylboronic acids/esters as .sup.18F
acceptors has been reported. This approach has circumvented the
previous practice of generating aryl fluorides in multi-step
procedures. .sup.18F radiolabeled substituted aryl-fluoroborates
for use in PET imaging have also been reported (see, for example,
WO 2009/012596).
SUMMARY
[0006] A consideration in the design of PET imaging agents is the
longevity of the agent itself. It is desirable that the imaging
agent be sufficiently stable with respect to loss of .sup.18F ions
(termed herein as `solvolytic de-18F-fluoridation, as quantified by
the half-life at physiological pH of the chemical bond that
attaches the 18F-atom to the tracer`). For example, in some
applications it is desirable for the imaging agent to have a
half-life with respect to solvolytic de-18F-fluoridation at
physiological pH that is greater than 10 times the rate of 18F
decay. In some applications it is desirable for the imaging agent
to have a half-life with respect to solvolytic de-18F-fluoridation
at physiological pH of around 1000 minutes or more. It is noted
that the rate of solvolytic de-18F-fluoridation is a chemical
process that involves bond dissociation, not radioactive decay, and
therefore the rate of de-18F-fluoridation is equal to that of
non-radioactive defluoridation, where the 18F-fluorine is replaced
with a nonradioactive 19F-fluorine atom.
[0007] The invention described herein is based, in part, on the
discovery that some organofluoroborates exhibit enhanced resistance
to solvolytic de-18F-fluoridation and can be useful as PET imaging
agents or precursors thereof.
[0008] An embodiment makes use of a positron emitting compound or
salt thereof, wherein the compound may be of the formula I:
##STR00001##
wherein:
[0009] B is boron;
[0010] A may be a linear or branched C.sub.1-C.sub.15 alkyl group,
a linear or branched C.sub.1-C.sub.15 alkenyl, group, a linear or
branched C.sub.1-C.sub.15 alkynyl group, or a C.sub.3-C.sub.18
non-aromatic cycloalkyl group, wherein each of the C.sub.1-C.sub.15
alkyl group, the linear or branched C.sub.1-C.sub.15 alkenyl group,
the linear or branched C.sub.1-C.sub.15 alkynyl group, and the
C.sub.3-C.sub.18 non-aromatic cycloalkyl group is unsubstituted or
substituted and optionally includes at least one heteroatom
interposed between two carbon atoms of the carbon chain of the
group, wherein each of the at least one heteroatom is independently
selected from the group consisting of O, S, N and P;
[0011] A may be joined to B through a carbon atom;
[0012] each Y.sup.1 may independently be selected from the group
consisting of R.sup.1, .sup.18F and .sup.19F;
[0013] n=1 or 2;
[0014] Y.sup.2 may be selected from the group consisting of
R.sup.2, .sup.18F and .sup.19F;
[0015] R.sup.1 may be a non-interfering substituent with regard to
fluoridation of B;
[0016] R.sup.2 may be a non-interfering substituent with regard to
fluoridation of B; and
[0017] at least one of (Y).about. and Y.sup.2 may be .sup.18F;
[0018] providing that A may be selected such that the pK.sub.a of
H.sup.a of the acid of the formula II:
##STR00002##
is less than or equal to about 2.8. When A is substituted at the
carbon alpha to the
##STR00003##
group with a functional group that has a dissociable proton, the
dissociable proton may have a pKa greater than about 9 and
contributes to a net positive charge on the functional group.
Moieties, A, when selected so that: [0019] i) the pK.sub.a of
H.sup.a of the acid of the formula II:
##STR00004##
[0019] is less than or equal to 2.8; and [0020] ii) when A is
substituted at the carbon alpha to the
##STR00005##
[0020] group with a functional group that has a dissociable proton,
the dissociable proton has a pKa>9 and contributes to a net
positive charge on the functional group, permit the resulting
fluoroborate to resist defluoridation. Half-lives with regard to
solvolytic de-18F-fluoridation of the resulting organofluoroborates
may be at least about 10 times longer or more than the rate of
decay of 18F. In other embodiments, half-lives with regard to
solvolytic de-18F-fluoridation of the resulting organofluoroborates
may be at least about 1000 minutes or more; or at least about 5000
minutes or more; or at least about 10000 minutes or more; or at
least about 15000 minutes or more; or at least about 20000 minutes
or more; or at least about 25000 minutes or more; or at least about
50000 minutes or more; or at least about 100000 minutes or more; or
at least about 125000 minutes or more; or at least about 150000
minutes or more. In some applications where loss of fluorine may be
desired (e.g. in comparison of externally bound ligand that loses
fluoride to the surrounding bone with internalized ligands that
keep the fluoride in a targeted cell) shorter half-lives may be
desirable. However, for whole body imaging, longer half-lives are
desirable.
[0021] In an embodiment, one or more counterions may be present
when the compound is charged.
[0022] In various embodiments, there is provided a method of making
a positron emitting compound or salt thereof, the method comprising
contacting an 18F source with a compound or salt thereof, wherein
the compound may be of the formula I:
##STR00006##
wherein:
[0023] B is boron;
[0024] A may be a linear or branched C.sub.1-C.sub.15 alkyl group,
a linear or branched C.sub.1-C.sub.15 alkenyl, group, a linear or
branched C.sub.1-C.sub.15 alkynyl group, or a C.sub.3-C.sub.18
non-aromatic cycloalkyl group, wherein each of the C.sub.1-C.sub.15
alkyl group, the linear or branched C.sub.1-C.sub.15 alkenyl group,
the linear or branched C.sub.1-C.sub.15 alkynyl group, and the
C.sub.3-C.sub.18 non-aromatic cycloalkyl group is unsubstituted or
substituted and optionally includes at least one heteroatom
interposed between two carbon atoms of the carbon chain of the
group, wherein each of the at least one heteroatom is independently
selected from the group consisting of O, S, N and P;
[0025] A may be joined to B through a carbon atom;
[0026] n=1 or 2;
[0027] each Y.sup.1 may independently be selected from the group
consisting of R.sup.1 and a leaving group that can be displaced by
18F-fluoride;
[0028] Y.sup.2 may be selected from the group consisting of R.sup.2
and a leaving group that can be displaced by fluoride
18F-fluoride;
[0029] at least one of (Y.sup.1).sub.n and Y.sup.2 may be the
leaving group when n is 2;
[0030] R.sup.1 may be a non-interfering substituent with regard to
fluoridation of B; and
[0031] R.sup.2 may be a non-interfering substituent with regard to
fluoridation of B;
[0032] providing that A may be selected such that the pK.sub.a of
H.sup.a of the acid of the formula II:
##STR00007##
may be less than or equal to 2.8. When A is substituted at the
carbon alpha to the
##STR00008##
group with a functional group that has a dissociable proton, the
dissociable proton may have a pKa greater than about 9 and
contributes to a net positive charge on the functional group.
[0033] In various embodiments, there is provided a method of
performing PET imaging by administering an imaging-effective amount
of a positron emitting compound or salt as defined anywhere herein
to a subject or object to be subjected to PET.
[0034] In various embodiments, there is provided a method of
selecting a PET imaging agent or precursor thereof having
resistance to solvolytic de-18F-fluoridation at physiological pH,
the method comprising:
[0035] (i) providing one or more compounds or salt thereof wherein
the compound may be of the formula I:
##STR00009##
wherein:
[0036] B is boron;
[0037] A may be a linear or branched C.sub.1-C.sub.15 alkyl group,
a linear or branched C.sub.1-C.sub.15 alkenyl, group, a linear or
branched C.sub.1-C.sub.15 alkynyl group, or a C.sub.3-C.sub.18
non-aromatic cycloalkyl group, wherein each of the C.sub.1-C.sub.15
alkyl group, the linear or branched C.sub.1-C.sub.15 alkenyl group,
the linear or branched C.sub.1-C.sub.15 alkynyl group, and the
C.sub.3-C.sub.18 non-aromatic cycloalkyl group is unsubstituted or
substituted and optionally includes at least one heteroatom
interposed between two carbon atoms of the carbon chain of the
group, wherein each of the at least one heteroatom is independently
selected from the group consisting of O, S, N and P;
[0038] A may be joined to B through a carbon atom;
[0039] each Y.sup.1 may independently be selected from the group
consisting of R.sup.1, .sup.18F and .sup.19F;
[0040] n=1 or 2;
[0041] Y.sup.2 may be selected from the group consisting of
R.sup.2, .sup.18F and .sup.19F;
[0042] R.sup.1 may be a non-interfering substituent with regard to
fluoridation of B;
[0043] R.sup.2 may be a non-interfering substituent with regard to
fluoridation of B; and
[0044] at least one of (Y.sup.1).sub.n and Y.sup.2 may be
.sup.18F;
[0045] providing that A may be selected such that the pK.sub.a of
H.sup.a of the acid of the formula II:
##STR00010##
may be less than or equal to about 2.8;
[0046] (ii) assessing the half-life of the presence of the fluorine
bound to B; and
[0047] (iii) selecting a compound or compounds having said
half-life of about 1000 minutes or more as said imaging agent or
precursor thereof. When A is substituted at the carbon alpha to
the
##STR00011##
group with a functional group that has a dissociable proton, the
dissociable proton may have a pKa greater than about 9 and
contributes to a net positive charge on the functional group
[0048] In various embodiments, there is provided a conjugate or
salt thereof comprising a peptide conjugated to a positron-emitting
compound or salt thereof as described above.
[0049] In various embodiments, there is provided a positron
emitting compound or salt thereof as described above, or a peptide
conjugated to such positron-emitting compound or salt thereof, for
use as a PET imaging agent or precursor thereof.
[0050] In various embodiments, there is provided a use of a
compound of formula I or salt thereof as a precursor in the
manufacture of an .sup.18F containing PET imaging agent.
[0051] In various embodiments, the compound may be of the formula
(IV):
##STR00012##
as defined anywhere herein, provided that when Q.sup.1 is
--CR.sup.3R.sup.4R.sup.5, at least one of R.sup.3, R.sup.4 and
R.sup.5 is F, Cl, Br, I, CX.sub.3,
--N.sup.+R.sup.15R.sup.16R.sup.17,
--P.sup.+R.sup.18R.sup.19R.sup.20, --S.sup.+R.sup.21R.sup.22 or
--NR.sup.23R.sup.24.
BRIEF DESCRIPTION OF THE DRAWINGS
[0052] FIGS. 1A, 1C, 1E, 1G, 1I, 1K, 1M, 1O, 1Q, 1S, 1U, 1W, 1Y,
1AA, 1CC, and 1EE show .sup.19F NMR spectral tracers for
fluoridated organotrifluoroborates in 200 mM phosphate buffer pH
7.5, demonstrating the relative amount of dissociation of .sup.19F
from the compounds at different times.
[0053] FIGS. 1B, 1D, 1F, 1H, 1J, 1L, 1N, 1P, 1R, 1T, 1V, 1X, 1Z,
1BB, 1DD, and 1FF show data for solvolytic defluoridation of the
fluoridated organoborate salts from the .sup.19F NMR measurement
plotted as a function of time. This plot can be fitted to a
pseudo-first-order rate equation that provides for the calculation
of a rate constant kB--F or alternatively referred to as
k.sub.solvolysis.
[0054] FIG. 1A shows .sup.19F NMR spectral traces for a certain
alkynyltrifluoroborate (Compound No. 6 of Table 1).
[0055] FIG. 1B shows data for solvolytic defluoridation of Compound
No. 6 of Table 1.
[0056] FIG. 1C shows .sup.19F NMR spectral tracers for a quaternary
ammoniummethyltrifluoroborate (Compound 9 of Table 1).
[0057] FIG. 1D shows data for solvolytic defluoridation of Compound
9 of Table 1.
[0058] FIG. 1E shows .sup.19F NMR spectral tracers for
butyltrifluoroborate (Compound No. 1 of Table 1).
[0059] FIG. 1F shows data for solvolytic defluoridation of Compound
No. 1 of Table 1.
[0060] FIG. 1G shows .sup.19F NMR spectral tracers for
vinyltrifluoroborate (Compound No. 2 of Table 1)
[0061] FIG. 1H shows data for solvolytic defluoridation of Compound
No. 2 of Table 1.
[0062] FIG. 1I shows .sup.19F NMR spectral tracers for
bromomethyltrifluoroborate (Compound No. 4 of Table 1).
[0063] FIG. 1J shows data for solvolytic defluoridation of Compound
No. 4 of Table 1).
[0064] FIG. 1K shows .sup.19F NMR spectral tracers for a certain
sulfoniumtrifluoroborate (Compound No. 11 of Table 1).
[0065] FIG. 1L shows data for solvolytic defluoridation of Compound
No. 11 of Table 1.
[0066] FIG. 1M shows .sup.19F NMR spectral tracers for Compound No.
12 of Table 1.
[0067] FIG. 1N shows data for solvolytic defluoridation of Compound
No. 12 of Table 1.
[0068] FIG. 1O shows .sup.19F NMR spectral tracers for
phenacyltrifluoroborate (Compound No. 7 of Table 1).
[0069] FIG. 1P shows data for solvolytic defluoridation of Compound
No. 7 of Table 1.
[0070] FIG. 1Q shows .sup.19F NMR spectral tracers for
benzoytrifluoroborate (Compound No. 8 of Table 1).
[0071] FIG. 1R shows data for solvolytic defluoridation of Compound
No. 8 of Table 1.
[0072] FIG. 1S shows .sup.19F NMR spectral tracers for
pyridinium-methyltrifluoroborate (Compound No. 13 of Table 1).
[0073] FIG. 1T shows data for solvolytic defluoridation of Compound
No. 13 of Table 1.
[0074] FIG. 1U shows .sup.19F NMR spectral tracers for Compound No.
9 of Table 1.
[0075] FIG. 1V shows data for solvolytic defluoridation of Compound
No. 9 of Table 1.
[0076] FIG. 1W shows .sup.19F NMR spectral tracers for
dichloromethyltrifluoroborate (Compound No. 10 of Table 1).
[0077] FIG. 1X shows data for solvolytic defluoridation of Compound
No. 10 of Table 1).
[0078] FIG. 1Y shows .sup.19F NMR spectral tracers for Compound No.
14 of Table 1.
[0079] FIG. 1Z shows data for solvolytic defluoridation of Compound
No. 14 of Table 1).
[0080] FIG. 1AA shows .sup.19F NMR spectral tracers for Compound
No. 15 of Table 1.
[0081] FIG. 1BB shows data for solvolytic defluoridation of
Compound No. 15 of Table 1.
[0082] FIG. 1CC shows .sup.19F NMR spectral tracers for Compound
No. 16 of Table 1.
[0083] FIG. 1DD shows data for solvolytic defluoridation of
Compound No. 16 of Table 1.
[0084] FIG. 1EE shows .sup.19F NMR spectral tracers for Compound
No. 17 of Table 1.
[0085] FIG. 1FF shows data for solvolytic defluoridation of
Compound No. 17 of Table 1.
[0086] FIG. 2 shows pk.sub.B--F values (pk.sub.B--F=-log
k.sub.solvolysis) of a number of fluoridated organotrifluoroborates
i.e. RBF.sub.3.sup.- compositions plotted as a function of the pKa
values for the corresponding carboxylic acid RCOOH. The slope of
the graph may be represented as pk(B--F)=-1.40 pKa+7.12
(R.sup.2=0.994).
[0087] FIG. 3 shows TLC chromatograms for Rhodamine-ArBF.sub.3,
Rhodamine-PyrBF.sub.3, and Rhodamine-Compound 9 of Table 1. The
symbols A, B, C represent Rhodamine-ArBF.sub.3,
Rhodamine-PyrBF.sub.3, and Rhodamine-Compound 9 of Table 1,
respectively. The subscript numbers 1, 2, 3 represent different
test conditions: Plasma 1, Plasma 2 and PBS buffer (Plasma 1 and
Plasma 2 were acquired from different mice).
[0088] FIG. 4A shows an HPLC chromatogram for investigating the
serum stability of Rhodamine-Compound 10 of Table 1 at O minutes.
FIG. 4B shows an HPLC chromatogram for investigating the serum
stability of Rhodamine-Compound 10 of Table 1 at 80 minutes. FIG.
4C shows an HPLC chromatogram for investigating the serum stability
of Rhodamine-Compound 10 of Table 1 at 150 minutes. FIG. 4D shows
an HPLC chromatogram for investigating the serum stability of
Rhodamine-Compound 10 of Table 1 at O minutes. FIG. 4E shows an
HPLC chromatogram for investigating the serum stability of
Rhodamine-Compound 10 of Table 1 at 150 minutes. FIG. 4F shows an
HPLC chromatogram for investigating the serum stability of
Rhodamine-Compound 10 of Table 1 at 150 minutes.
[0089] FIG. 5A shows HPLC traces of radioactivity in the plasma of
a mouse injected with Compound 18 at 0, 80 and 150 min post
injection.
[0090] FIG. 5B shows PET-CT images of a mouse at 10, 30, and 60 min
post injection with Compound 18.
[0091] FIG. 6A shows a histogram indicated the uptake value of
different organs for Compound 19 at 60 min post injection.
[0092] FIG. 6B shows a PET/CT image of a mouse injected with
Compound 19 at 60 min post injection.
[0093] FIG. 7 shows PET-CT images of mice injected with Compound
20. T=tumor, K=kidney, B=bladder. The mouse on the left was imaged
with Compound 20 at 3 Ci/.mu.mol, whereas the mouse on the right
was imaged with Compound 20 at 0.01 Ci/.mu.mol. The bottom shows a
pure CT showing tumors.
DETAILED DESCRIPTION
[0094] Any terms not directly defined herein shall be understood to
have the meanings commonly associated with them as understood
within the art of the invention. Certain terms are discussed below,
or elsewhere in the specification, to provide additional guidance
to the practitioner in describing the devices, methods and
embodiments of the invention, and how to make or use them. It will
be appreciated that the same thing may be said in more than one
way. Consequently, alternative language and synonyms may be used
for any one or more of the terms discussed herein. No significance
is to be placed upon whether or not a term is elaborated or
discussed herein. Some synonyms or substitutable methods, materials
and the like are provided. Recital of one or a few synonyms or
equivalents does not exclude use of other synonyms or equivalents,
unless it may be explicitly stated. Use of examples in the
specification, including examples of terms, may be for illustrative
purposes only and does not limit the scope and meaning of the
embodiments of the invention herein.
[0095] "Fluoridation" or "fluorination" are used synonymously
herein to refer generally to a chemical reaction by which fluorine
is introduced into a compound.
[0096] As used herein, the symbol `pKa` is normally understood to a
person skilled in the art and refers to the logarithmic constant,
pKa, where pKa=-log.sub.10 Ka. The symbol `Ka` refers to an acid
dissociation constant, which is the equilibrium constant for the
proton-transfer reaction between a weak acid, HA, and water,
H.sub.2O. The acid dissociation constant, Ka, for a monoprotic
acid, HA, is given by the expression
Ka=[A.sup.-][H.sub.3O+]/[HA].
[0097] As used herein, the phrase `C.sub.x-C.sub.y alkyl` group may
be used as it is normally understood to a person of skill in the
art and often refers to a chemical entity that has a carbon
skeleton or main carbon chain comprising a number from x to y (with
all individual integers within the range included, including
integers x and y) of carbon atoms. For example a `C.sub.1-C.sub.15
alkyl` group may be a chemical entity that has 1, 2, 3, 4, 5, 6, 7,
8, 9, 10, 11, 12, 13, 14 or 15 carbon atom(s) in its carbon
skeleton or main chain.
[0098] As used herein, the term `linear` may be used as it is
normally understood to a person of skill in the art and often
refers to a chemical entity that comprises a skeleton or main chain
that does not split off into more that one contiguous chain.
Non-limiting examples of linear alkyls include methyl, ethyl,
n-propyl, and n-butyl.
[0099] As used herein, the term `branched` may be used as it is
normally understood to a person of skill in the art and often
refers to a chemical entity that comprises a skeleton or main chain
that splits off into more than one contiguous chain. The portions
of the skeleton or main chain that split off in more than one
direction may be linear, cyclic or any combination thereof.
Non-limiting examples of a branched alkyl group include tert-butyl
and isopropyl.
[0100] A linear or branched C.sub.1-C.sub.15 alkyl group may
include a linear or branched saturated C.sub.1-C.sub.15 alkyl
group, a linear or branched C.sub.2-C.sub.15 alkenyl group and a
linear or branched C.sub.2-C.sub.15 alkynyl group. As used herein,
the term `saturated` when referring to a chemical entity may be
used as it is normally understood to a person of skill in the art
and often refers to a chemical entity that comprises only single
bonds. Non-limiting examples of saturated C.sub.1-C.sub.15 alkyl
group may include methyl, ethyl, n-propyl, i-propyl, sec-propyl,
n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, i-pentyl,
sec-pentyl, t-pentyl, n-hexyl, i-hexyl, 1,2-dimethylpropyl,
2-ethylpropyl, 1-methyl-2-ethylpropyl, 1-ethyl-2-methylpropyl,
1,1,2-trimethylpropyl, 1,1,2-triethylpropyl, 1,1-dimethylbutyl,
2,2-dimethylbutyl, 2-ethylbutyl, 1,3-dimethylbutyl, 2-methylpentyl,
3-methylpentyl, sec-hexyl, t-hexyl, n-heptyl, i-heptyl, sec-heptyl,
t-heptyl, n-octyl, i-octyl, sec-octyl, t-octyl, n-nonyl, i-nonyl,
sec-nonyl, t-nonyl, n-decyl, i-decyl, sec-decyl and t-decyl.
Non-limiting examples of C.sub.2-C.sub.15 alkenyl group may include
vinyl, allyl, isopropenyl, 1-propene-2-yl, 1-butene-1-yl,
1-butene-2-yl, 1-butene-3-yl, 2-butene-1-yl, 2-butene-2-yl, octenyl
and decenyl. Non-limiting examples of C.sub.2-C.sub.15 alkynyl
group may include ethynyl, propynyl, butynyl, pentynyl, hexynyl,
heptynyl, octynyl, nonynyl and decynyl. The saturated
C.sub.1-C.sub.15 alkyl group, C.sub.2-C.sub.15 alkenyl group or
C.sub.2-C.sub.15 alkynyl group may be, for example, and without
limitation, interrupted by one or more heteroatoms which may
independently be nitrogen, sulfur, oxygen or phosphorus.
[0101] As used herein, the term `C.sub.x-C.sub.y cycloalkyl` group
may be used as it is normally understood to a person of skill in
the art and often refers to a compound or a chemical entity in
which at least a portion of the carbon skeleton or main chain of
the chemical entity may be bonded in such a way so as to form a
`loop`, circle or ring of atoms that are bonded together. The atoms
do not have to all be directly bonded to each other, but rather may
be directly bonded to as few as two other atoms in the `loop`. As
used herein, C.sub.3-C.sub.18 cycloalkyl group may include a
non-aromatic C.sub.3-C.sub.18 cycloalkyl group and an aromatic
C.sub.3-C.sub.18 cycloalkyl group.
[0102] A C.sub.3-C.sub.18 cycloalkyl group may include, for
example, and without limitation, a saturated C.sub.3-C.sub.18
cycloalkyl group, a C.sub.3-C.sub.18 cycloalkenyl group, a
C.sub.3-C.sub.18 cycloalkynyl group, a C.sub.3-C.sub.18 aryl group,
a C.sub.3-C.sub.18 non-aromatic heterocyclic group containing one
or more heteroatoms which may independently be nitrogen, sulfur,
phosphorus or oxygen, and a C.sub.3-C.sub.18 aromatic heterocyclic
group containing one or more heteroatoms which may independently be
nitrogen, sulfur, phosphorus or oxygen. Non-limiting examples of
the saturated C.sub.3-C.sub.18 cycloalkyl group may include
cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl,
cycloheptanyl, cyclooctanyl, cyclononanyl and cyclodecanyl.
Non-limiting examples of the C.sub.3-C.sub.18 cycloalkenyl group
may include cyclopropenyl, cyclobutenyl, cyclopentenyl,
cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononanenyl and
cyclodecanenyl. Non-limiting examples of the C.sub.3-C.sub.18 aryl
group may include phenyl (Ph), pentalenyl, indenyl, naphthyl, and
azulenyl.
[0103] Non-limiting examples of the C.sub.3-C.sub.18 non-aromatic
heterocyclic group may include aziridinyl, azetidinyl,
diazetidinyl, pyrrolidinyl, pyrrolinyl, piperidinyl, piperazinyl,
imidazolinyl, pyrazolidinyl, imidazolydinyl, phthalimidyl and
succinimidyl, oxiranyl, tetrahydropyranyl, oxetanyl, dioxanyl,
thietanyl, thiepinyl, morpholinyl, and oxathiolanyl. Non-limiting
examples of the C.sub.3-C.sub.18 aromatic heterocyclic group may
include pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyridazinyl,
pyrimidinyl, pirazinyl, quinolinyl, isoquinolinyl, acridinyl,
indolyl, isoindolyl, indolizinyl, purinyl, carbazolyl, indazolyl,
phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl,
cinnolinyl, pteridinyl, phenanthridinyl, phenazinyl,
phenanthrolinyl, perimidinyl, furyl, dibenzofuryl, xanthenyl,
benzofuryl, thiophenyl, thianthrenyl, benzothiophenyl,
phosphorinyl, phosphinolinyl, phosphindolyl, thiazolyl, oxazolyl,
and isoxazolyl.
[0104] As used herein, the term `substituted` may be used as it is
normally understood to a person of skill in the art and often
refers to a chemical entity that has one chemical group replaced
with a different chemical group that contains one or more
heteroatoms. Unless otherwise specified, a substituted alkyl may be
an alkyl in which one or more hydrogen atom(s) may be/are replaced
with one or more atom(s) that may be/are not hydrogen(s). For
example, chloromethyl may be a non-limiting example of a
substituted alkyl, more particularly an example of a substituted
methyl. Aminoethyl may be another non-limiting example of a
substituted alkyl, more particularly it may be a substituted
ethyl.
[0105] As used herein, the term `unsubstituted` may be used as it
may be normally understood to a person of skill in the art and
often refers to a chemical entity that may be a hydrocarbon and/or
does not contain a heteroatom. Non-limiting examples of
unsubstituted alkyls include methyl, ethyl, tert-butyl, and
pentyl.
[0106] "Intercepted", as used herein with respect to the
positioning heteroatoms, pertains to a carbon chain in which a
heteroatom is interposed between two carbon atoms of the carbon
chain.
[0107] In an embodiment, the compound may be of the formula I:
##STR00013##
wherein each of B, A, Y.sup.1, n, Y.sup.2, R.sup.1, and R.sup.2 may
be as defined anywhere herein.
[0108] In further embodiments, A may be selected such that the
pK.sub.a of H.sup.a of the acid of the formula II:
##STR00014##
may be less than or equal to 5.0, less than or equal to 4.5, less
than or equal to 4.0, less than or equal to 3.5, less than or equal
to 3.0, less than or equal to 2.9, less than or equal to 2.8, less
than or equal to 2.7, less than or equal to 2.6, less than or equal
to 2.5, less than or equal to 2.4, less than or equal to 2.3, less
than or equal to 2.2, less than or equal to 2.1, less than or equal
to 2.0, less than or equal to 1.9, less than or equal to 1.8, less
than or equal to 1.7, less than or equal to 1.96, less than or
equal to 1.5, less than or equal to 1.4, less than or equal to 1.3,
less than or equal to 1.2, less than or equal to 1.1, less than or
equal to 1.0, less than or equal to 0.9, less than or equal to 0.8,
less than or equal to 0.6, less than or equal to 0.4, or less than
or equal to 0.2. When A is substituted at the carbon alpha to
the
##STR00015##
group with a functional group that has a dissociable proton, the
dissociable proton has a pKa>9 and contributes to a net positive
charge on the functional group.
[0109] In further embodiments, A may be selected such that the
pK.sub.a of H.sup.a of the acid of the formula II:
##STR00016##
may be from 0.2 to 0.4, 0.2 to 0.6, 0.2 to 0.8, 0.2 to 1.0, 0.2 to
1.2, 0.2 to 1.4, 0.2 to 1.8, 0.2 to 2.0, 0.2 to 2.2, 0.2 to 2.4,
0.2 to 2.6, 0.2 to 2.8, 0.2 to 2.9, 0.4 to 2.4, 0.6 to 2.4, 0.8 to
2.4, 1.0 to 2.4, 1.2 to 2.4, 1.4 to 2.4, 1.6 to 2.4, 1.8 to 2.4,
2.0 to 2.4, or 2.2 to 2.4. When A is substituted at the carbon
alpha to the
##STR00017##
group with a functional group that has a dissociable proton, the
dissociable proton has a pKa>9 and contributes to a net positive
charge on the functional group.
[0110] In various embodiments, the positron emitting compound or
salt may have a solvolytic de-18F-fluoridation half-life at
physiological pH of about 1000 minutes or more, about 5000 minutes
or more, about 10000 minutes or more, about 15000 minutes or more,
about 20000 minutes or more, about 25000 minutes or more, about
50000 minutes or more, about 100000 minutes or more, about 125000
minutes or more, about 150000 minutes or more, or about 200000
minutes or more. In various embodiments, the positron emitting
compound or salt may have a solvolytic de-18F-fluoridation
half-life at physiological pH from about 1000 minutes to about
200000 minutes, from about 5000 minutes to about 200000 minutes,
from about 10000 minutes to about 200000 minutes, from about 15000
minutes to about 200000 minutes, from about 20000 minutes to about
200000 minutes, from about 25000 minutes to about 200000 minutes,
from about 50000 minutes to about 200000 minutes, from about 100000
minutes to about 200000 minutes, from about 125000 minutes to about
200000 minutes, or from about 150000 minutes to about 200000
minutes.
[0111] In various embodiments, the compound may be of the formula
(I), wherein A may be substituted with one or more substituents
selected from the group consisting of F, Cl, Br, I,
--N.sup.+(C.sub.1-15alkyl).sub.3,
--N.sup.+(C.sub.2-15alkenyl).sub.3,
--N.sup.+(C.sub.2-15alkynyl).sub.3,
--N.sup.+H(C.sub.1-15alkyl).sub.2,
--N.sup.+H(C.sub.2-15alkenyl).sub.2,
--N.sup.+H(C.sub.2-15alkynyl).sub.2,
P.sup.+(C.sub.1-15alkyl).sub.3, P.sup.+(C.sub.2-15alkenyl).sub.3,
P.sup.+(C.sub.2-15alkynyl).sub.3, S.sup.+(C.sub.1-15alkyl).sub.2,
S.sup.+(C.sub.2-15alkenyl).sub.2, S.sup.+(C.sub.2-15alkynyl).sub.2,
oxo (i.e., .dbd.O), OH, --OC.sub.1-15alkyl, unsubstituted or
substituted aromatic C.sub.3-C.sub.18 cycloalkyl, unsubstituted or
substituted non-aromatic C.sub.3-C.sub.18 heterocyclic group,
unsubstituted or substituted aromatic C.sub.3-C.sub.18 heterocyclic
group, .dbd.NH, --C.sub.1-C.sub.15alkyl, non-aromatic
C.sub.3-C.sub.18 cycloalkyl, --N(C.sub.1-15alkyl).sub.2,
--N(C.sub.2-15alkenyl).sub.2, --N(C.sub.2-15alkynyl).sub.2, --COOH,
--NH.sub.2, --SH, a biomolecule, and a linking group optionally
joined to a biomolecule. In various embodiments, A may be
substituted with one or more substituents selected from the group
consisting of F, Cl, Br, I, --N.sup.+(C.sub.1-15alkyl).sub.3,
--N.sup.+(C.sub.2-15alkenyl).sub.3,
--N.sup.+(C.sub.2-15alkynyl).sub.3,
--N.sup.+H(C.sub.1-15alkyl).sub.2,
--N.sup.+H(C.sub.2-15alkenyl).sub.2,
--N.sup.+H(C.sub.2-15alkynyl).sub.2,
P.sup.+(C.sub.1-15alkyl).sub.3, P.sup.+(C.sub.2-15alkenyl).sub.3,
P.sup.+(C.sub.2-15alkynyl).sub.3, oxo (i.e., .dbd.O), OH,
unsubstituted or substituted aromatic C.sub.3-C.sub.18 cycloalkyl,
unsubstituted or substituted non-aromatic C.sub.3-C.sub.18
heterocyclic group, unsubstituted or substituted aromatic
C.sub.3-C.sub.18 heterocyclic group, .dbd.NH,
--C.sub.1-C.sub.15alkyl, non-aromatic C.sub.3-C.sub.18 cycloalkyl,
--N(C.sub.1-15alkyl).sub.2, --N(C.sub.2-15alkenyl).sub.2,
--N(C.sub.2-15alkynyl).sub.2, --COOH, --NH.sub.2, --SH, a
biomolecule, and a linking group optionally joined to a
biomolecule. In various embodiments, A may be substituted with one
or more substituents selected from the group consisting of F, Cl,
Br, I, --N.sup.+(C.sub.1-15alkyl).sub.3,
--N.sup.+(C.sub.2-15alkenyl).sub.3,
--N.sup.+(C.sub.2-15alkynyl).sub.3,
--N.sup.+H(C.sub.1-15alkyl).sub.2,
--N.sup.+H(C.sub.2-15alkenyl).sub.2,
--N.sup.+H(C.sub.2-15alkynyl).sub.2,
P.sup.+(C.sub.1-15alkyl).sub.3, P.sup.+(C.sub.2-15alkenyl).sub.3,
P.sup.+(C.sub.2-15alkynyl).sub.3, oxo (i.e., .dbd.O), OH,
unsubstituted or substituted aromatic C.sub.3-C.sub.18 cycloalkyl,
unsubstituted or substituted non-aromatic C.sub.3-C.sub.18
heterocyclic group, unsubstituted or substituted aromatic
C.sub.3-C.sub.18 heterocyclic group, --C.sub.1-C.sub.15alkyl,
non-aromatic C.sub.3-C.sub.18 cycloalkyl,
--N(C.sub.1-15alkyl).sub.2, --N(C.sub.2-15alkenyl).sub.2,
--N(C.sub.2-15alkynyl).sub.2, --COOH, --NH.sub.2, --SH, a
biomolecule, and a linking group optionally joined to a
biomolecule. In various embodiments, A may be substituted with at
least one substituent that may be a biomolecule or a linking group
optionally joined to a biomolecule.
[0112] In various embodiments, the compound may be of the formula
(IV):
##STR00018##
wherein Q.sup.1 may be --CR.sup.3R.sup.4R.sup.5,
--C.ident.CR.sup.8,
##STR00019##
or --R.sup.10C.dbd.CR.sup.11R.sup.12; and each of R.sup.3, R.sup.4,
R.sup.5, R.sup.8, R.sup.9, R.sup.10, R.sup.11, and R.sup.12 may be
as defined anywhere herein. In various embodiments, Q.sup.1 may be
--CR.sup.3R.sup.4R.sup.5, --C.ident.CR.sup.8, or
--R.sup.10C.dbd.CR.sup.11R.sup.12; and each of R.sup.3, R.sup.4,
R.sup.5, R.sup.8, R.sup.10, R.sup.11, and R.sup.12 may be as
defined anywhere herein. In various embodiments, Q.sup.1 may be
--CR.sup.3R.sup.4R.sup.5,
##STR00020##
or --R.sup.10C.dbd.CR.sup.11R.sup.12; and each of R.sup.3, R.sup.4,
R.sup.5, R.sup.9, R.sup.10, R.sup.11, and R.sup.12 may be as
defined anywhere herein. In various embodiments, Q.sup.1 may be
--C.ident.CR.sup.8,
##STR00021##
or --R.sup.10C.dbd.CR.sup.11R.sup.12; and each of R.sup.8, R.sup.9,
R.sup.10, R.sup.11, and R.sup.12 may be as defined anywhere herein.
In various embodiments, Q.sup.1 may be --CR.sup.3R.sup.4R.sup.5
or
##STR00022##
and each of R.sup.3, R.sup.4, R.sup.5, and R.sup.9 may be as
defined anywhere herein. In various embodiments, Q.sup.1 may be
--CR.sup.3R.sup.4R.sup.5 or --R.sup.10C.dbd.CR.sup.11R.sup.12; and
each of R.sup.3, R.sup.4, R.sup.5, R.sup.10, R.sup.11, and R.sup.12
may be as defined anywhere herein. In an embodiment, Q.sup.1 may be
--C.ident.CR.sup.8 or
##STR00023##
and each of R.sup.8 and R.sup.9 may be as defined anywhere herein.
In an embodiment, Q.sup.1 may be --C.ident.CR.sup.8 or
--R.sup.10C.dbd.CR.sup.11R.sup.12; and each of R.sup.8, R.sup.10,
R.sup.11, and R.sup.12 may be as defined anywhere herein. In
various embodiments, Q.sup.1 may be
##STR00024##
or --R.sup.10C.dbd.CR.sup.11R.sup.12; and each of R.sup.9,
R.sup.10, R.sup.11, and R.sup.12 may be as defined anywhere herein.
In an embodiment, Q.sup.1 may be
##STR00025##
and R.sup.9 may be as defined anywhere herein. In an embodiment,
Q.sup.1 may be --R.sup.10C.dbd.CR.sup.11R.sup.12; and each of
R.sup.10, R.sup.11, and R.sup.12 may be as defined anywhere herein.
In various embodiments, Q.sup.1 may be --CR.sup.3R.sup.4R.sup.5,
--C.ident.CR.sup.8, or
##STR00026##
and each of R.sup.3, R.sup.4, R.sup.5, R.sup.8, and R.sup.9 may be
as defined anywhere herein. In an embodiment, Q.sup.1 may be
--CR.sup.3R.sup.4R.sup.5 or --C.ident.CR.sup.8; and each of
R.sup.3, R.sup.4, R.sup.5, and R.sup.8 may be as defined anywhere
herein. In an embodiment, Q.sup.1 may be --C.ident.CR.sup.8; and
R.sup.8 may be as defined anywhere herein. In various embodiments,
Q.sup.1 may be --CR.sup.3R.sup.4R.sup.5; and each of R.sup.3,
R.sup.4, and R.sup.5 may be as defined anywhere herein.
[0113] In various embodiments, the compound may be of the formula
(IV):
##STR00027##
wherein Q.sup.1 may be --CR.sup.3R.sup.4R.sup.5; and each of
R.sup.3, R.sup.4, and R may be as defined anywhere herein. Each of
R.sup.3, R.sup.4, and R.sup.5 may independently be H, D, F, Cl, Br,
I, CX.sub.3, --N.sup.+R.sup.15R.sup.16R.sup.17,
--P.sup.+R.sup.18R.sup.19R.sup.20, --S.sup.+R.sup.21R.sup.22,
--NR.sup.23R.sup.24, NHR.sup.23, NHR.sup.23, a biomolecule, a
linking group optionally joined to a biomolecule, a linear or
branched C.sub.1-C.sub.15 alkyl group, or a C.sub.3-C.sub.18
cycloalkyl group, wherein each of the C.sub.1-C.sub.15 alkyl group
and the C.sub.3-C.sub.18 cycloalkyl group may be unsubstituted or
substituted and may be optionally intercepted with at least one
heteroatom selected from the group consisting of O, S, N and P;
each of the C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18
cycloalkyl group may be joined to the carbon atom of
--CR.sup.3R.sup.4R.sup.5 through a carbon atom; each X may be the
same or different and may be F, Cl, Br, or I; each of R.sup.15,
R.sup.16, R.sup.17, R.sup.18, R.sup.19, R.sup.20, R.sup.21,
R.sup.22, R.sup.23 and R.sup.24 may be as defined anywhere herein;
at least one of R.sup.3, R.sup.4 and R.sup.5 may be F, Cl, Br, I,
CX.sub.3, --N.sup.+R.sup.15R.sup.16R.sup.17,
--P.sup.+R.sup.18R.sup.19R.sup.20, --S.sup.+R.sup.21R.sup.22 or
--NR.sup.23R.sup.24; NHR.sup.23; and at least one of R.sup.3,
R.sup.4, R.sup.5, R.sup.15, R.sup.16, R.sup.17, R.sup.18, R.sup.19,
R.sup.20, R.sup.21, R.sup.22, R.sup.23, and R.sup.24 may be a
biomolecule, a linking group optionally joined to a biomolecule, or
a group that may be substituted with at least one substituent that
may be a biomolecule, or forms a group that is substituted with at
least one substituent that is a biomolecule. In various
embodiments, at least two of R.sup.3, R.sup.4 and R.sup.5 may
independently be F, Cl, Br, I, or CX.sub.3, or at least one of
R.sup.3, R.sup.4 and R.sup.5 may be
--N.sup.+R.sup.15R.sup.16R.sup.17,
--P.sup.+R.sup.18R.sup.19R.sup.20, --S.sup.+R.sup.21R.sup.22, or
--NR.sup.23R.sup.24, and at least one of R.sup.3, R.sup.4, R.sup.5,
R.sup.15, R.sup.16, R.sup.17, R.sup.18, R.sup.19, R.sup.20,
R.sup.21, R.sup.22, R.sup.23, and R.sup.24 may be a biomolecule, a
linking group optionally joined to a biomolecule, or a group that
may be substituted with at least one substituent that may be a
biomolecule, or forms a group that is substituted with at least one
substituent that is a biomolecule. In various embodiments, two of
R.sup.3, R.sup.4 and R.sup.5 may independently be F, Cl, Br, I, or
CX.sub.3, or one of R.sup.3, R.sup.4 and R.sup.5 may be
--N.sup.+R.sup.15R.sup.16R.sup.17,
--P.sup.+R.sup.18R.sup.19R.sup.20, --S.sup.+R.sup.21R.sup.22, or
--NR.sup.23R.sup.24; and at least one of R.sup.3, R.sup.4, R.sup.5,
R.sup.15, R.sup.16, R.sup.17, R.sup.18, R.sup.19, R.sup.20,
R.sup.21, R.sup.22, R.sup.23, and R.sup.24 may be a biomolecule, a
linking group optionally joined to a biomolecule, or a group that
may be substituted with at least one substituent that may be a
biomolecule, or forms a group that is substituted with at least one
substituent that is a biomolecule.
[0114] In various embodiments, each of R.sup.3, R.sup.4, and
R.sup.5 may independently be H, D, F, Cl, Br, I, CX.sub.3,
--N.sup.+R.sup.15R.sup.16R.sup.17,
--P.sup.+R.sup.18R.sup.19R.sup.20, --S.sup.+R.sup.21R.sup.22, a
biomolecule, a linking group optionally joined to a biomolecule, a
linear or branched C.sub.1-C.sub.15 alkyl group, or a
C.sub.3-C.sub.18 cycloalkyl group, wherein each of the
C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18 cycloalkyl
group may be unsubstituted or substituted and may be optionally
intercepted with at least one heteroatom selected from the group
consisting of O, S, N and P; each of the C.sub.1-C.sub.15 alkyl
group and the C.sub.3-C.sub.18 cycloalkyl group may be joined to
the carbon atom of --CR.sup.3R.sup.4R.sup.5 through a carbon atom;
each X may be the same or different and may be F, Cl, Br, or I;
each of R.sup.15, R.sup.16, R.sup.17, R.sup.18, R.sup.19, R.sup.20,
R.sup.21 and R.sup.22 may be as defined anywhere herein; at least
one of R.sup.3, R.sup.4 and R.sup.5 may be F, Cl, Br, I, CX.sub.3,
--N.sup.+R.sup.15R.sup.16R.sup.17,
--P.sup.+R.sup.18R.sup.19R.sup.20, or --S.sup.+R.sup.21R.sup.22;
and at least one of R.sup.3, R.sup.4, R.sup.5, R.sup.15, R.sup.16,
R.sup.17, R.sup.18, R.sup.19, R.sup.20, R.sup.21, and R.sup.22 may
be a biomolecule, a linking group optionally joined to a
biomolecule, or a group that may be substituted with at least one
substituent that may be a biomolecule, or forms a group that is
substituted with at least one substituent that is a biomolecule. In
various embodiments, at least two of R.sup.3, R.sup.4 and R.sup.5
may independently be F, Cl, Br, I, or CX.sub.3, or at least one of
R.sup.3, R.sup.4 and R.sup.5 may be
--N.sup.+R.sup.15R.sup.16R.sup.17,
--P.sup.+R.sup.18R.sup.19R.sup.20, or --S.sup.+R.sup.21R.sup.22;
and at least one of R.sup.3, R.sup.4, R.sup.5, R.sup.15, R.sup.16,
R.sup.17, R.sup.18, R.sup.19, R.sup.20, R.sup.21, and R.sup.22 may
be a biomolecule, a linking group optionally joined to a
biomolecule, or a group that may be substituted with at least one
substituent that may be a biomolecule, or forms a group that is
substituted with at least one substituent that is a biomolecule. In
various embodiments, two of R.sup.3, R.sup.4 and R.sup.5 may
independently be F, Cl, Br, I, or CX.sub.3, or one of R.sup.3,
R.sup.4 and R.sup.5 may be --N.sup.+R.sup.15R.sup.16R.sup.17,
--P.sup.+R.sup.18R.sup.19R.sup.20, or --S.sup.+R.sup.21R.sup.22;
and at least one of R.sup.3, R.sup.4, R.sup.5, R.sup.15, R.sup.16,
R.sup.17, R.sup.18, R.sup.19, R.sup.20, R.sup.21, and R.sup.22 may
be a biomolecule, a linking group optionally joined to a
biomolecule, or a group that may be substituted with at least one
substituent that may be a biomolecule, or forms a group that is
substituted with at least one substituent that is a
biomolecule.
[0115] In various embodiments, each of R.sup.3, R.sup.4, and
R.sup.5 may independently be H, D, F, Cl, Br, I, CX.sub.3,
--N.sup.+R.sup.15R.sup.16R.sup.17,
--P.sup.+R.sup.18R.sup.19R.sup.20, --NR.sup.23R.sup.24, NHR.sup.23,
a biomolecule, a linking group optionally joined to a biomolecule,
a linear or branched C.sub.1-C.sub.15 alkyl group, or a
C.sub.3-C.sub.18 cycloalkyl group, wherein each of the
C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18 cycloalkyl
group may be unsubstituted or substituted and may be optionally
intercepted with at least one heteroatom selected from the group
consisting of O, S, N and P; each of the C.sub.1-C.sub.15 alkyl
group and the C.sub.3-C.sub.18 cycloalkyl group may be joined to
the carbon atom of --CR.sup.3R.sup.4R.sup.5 through a carbon atom;
each X may be the same or different and may be F, Cl, Br, or I;
each of R.sup.15, R.sup.16, R.sup.17, R.sup.18, R.sup.19, R.sup.20,
R.sup.23 and R.sup.24 may be as defined anywhere herein; at least
one of R.sup.3, R.sup.4 and R.sup.5 may be F, Cl, Br, I, CX.sub.3,
--N.sup.+R.sup.15R.sup.16R.sup.17,
--P.sup.+R.sup.18R.sup.19R.sup.20, or --NR.sup.23R.sup.24; and at
least one of R.sup.3, R.sup.4, R.sup.5, R.sup.15, R.sup.16,
R.sup.17, R.sup.18, R.sup.19, R.sup.20, R.sup.23, and R.sup.24 may
be a biomolecule, a linking group optionally joined to a
biomolecule, or a group that may be substituted with at least one
substituent that may be a biomolecule, or forms a group that is
substituted with at least one substituent that is a biomolecule. In
various embodiments, at least two of R.sup.3, R.sup.4 and R.sup.5
may independently be F, Cl, Br, I, or CX.sub.3, or at least one of
R.sup.3, R.sup.4 and R.sup.5 may be
--N.sup.+R.sup.15R.sup.16R.sup.17,
--P.sup.+R.sup.18R.sup.19R.sup.20, or --NR.sup.23R.sup.24; and at
least one of R.sup.3, R.sup.4, R.sup.5, R.sup.15, R.sup.16,
R.sup.17, R.sup.18, R.sup.19, R.sup.20, R.sup.23, and R.sup.24 may
be a biomolecule, a linking group optionally joined to a
biomolecule, or a group that may be substituted with at least one
substituent that may be a biomolecule, or forms a group that is
substituted with at least one substituent that is a biomolecule. In
various embodiments, two of R.sup.3, R.sup.4 and R.sup.5 may
independently be F, Cl, Br, I, or CX.sub.3, or one of R.sup.3,
R.sup.4 and R.sup.5 may be --N.sup.+R.sup.15R.sup.16R.sup.17,
--P.sup.+R.sup.18R.sup.19R.sup.20, or --NR.sup.23R.sup.24; and at
least one of R.sup.3, R.sup.4, R.sup.5, R.sup.15, R.sup.16,
R.sup.17, R.sup.18, R.sup.19, R.sup.20, R.sup.23, and R.sup.24 may
be a biomolecule, a linking group optionally joined to a
biomolecule, or a group that may be substituted with at least one
substituent that may be a biomolecule, or forms a group that is
substituted with at least one substituent that is a
biomolecule.
[0116] In an embodiment, each of R.sup.3, R.sup.4, and R.sup.5 may
independently be H, D, F, Cl, Br, I, CX.sub.3,
--N.sup.+R.sup.15R.sup.16R.sup.17, --S.sup.+R.sup.21R.sup.22,
--NR.sup.23R.sup.24, NHR.sup.23, a biomolecule, a linking group
optionally joined to a biomolecule, a linear or branched
C.sub.1-C.sub.15 alkyl group, or a C.sub.3-C.sub.18 cycloalkyl
group, wherein each of the C.sub.1-C.sub.15 alkyl group and the
C.sub.3-C.sub.18 cycloalkyl group may be unsubstituted or
substituted and may be optionally intercepted with at least one
heteroatom selected from the group consisting of O, S, N and P;
each of the C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18
cycloalkyl group may be joined to the carbon atom of
--CR.sup.3R.sup.4R.sup.5 through a carbon atom; each X may be the
same or different and may be F, Cl, Br, or I; each of R.sup.15,
R.sup.16, R.sup.17, R.sup.21, R.sup.22, R.sup.23 and R.sup.24 may
be as defined anywhere herein; at least one of R.sup.3, R.sup.4 and
R.sup.5 may be F, Cl, Br, I, CX.sub.3,
--N.sup.+R.sup.15R.sup.16R.sup.17, --S.sup.+R.sup.21R.sup.22 or
--NR.sup.23R.sup.24; and at least one of R.sup.3, R.sup.4, R.sup.5,
R.sup.15, R.sup.16, R.sup.17, R.sup.21, R.sup.22, R.sup.23 and
R.sup.24 may be a biomolecule, a linking group optionally joined to
a biomolecule, or a group that may be substituted with at least one
substituent that may be a biomolecule, or forms a group that is
substituted with at least one substituent that is a biomolecule. In
various embodiments, at least two of R.sup.3, R.sup.4 and R.sup.5
may independently be F, Cl, Br, I, or CX.sub.3, or at least one of
R.sup.3, R.sup.4 and R.sup.5 may be
--N.sup.+R.sup.15R.sup.16R.sup.17, --S.sup.+R.sup.21R.sup.22 or
--NR.sup.23R.sup.24; and at least one of R.sup.3, R.sup.4, R.sup.5,
R.sup.15, R.sup.16, R.sup.17, R.sup.21, R.sup.22, R.sup.23, and
R.sup.24 may be a biomolecule, a linking group optionally joined to
a biomolecule, or a group that may be substituted with at least one
substituent that may be a biomolecule, or forms a group that is
substituted with at least one substituent that is a biomolecule. In
various embodiments, two of R.sup.3, R.sup.4 and R.sup.5 may
independently be F, Cl, Br, I, or CX.sub.3, or one of R.sup.3,
R.sup.4 and R.sup.5 may be --N.sup.+R.sup.15R.sup.16R.sup.17,
--S.sup.+R.sup.21R.sup.22 or --NR.sup.23R.sup.24; and at least one
of R.sup.3, R.sup.4, R.sup.5, R.sup.15, R.sup.16, R.sup.17,
R.sup.21, R.sup.22, R.sup.23, and R.sup.24 may be a biomolecule, a
linking group optionally joined to a biomolecule, or a group that
may be substituted with at least one substituent that may be a
biomolecule, or forms a group that is substituted with at least one
substituent that is a biomolecule.
[0117] In various embodiments, each of R.sup.3, R.sup.4, and
R.sup.5 may independently be H, D, F, Cl, Br, I, CX.sub.3,
--P.sup.+R.sup.18R.sup.19R.sup.20, --S.sup.+R.sup.21R.sup.22,
--NR.sup.23R.sup.24, a biomolecule, a linking group optionally
joined to a biomolecule, a linear or branched C.sub.1-C.sub.15
alkyl group, or a C.sub.3-C.sub.18 cycloalkyl group, wherein each
of the C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18
cycloalkyl group may be unsubstituted or substituted and may be
optionally intercepted with at least one heteroatom selected from
the group consisting of O, S, N and P; each of the C.sub.1-C.sub.15
alkyl group and the C.sub.3-C.sub.18 cycloalkyl group may be joined
to the carbon atom of --CR.sup.3R.sup.4R.sup.5 through a carbon
atom; each X may be the same or different and may be F, Cl, Br, or
I; each of R.sup.18, R.sup.19, R.sup.20, R.sup.21, R.sup.22,
R.sup.23 and R.sup.24 may be as defined anywhere herein; at least
one of R.sup.3, R.sup.4 and R.sup.5 may be F, Cl, Br, I, CX.sub.3,
--P.sup.+R.sup.18R.sup.19R.sup.20, --S.sup.+R.sup.21R.sup.22 or
--NR.sup.23R.sup.24; and at least one of R.sup.3, R.sup.4, R.sup.5,
R.sup.18, R.sup.19, R.sup.20, R.sup.21, R.sup.22, R.sup.23, and
R.sup.24 may be a biomolecule, a linking group optionally joined to
a biomolecule, or a group that may be substituted with at least one
substituent that may be a biomolecule. In various embodiments, at
least two of R.sup.3, R.sup.4 and R.sup.5 may independently be F,
Cl, Br, I, or CX.sub.3, or at least one of R.sup.3, R.sup.4 and
R.sup.5 may be --P.sup.+R.sup.18R.sup.19R.sup.20,
--S.sup.+R.sup.21R.sup.22 or --NR.sup.23R.sup.24; and at least one
of R.sup.3, R.sup.4, R.sup.5, R.sup.18, R.sup.19, R.sup.20,
R.sup.21, R.sup.22, R.sup.23, and R.sup.24 may be a biomolecule, a
linking group optionally joined to a biomolecule, or a group that
may be substituted with at least one substituent that may be a
biomolecule. In various embodiments, two of R.sup.3, R.sup.4 and
R.sup.5 may independently be F, Cl, Br, I, or CX.sub.3, or one of
R.sup.3, R.sup.4 and R.sup.5 may be
--P.sup.+R.sup.18R.sup.19R.sup.20, --S.sup.+R.sup.21R.sup.22 or
--NR.sup.23R.sup.24; and at least one of R.sup.3, R.sup.4, R.sup.5,
R.sup.18, R.sup.19, R.sup.20, R.sup.21, R.sup.22, R.sup.23, and
R.sup.24 may be a biomolecule, a linking group optionally joined to
a biomolecule, or a group that may be substituted with at least one
substituent that may be a biomolecule.
[0118] In an embodiment, each of R.sup.3, R.sup.4, and R.sup.5 may
independently be H, D, --N.sup.+R.sup.15R.sup.16R.sup.17,
--P.sup.+R.sup.18R.sup.19R.sup.20, --S.sup.+R.sup.21R.sup.22,
--NR.sup.23R.sup.24, a biomolecule, a linking group optionally
joined to a biomolecule, a linear or branched C.sub.1-C.sub.15
alkyl group, or a C.sub.3-C.sub.18 cycloalkyl group, wherein each
of the C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18
cycloalkyl group may be unsubstituted or substituted and may be
optionally intercepted with at least one heteroatom selected from
the group consisting of O, S, N and P; each of the C.sub.1-C.sub.15
alkyl group and the C.sub.3-C.sub.18 cycloalkyl group may be joined
to the carbon atom of --CR.sup.3R.sup.4R.sup.5 through a carbon
atom; each of R.sup.15, R.sup.16, R.sup.17, R.sup.18, R.sup.19,
R.sup.20, R.sup.21, R.sup.22, R.sup.23 and R.sup.24 may be as
defined anywhere herein; at least one of R.sup.3, R.sup.4 and
R.sup.5 may be --N.sup.+R.sup.15R.sup.16R.sup.17,
--P.sup.+R.sup.18R.sup.19R.sup.20, --S.sup.+R.sup.21R.sup.22 or
--NR.sup.23R.sup.24; and at least one of R.sup.3, R.sup.4, R.sup.1,
R.sup.15, R.sup.16, R.sup.17, R.sup.18, R.sup.19, R.sup.20,
R.sup.21, R.sup.22, R.sup.23, and R.sup.24 may be a biomolecule, a
linking group optionally joined to a biomolecule, or a group that
may be substituted with at least one substituent that may be a
biomolecule, or forms a group that is substituted with at least one
substituent that is a biomolecule. In various embodiments, one of
R.sup.3, R.sup.4 and R.sup.5 may be
--N.sup.+R.sup.15R.sup.16R.sup.17,
--P.sup.+R.sup.18R.sup.19R.sup.20, --S.sup.+R.sup.21R.sup.22 or
--NR.sup.23R.sup.24; and at least one of R.sup.3, R.sup.4, R.sup.5,
R.sup.15, R.sup.16, R.sup.17, R.sup.18, R.sup.19, R.sup.20,
R.sup.21, R.sup.22, R.sup.23, and R.sup.24 may be a biomolecule, a
linking group optionally joined to a biomolecule, or a group that
may be substituted with at least one substituent that may be a
biomolecule, or forms a group that is substituted with at least one
substituent that is a biomolecule.
[0119] In an embodiment, each of R.sup.3, R.sup.4, and R.sup.5 may
independently be H, D, F, Cl, Br, I, CX.sub.3,
--N.sup.+R.sup.15R.sup.16R.sup.17,
--P.sup.+R.sup.18R.sup.19R.sup.20, a biomolecule, a linking group
optionally joined to a biomolecule, a linear or branched
C.sub.1-C.sub.15 alkyl group, or a C.sub.3-C.sub.18 cycloalkyl
group, wherein each of the C.sub.1-C.sub.15 alkyl group and the
C.sub.3-C.sub.18 cycloalkyl group may be unsubstituted or
substituted and may be optionally intercepted with at least one
heteroatom selected from the group consisting of O, S, N and P;
each of the C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18
cycloalkyl group may be joined to the carbon atom of
--CR.sup.3R.sup.4R.sup.5 through a carbon atom; each X may be the
same or different and may be F, Cl, Br, or I; each of R.sup.15,
R.sup.16, R.sup.17, R.sup.18, R.sup.19, and R.sup.20 may be as
defined anywhere herein; at least one of R.sup.3, R.sup.4 and
R.sup.5 may be F, Cl, Br, I, CX.sub.3,
--N.sup.+R.sup.15R.sup.16R.sup.17, or
--P.sup.+R.sup.18R.sup.19R.sup.20; and at least one of R.sup.3,
R.sup.4, R.sup.5, R.sup.15, R.sup.16, R.sup.17, R.sup.18, R.sup.19,
and R.sup.20 may be a biomolecule, a linking group optionally
joined to a biomolecule, or a group that may be substituted with at
least one substituent that may be a biomolecule, or forms a group
that is substituted with at least one substituent that is a
biomolecule. In various embodiments, at least two of R.sup.3,
R.sup.4 and R.sup.5 may independently be F, Cl, Br, I, or CX.sub.3,
or at least one of R.sup.3, R.sup.4 and R.sup.5 may be
--N.sup.+R.sup.15R.sup.16R.sup.17, or
--P.sup.+R.sup.18R.sup.19R.sup.20; and at least one of R.sup.3,
R.sup.4, R.sup.5, R.sup.15, R.sup.16, R.sup.17, R.sup.18, R.sup.19,
and R.sup.20 may be a biomolecule, a linking group optionally
joined to a biomolecule, or a group that may be substituted with at
least one substituent that may be a biomolecule, or forms a group
that is substituted with at least one substituent that is a
biomolecule. In various embodiments, two of R.sup.3, R.sup.4 and
R.sup.5 may independently be F, Cl, Br, I, or CX.sub.3, or one of
R.sup.3, R.sup.4 and R.sup.5 may be
--N.sup.+R.sup.15R.sup.16R.sup.17, or
--P.sup.+R.sup.18R.sup.19R.sup.20; and at least one of R.sup.3,
R.sup.4, R.sup.5, R.sup.15, R.sup.16, R.sup.17, R.sup.18, R.sup.19,
and R.sup.20 may be a biomolecule, a linking group optionally
joined to a biomolecule, or a group that may be substituted with at
least one substituent that may be a biomolecule, or forms a group
that is substituted with at least one substituent that is a
biomolecule.
[0120] In various embodiments, each of R.sup.3, R.sup.4, and
R.sup.5 may independently be H, D, F, Cl, Br, I, CX.sub.3,
--N.sup.+R.sup.15R.sup.16R.sup.17, --S.sup.+R.sup.21R.sup.22, a
biomolecule, a linking group optionally joined to a biomolecule, a
linear or branched C.sub.1-C.sub.15 alkyl group, or a
C.sub.3-C.sub.18 cycloalkyl group, wherein each of the
C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18 cycloalkyl
group may be unsubstituted or substituted and may be optionally
intercepted with at least one heteroatom selected from the group
consisting of O, S, N and P; each of the C.sub.1-C.sub.15 alkyl
group and the C.sub.3-C.sub.18 cycloalkyl group may be joined to
the carbon atom of --CR.sup.3R.sup.4R.sup.5 through a carbon atom;
each X may be the same or different and may be F, Cl, Br, or I;
each of R.sup.15, R.sup.16, R.sup.17, R.sup.21 and R.sup.22 may be
as defined anywhere herein; at least one of R.sup.3, R.sup.4 and
R.sup.5 may be F, Cl, Br, I, CX.sub.3,
--N.sup.+R.sup.15R.sup.16R.sup.17, or --S.sup.+R.sup.21R.sup.22;
and at least one of R.sup.3, R.sup.4, R.sup.5, R.sup.15, R.sup.16,
R.sup.17, R.sup.21, and R.sup.22 may be a biomolecule, a linking
group optionally joined to a biomolecule, or a group that may be
substituted with at least one substituent that may be a
biomolecule, or forms a group that is substituted with at least one
substituent that is a biomolecule. In various embodiments, at least
two of R.sup.3, R.sup.4 and R.sup.5 may independently be F, Cl, Br,
I, or CX.sub.3, or at least one of R.sup.3, R.sup.4 and R.sup.5 may
be --N.sup.+R.sup.15R.sup.16R.sup.17, or --S.sup.+R.sup.21R.sup.22;
and at least one of R.sup.3, R.sup.4, R.sup.5, R.sup.15, R.sup.16,
R.sup.17, R.sup.21, and R.sup.22 may be a biomolecule, a linking
group optionally joined to a biomolecule, or a group that may be
substituted with at least one substituent that may be a
biomolecule, or forms a group that is substituted with at least one
substituent that is a biomolecule. In various embodiments, two of
R.sup.3, R.sup.4 and R.sup.5 may independently be F, Cl, Br, I, or
CX.sub.3, or one of R.sup.3, R.sup.4 and R.sup.5 may be
--N.sup.+R.sup.15R.sup.16R.sup.17, or --S.sup.+R.sup.21R.sup.22;
and at least one of R.sup.3, R.sup.4, R.sup.5, R.sup.15, R.sup.16,
R.sup.17, R.sup.21, and R.sup.22 may be a biomolecule, a linking
group optionally joined to a biomolecule, or a group that may be
substituted with at least one substituent that may be a
biomolecule, or forms a group that is substituted with at least one
substituent that is a biomolecule.
[0121] In an embodiment, each of R.sup.3, R.sup.4, and R.sup.5 may
independently be H, D, F, Cl, Br, I, CX.sub.3,
--N.sup.+R.sup.15R.sup.16R.sup.17, --NR.sup.23R.sup.24, NHR.sup.23,
a biomolecule, a linking group optionally joined to, a linear or
branched C.sub.1-C.sub.15 alkyl group, or a C.sub.3-C.sub.18
cycloalkyl group, wherein each of the C.sub.1-C.sub.15 alkyl group
and the C.sub.3-C.sub.18 cycloalkyl group may be unsubstituted or
substituted and may be optionally intercepted with at least one
heteroatom selected from the group consisting of O, S, N and P;
each of the C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18
cycloalkyl group may be joined to the carbon atom of
--CR.sup.3R.sup.4R.sup.5 through a carbon atom; each X may be the
same or different and may be F, Cl, Br, or I; each of R.sup.15,
R.sup.16, R.sup.17, R.sup.23 and R.sup.24 may be as defined
anywhere herein; at least one of R.sup.3, R.sup.4 and R.sup.5 may
be F, Cl, Br, I, CX.sub.3, --N.sup.+R.sup.15R.sup.16R.sup.17, or
--NR.sup.23R.sup.24; and at least one of R.sup.3, R.sup.4, R.sup.5,
R.sup.15, R.sup.16, R.sup.17, R.sup.23, and R.sup.24 may be a
biomolecule, a linking group optionally joined to a biomolecule, or
a group that may be substituted with at least one substituent that
may be a biomolecule, or forms a group that is substituted with at
least one substituent that is a biomolecule. In various
embodiments, at least two of R.sup.3, R.sup.4 and R.sup.5 may
independently be F, Cl, Br, I, or CX.sub.3, or at least one of
R.sup.3, R.sup.4 and R.sup.5 may be
--N.sup.+R.sup.15R.sup.16R.sup.17, --NR.sup.23R.sup.24, or
NHR.sup.23; and at least one of R.sup.3, R.sup.4, R.sup.5,
R.sup.15, R.sup.16, R.sup.17, R.sup.23, and R.sup.24 may be a
biomolecule, a linking group optionally joined to a biomolecule, or
a group that may be substituted with at least one substituent that
may be a biomolecule, or forms a group that is substituted with at
least one substituent that is a biomolecule. In various
embodiments, two of R.sup.3, R.sup.4 and R.sup.5 may independently
be F, Cl, Br, I, or CX.sub.3, or one of R.sup.3, R.sup.4 and
R.sup.5 may be --N.sup.+R.sup.15R.sup.16R.sup.17, or
--NR.sup.23R.sup.24; and at least one of R.sup.3, R.sup.4, R.sup.5,
R.sup.15, R.sup.16, R.sup.17, R.sup.23, and R.sup.24 may be a
biomolecule, a linking group optionally joined to a biomolecule, or
a group that may be substituted with at least one substituent that
may be a biomolecule, or forms a group that is substituted with at
least one substituent that is a biomolecule.
[0122] In various embodiments, each of R.sup.3, R.sup.4, and
R.sup.5 may independently be H, D, F, Cl, Br, I, CX.sub.3,
--P.sup.+R.sup.18R.sup.19R.sup.20, --S.sup.+R.sup.21R.sup.22, a
biomolecule, a linking group optionally joined to a biomolecule, a
linear or branched C.sub.1-C.sub.15 alkyl group, or a
C.sub.3-C.sub.18 cycloalkyl group, wherein each of the
C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18 cycloalkyl
group may be unsubstituted or substituted and may be optionally
intercepted with at least one heteroatom selected from the group
consisting of O, S, N and P; each of the C.sub.1-C.sub.15 alkyl
group and the C.sub.3-C.sub.18 cycloalkyl group may be joined to
the carbon atom of --CR.sup.3R.sup.4R.sup.5 through a carbon atom;
each X may be the same or different and may be F, Cl, Br, or I;
each of R.sup.18, R.sup.19, R.sup.20, R.sup.21 and R.sup.22 may be
as defined anywhere herein; at least one of R.sup.3, R.sup.4 and
R.sup.5 may be F, Cl, Br, I, CX.sub.3,
--P.sup.+R.sup.18R.sup.19R.sup.20, or --S.sup.+R.sup.21R.sup.22;
and at least one of R.sup.3, R.sup.4, R.sup.5, R.sup.18, R.sup.19,
R.sup.20, R.sup.21, and R.sup.22 may be a biomolecule, a linking
group optionally joined to a biomolecule, or a group that may be
substituted with at least one substituent that may be a
biomolecule. In various embodiments, at least two of R.sup.3,
R.sup.4 and R.sup.5 may independently be F, Cl, Br, I, or CX.sub.3,
or at least one of R.sup.3, R.sup.4 and R.sup.5 may be
--P.sup.+R.sup.18R.sup.19R.sup.20, or --S.sup.+R.sup.21R.sup.22;
and at least one of R.sup.3, R.sup.4, R.sup.5, R.sup.18, R.sup.19,
R.sup.20, R.sup.21, and R.sup.22 may be a biomolecule, a linking
group optionally joined to a biomolecule, or a group that may be
substituted with at least one substituent that may be a
biomolecule. In various embodiments, two of R.sup.3, R.sup.4 and
R.sup.5 may independently be F, Cl, Br, I, or CX.sub.3, or one of
R.sup.3, R.sup.4 and R.sup.5 may be
--P.sup.+R.sup.18R.sup.19R.sup.20, or --S.sup.+R.sup.21R.sup.22;
and at least one of R.sup.3, R.sup.4, R.sup.5, R.sup.18, R.sup.19,
R.sup.20, R.sup.21, and R.sup.22 may be a biomolecule, a linking
group optionally joined to a biomolecule, or a group that may be
substituted with at least one substituent that may be a
biomolecule.
[0123] In various embodiments, each of R.sup.3, R.sup.4, and
R.sup.5 may independently be H, D, F, Cl, Br, I, CX.sub.3,
--P.sup.+R.sup.18R.sup.19R.sup.20, --NR.sup.23R.sup.24, a
biomolecule, a linking group optionally joined to a biomolecule, a
linear or branched C.sub.1-C.sub.15 alkyl group, or a
C.sub.3-C.sub.18 cycloalkyl group, wherein each of the
C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18 cycloalkyl
group may be unsubstituted or substituted and may be optionally
intercepted with at least one heteroatom selected from the group
consisting of O, S, N and P; each of the C.sub.1-C.sub.15 alkyl
group and the C.sub.3-C.sub.18 cycloalkyl group may be joined to
the carbon atom of --CR.sup.3R.sup.4R.sup.5 through a carbon atom;
each X may be the same or different and may be F, Cl, Br, or I;
each of R.sup.18, R.sup.19, R.sup.20, R.sup.23 and R.sup.24 may be
as defined anywhere herein; at least one of R.sup.3, R.sup.4 and
R.sup.5 may be F, Cl, Br, I, CX.sub.3,
--P.sup.+R.sup.18R.sup.19R.sup.20, or --NR.sup.23R.sup.24 and at
least one of R.sup.3, R.sup.4, R.sup.5, R.sup.18, R.sup.19,
R.sup.20, R.sup.23, and R.sup.24 may be a biomolecule, a linking
group optionally joined to a biomolecule, or a group that may be
substituted with at least one substituent that may be a
biomolecule. In various embodiments, at least two of R.sup.3,
R.sup.4 and R.sup.5 may independently be F, Cl, Br, I, or CX.sub.3,
or at least one of R.sup.3, R.sup.4 and R.sup.5 may be
--P.sup.+R.sup.18R.sup.19R.sup.20, or --NR.sup.23R.sup.24 and at
least one of R.sup.3, R.sup.4, R.sup.5, R.sup.18, R.sup.19,
R.sup.20, R.sup.23, and R.sup.24 may be a biomolecule, a linking
group optionally joined to a biomolecule, or a group that may be
substituted with at least one substituent that may be a
biomolecule. In various embodiments, two of R.sup.3, R.sup.4 and
R.sup.5 may independently be F, Cl, Br, I, or CX.sub.3, or one of
R.sup.3, R.sup.4 and R.sup.5 may be
--P.sup.+R.sup.18R.sup.19R.sup.20, or --NR.sup.23R.sup.24; and at
least one of R.sup.3, R.sup.4, R.sup.5, R.sup.18, R.sup.19,
R.sup.20, R.sup.23, and R.sup.24 may be a biomolecule, a linking
group optionally joined to a biomolecule, or a group that may be
substituted with at least one substituent that may be a
biomolecule.
[0124] In various embodiments, each of R.sup.3, R.sup.4, and
R.sup.5 may independently be H, D, F, Cl, Br, I, CX.sub.3,
--S.sup.+R.sup.21R.sup.22, --NR.sup.23R.sup.24, a biomolecule, a
linking group optionally joined to a biomolecule, a linear or
branched C.sub.1-C.sub.15 alkyl group, or a C.sub.3-C.sub.18
cycloalkyl group, wherein each of the C.sub.1-C.sub.15 alkyl group
and the C.sub.3-C.sub.18 cycloalkyl group may be unsubstituted or
substituted and may be optionally intercepted with at least one
heteroatom selected from the group consisting of O, S, N and P;
each of the C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18
cycloalkyl group may be joined to the carbon atom of
--CR.sup.3R.sup.4R.sup.5 through a carbon atom; each X may be the
same or different and may be F, Cl, Br, or I; each of R.sup.21,
R.sup.22, R.sup.23 and R.sup.24 may be as defined anywhere herein;
at least one of R.sup.3, R.sup.4 and R.sup.5 may be F, Cl, Br, I,
CX.sub.3, --S.sup.+R.sup.21R.sup.22 or --NR.sup.23R.sup.24; and at
least one of R.sup.3, R.sup.4, R.sup.5, R.sup.21, R.sup.22,
R.sup.23, and R.sup.24 may be a biomolecule, a linking group
optionally joined to a biomolecule, or a group that may be
substituted with at least one substituent that may be a
biomolecule. In various embodiments, at least two of R.sup.3,
R.sup.4 and R.sup.5 may independently be F, Cl, Br, I, or CX.sub.3,
or at least one of R.sup.3, R.sup.4 and R.sup.5 may be
--S.sup.+R.sup.21R.sup.22 or --NR.sup.23R.sup.24; and at least one
of R.sup.3, R.sup.4, R.sup.5, R.sup.21, R.sup.22, R.sup.23, and
R.sup.24 may be a biomolecule, a linking group optionally joined to
a biomolecule, or a group that may be substituted with at least one
substituent that may be a biomolecule. In various embodiments, two
of R.sup.3, R.sup.4 and R.sup.5 may independently be F, Cl, Br, I,
or CX.sub.3, or one of R.sup.3, R.sup.4 and R.sup.5 may be
--S.sup.+R.sup.21R.sup.22 or --NR.sup.23R.sup.24; and at least one
of R.sup.3, R.sup.4, R.sup.5, R.sup.21, R.sup.22, R.sup.23, and
R.sup.24 may be a biomolecule, a linking group optionally joined to
a biomolecule, or a group that may be substituted with at least one
substituent that may be a biomolecule.
[0125] In an embodiment, each of R.sup.3, R.sup.4, and R.sup.5 may
independently be H, D, --N.sup.+R.sup.15R.sup.16R.sup.17,
--P.sup.+R.sup.18R.sup.19R.sup.20, --S.sup.+R.sup.21R.sup.22, a
biomolecule, a linking group optionally joined to a biomolecule, a
linear or branched C.sub.1-C.sub.15 alkyl group, or a
C.sub.3-C.sub.18 cycloalkyl group, wherein each of the
C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18 cycloalkyl
group may be unsubstituted or substituted and may be optionally
intercepted with at least one heteroatom selected from the group
consisting of O, S, N and P; each of the C.sub.1-C.sub.15 alkyl
group and the C.sub.3-C.sub.18 cycloalkyl group may be joined to
the carbon atom of --CR.sup.3R.sup.4R.sup.5 through a carbon atom;
each of R.sup.15, R.sup.16, R.sup.17, R.sup.18, R.sup.19, R.sup.20,
R.sup.21 and R.sup.22 may be as defined anywhere herein; at least
one of R.sup.3, R.sup.4 and R.sup.5 may be
--N.sup.+R.sup.15R.sup.16R.sup.17,
--P.sup.+R.sup.18R.sup.19R.sup.20, or --S.sup.+R.sup.21R.sup.22;
and at least one of R.sup.3, R.sup.4, R.sup.5, R.sup.15, R.sup.16,
R.sup.17, R.sup.18, R.sup.19, R.sup.20, R.sup.21, and R.sup.22 may
be a biomolecule, a linking group optionally joined to a
biomolecule, or a group that may be substituted with at least one
substituent that may be a biomolecule, or forms a group that is
substituted with at least one substituent that is a biomolecule. In
various embodiments, one of R.sup.3, R.sup.4 and R.sup.5 may be
--N.sup.+R.sup.15R.sup.16R.sup.17,
--P.sup.+R.sup.18R.sup.19R.sup.20, or --S.sup.+R.sup.21R.sup.22;
and at least one of R.sup.3, R.sup.4, R.sup.5, R.sup.15, R.sup.16,
R.sup.17, R.sup.18, R.sup.19, R.sup.20, R.sup.21, and R.sup.22 may
be a biomolecule, a linking group optionally joined to a
biomolecule, or a group that may be substituted with at least one
substituent that may be a biomolecule, or forms a group that is
substituted with at least one substituent that is a
biomolecule.
[0126] In an embodiment, each of R.sup.3, R.sup.4, and R.sup.5 may
independently be H, D, --N.sup.+R.sup.15R.sup.16R.sup.17,
--P.sup.+R.sup.18R.sup.19R.sup.20, --NR.sup.23R.sup.24, a
biomolecule, a linking group optionally joined to a biomolecule, a
linear or branched C.sub.1-C.sub.15 alkyl group, or a
C.sub.3-C.sub.18 cycloalkyl group, wherein each of the
C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18 cycloalkyl
group may be unsubstituted or substituted and may be optionally
intercepted with at least one heteroatom selected from the group
consisting of O, S, N and P; each of the C.sub.1-C.sub.15 alkyl
group and the C.sub.3-C.sub.18 cycloalkyl group may be joined to
the carbon atom of --CR.sup.3R.sup.4R.sup.5 through a carbon atom;
each of R.sup.15, R.sup.16, R.sup.17, R.sup.18, R.sup.19, R.sup.20,
R.sup.23 and R.sup.24 may be as defined anywhere herein; at least
one of R.sup.3, R.sup.4 and R.sup.5 may be
--N.sup.+R.sup.15R.sup.16R.sup.17,
--P.sup.+R.sup.18R.sup.19R.sup.20, or --NR.sup.23R.sup.24; and at
least one of R.sup.3, R.sup.4, R.sup.5, R.sup.15, R.sup.16,
R.sup.17, R.sup.18, R.sup.19, R.sup.20, R.sup.23, and R.sup.24 may
be a biomolecule, a linking group optionally joined to a
biomolecule, or a group that may be substituted with at least one
substituent that may be a biomolecule, or forms a group that is
substituted with at least one substituent that is a biomolecule. In
various embodiments, one of R.sup.3, R.sup.4 and R.sup.5 may be
--N.sup.+R.sup.15R.sup.16R.sup.17,
--P.sup.+R.sup.18R.sup.19R.sup.20, or --NR.sup.23R.sup.24 and at
least one of R.sup.3, R.sup.4, R.sup.5, R.sup.15, R.sup.16,
R.sup.17, R.sup.18, R.sup.19, R.sup.20, R.sup.23, and R.sup.24 may
be a biomolecule, a linking group optionally joined to a
biomolecule, or a group that may be substituted with at least one
substituent that may be a biomolecule, or forms a group that is
substituted with at least one substituent that is a
biomolecule.
[0127] In an embodiment, each of R.sup.3, R.sup.4, and R.sup.5 may
independently be H, D, --N.sup.+R.sup.15R.sup.16R.sup.17,
--S.sup.+R.sup.21R.sup.22, --NR.sup.23R.sup.24, a biomolecule, a
linking group optionally joined to a biomolecule, a linear or
branched C.sub.1-C.sub.15 alkyl group, or a C.sub.3-C.sub.18
cycloalkyl group, wherein each of the C.sub.1-C.sub.15 alkyl group
and the C.sub.3-C.sub.18 cycloalkyl group may be unsubstituted or
substituted and may be optionally intercepted with at least one
heteroatom selected from the group consisting of O, S, N and P;
each of the C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18
cycloalkyl group may be joined to the carbon atom of
--CR.sup.3R.sup.4R.sup.5 through a carbon atom; each of R.sup.15,
R.sup.16, R.sup.17, R.sup.21, R.sup.22, R.sup.23 and R.sup.24 may
be as defined anywhere herein; at least one of R.sup.3, R.sup.4 and
R.sup.5 may be --N.sup.+R.sup.15R.sup.16R.sup.17,
--S.sup.+R.sup.2R.sup.2 or --NR.sup.23R.sup.24; and at least one of
R.sup.3, R.sup.4, R.sup.5, R.sup.15, R.sup.16, R.sup.17, R.sup.21,
R.sup.22, R.sup.23, and R.sup.24 may be a biomolecule, a linking
group optionally joined to a biomolecule, or a group that may be
substituted with at least one substituent that may be a
biomolecule, or forms a group that is substituted with at least one
substituent that is a biomolecule. In various embodiments, one of
R.sup.3, R.sup.4 and R.sup.5 may be
--N.sup.+R.sup.15R.sup.16R.sup.17, --S.sup.+R.sup.21R.sup.22 or
--NR.sup.23R.sup.24 and at least one of R.sup.3, R.sup.4, R.sup.5,
R.sup.15, R.sup.16, R.sup.17, R.sup.21, R.sup.22, R.sup.23, and
R.sup.24 may be a biomolecule, a linking group optionally joined to
a biomolecule, or a group that may be substituted with at least one
substituent that may be a biomolecule, or forms a group that is
substituted with at least one substituent that is a
biomolecule.
[0128] In various embodiments, each of R.sup.3, R.sup.4, and
R.sup.5 may independently be H, D,
--P.sup.+R.sup.18R.sup.19R.sup.20, --S.sup.+R.sup.21R.sup.22,
--NR.sup.23R.sup.24, a biomolecule, a linking group optionally
joined to a biomolecule, a linear or branched C.sub.1-C.sub.15
alkyl group, or a C.sub.3-C.sub.18 cycloalkyl group, wherein each
of the C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18
cycloalkyl group may be unsubstituted or substituted and may be
optionally intercepted with at least one heteroatom selected from
the group consisting of O, S, N and P; each of the C.sub.1-C.sub.15
alkyl group and the C.sub.3-C.sub.18 cycloalkyl group may be joined
to the carbon atom of --CR.sup.3R.sup.4R.sup.5 through a carbon
atom; each of R.sup.18, R.sup.19, R.sup.20, R.sup.21, R.sup.22,
R.sup.23 and R.sup.24 may be as defined anywhere herein; at least
one of R.sup.3, R.sup.4 and R.sup.5 may be
--P.sup.+R.sup.18R.sup.19R.sup.20, --S.sup.+R.sup.21R.sup.22 or
--NR.sup.23R.sup.24; and at least one of R.sup.3, R.sup.4, R.sup.5,
R.sup.18, R.sup.19, R.sup.20, R.sup.21, R.sup.22, R.sup.23, and
R.sup.24 may be a biomolecule, a linking group optionally joined to
a biomolecule, or a group that may be substituted with at least one
substituent that may be a biomolecule. In various embodiments, one
of R.sup.3, R.sup.4 and R.sup.5 may be
--P.sup.+R.sup.18R.sup.19R.sup.20, --S.sup.+R.sup.21R.sup.22 or
--NR.sup.23R.sup.24 and at least one of R.sup.3, R.sup.4, R.sup.5,
R.sup.18, R.sup.19, R.sup.20, R.sup.21, R.sup.22, R.sup.23, and
R.sup.24 may be a biomolecule, a linking group optionally joined to
a biomolecule, or a group that may be substituted with at least one
substituent that may be a biomolecule.
[0129] In an embodiment, each of R.sup.3, R.sup.4, and R.sup.5 may
independently be H, D, F, Cl, Br, I, CX.sub.3,
--P.sup.+R.sup.18R.sup.19R.sup.20, a biomolecule, a linking group
optionally joined to a biomolecule, a linear or branched
C.sub.1-C.sub.15 alkyl group, or a C.sub.3-C.sub.18 cycloalkyl
group, wherein each of the C.sub.1-C.sub.15 alkyl group and the
C.sub.3-C.sub.18 cycloalkyl group may be unsubstituted or
substituted and may be optionally intercepted with at least one
heteroatom selected from the group consisting of O, S, N and P;
each of the C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18
cycloalkyl group may be joined to the carbon atom of
--CR.sup.3R.sup.4R.sup.5 through a carbon atom; each X may be the
same or different and may be F, Cl, Br, or I; each of R.sup.18,
R.sup.19, and R.sup.20 may be as defined anywhere herein; at least
one of R.sup.3, R.sup.4 and R.sup.5 may be F, Cl, Br, I, CX.sub.3,
or --P.sup.+R.sup.18R.sup.19R.sup.20; and at least one of R.sup.3,
R.sup.4, R.sup.5, R.sup.18, R.sup.19, and R.sup.20 may be a
biomolecule, a linking group optionally joined to a biomolecule, or
a group that may be substituted with at least one substituent that
may be a biomolecule. In various embodiments, at least two of
R.sup.3, R.sup.4 and R.sup.5 may independently be F, Cl, Br, I, or
CX.sub.3, or at least one of R.sup.3, R.sup.4 and R.sup.5 may be
--P.sup.+R.sup.18R.sup.19R.sup.20; and at least one of R.sup.3,
R.sup.4, R.sup.5, R.sup.18, R.sup.19, and R.sup.20 may be a
biomolecule, a linking group optionally joined to a biomolecule, or
a group that may be substituted with at least one substituent that
may be a biomolecule. In various embodiments, two of R.sup.3,
R.sup.4 and R.sup.5 may independently be F, Cl, Br, I, or CX.sub.3,
or one of R.sup.3, R.sup.4 and R.sup.5 may be
--P.sup.+R.sup.18R.sup.19R.sup.20; and at least one of R.sup.3,
R.sup.4, R.sup.5, R.sup.18, R.sup.19, and R.sup.20 may be a
biomolecule, a linking group optionally joined to a biomolecule, or
a group that may be substituted with at least one substituent that
may be a biomolecule.
[0130] In various embodiments, each of R.sup.3, R.sup.4, and
R.sup.5 may independently be H, D, F, Cl, Br, I, CX.sub.3,
--S.sup.+R.sup.21R.sup.22, a biomolecule, a linking group
optionally joined to a biomolecule, a linear or branched
C.sub.1-C.sub.15 alkyl group, or a C.sub.3-C.sub.18 cycloalkyl
group, wherein each of the C.sub.1-C.sub.15 alkyl group and the
C.sub.3-C.sub.18 cycloalkyl group may be unsubstituted or
substituted and may be optionally intercepted with at least one
heteroatom selected from the group consisting of O, S, N and P;
each of the C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18
cycloalkyl group may be joined to the carbon atom of
--CR.sup.3R.sup.4R.sup.5 through a carbon atom; each X may be the
same or different and may be F, Cl, Br, or I; each of R.sup.21 and
R.sup.22 may be as defined anywhere herein; at least one of
R.sup.3, R.sup.4 and R.sup.5 may be F, Cl, Br, I, CX.sub.3, or
--S.sup.+R.sup.21R.sup.22; and at least one of R.sup.3, R.sup.4,
R.sup.5, R.sup.21, and R.sup.22 may be a biomolecule, a linking
group optionally joined to a biomolecule, or a group that may be
substituted with at least one substituent that may be a
biomolecule. In various embodiments, at least two of R.sup.3,
R.sup.4 and R.sup.5 may independently be F, Cl, Br, I, or CX.sub.3,
or at least one of R.sup.3, R.sup.4 and R.sup.5 may be
--S.sup.+R.sup.21R.sup.22; and at least one of R.sup.3, R.sup.4,
R.sup.5, R.sup.21, and R.sup.22 may be a biomolecule, a linking
group optionally joined to a biomolecule, or a group that may be
substituted with at least one substituent that may be a
biomolecule. In various embodiments, two of R.sup.3, R.sup.4 and
R.sup.5 may independently be F, Cl, Br, I, or CX.sub.3, or one of
R.sup.3, R.sup.4 and R.sup.5 may be --S.sup.+R.sup.21R.sup.22; and
at least one of R.sup.3, R.sup.4, R.sup.5, R.sup.21, and R.sup.22
may be a biomolecule, a linking group optionally joined to a
biomolecule, or a group that may be substituted with at least one
substituent that may be a biomolecule.
[0131] In an embodiment, each of R.sup.3, R.sup.4, and R.sup.5 may
independently be H, D, F, Cl, Br, I, CX.sub.3, --NR.sup.23R.sup.24,
a biomolecule, a linking group optionally joined to a biomolecule,
a linear or branched C.sub.1-C.sub.15 alkyl group, or a
C.sub.3-C.sub.18 cycloalkyl group, wherein each of the
C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18 cycloalkyl
group may be unsubstituted or substituted and may be optionally
intercepted with at least one heteroatom selected from the group
consisting of O, S, N and P; each of the C.sub.1-C.sub.15 alkyl
group and the C.sub.3-C.sub.18 cycloalkyl group may be joined to
the carbon atom of --CR.sup.3R.sup.4R.sup.5 through a carbon atom;
each X may be the same or different and may be F, Cl, Br, or I;
each of R.sup.23 and R.sup.24 may be as defined anywhere herein; at
least one of R.sup.3, R.sup.4 and R.sup.5 may be F, Cl, Br, I,
CX.sub.3, or --NR.sup.23R.sup.24; and at least one of R.sup.3,
R.sup.4, R.sup.5, R.sup.23, and R.sup.24 may be a biomolecule, a
linking group optionally joined to a biomolecule, or a group that
may be substituted with at least one substituent that may be a
biomolecule. In various embodiments, at least two of R.sup.3,
R.sup.4 and R.sup.5 may independently be F, Cl, Br, I, or CX.sub.3,
or at least one of R.sup.3, R.sup.4 and R.sup.5 may be
--NR.sup.23R.sup.24; and at least one of R.sup.3, R.sup.4, R.sup.5,
R.sup.23, and R.sup.24 may be a biomolecule, a linking group
optionally joined to a biomolecule, or a group that may be
substituted with at least one substituent that may be a
biomolecule. In various embodiments, two of R.sup.3, R.sup.4 and
R.sup.5 may independently be F, Cl, Br, I, or CX.sub.3, or one of
R.sup.3, R.sup.4 and R.sup.5 may be --NR.sup.23R.sup.24; and at
least one of R.sup.3, R.sup.4, R.sup.5, R.sup.23, and R.sup.24 may
be a biomolecule, a linking group optionally joined to a
biomolecule, or a group that may be substituted with at least one
substituent that may be a biomolecule.
[0132] In an embodiment, each of R.sup.3, R.sup.4, and R.sup.5 may
independently be H, D, --N.sup.+R.sup.15R.sup.16R.sup.17,
--P.sup.+R.sup.18R.sup.19R.sup.20, a biomolecule, a linking group
optionally joined to a biomolecule, a linear or branched
C.sub.1-C.sub.15 alkyl group, or a C.sub.3-C.sub.18 cycloalkyl
group, wherein each of the C.sub.1-C.sub.15 alkyl group and the
C.sub.3-C.sub.18 cycloalkyl group may be unsubstituted or
substituted and may be optionally intercepted with at least one
heteroatom selected from the group consisting of O, S, N and P;
each of the C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18
cycloalkyl group may be joined to the carbon atom of
--CR.sup.3R.sup.4R.sup.5 through a carbon atom; each of R.sup.15,
R.sup.16, R.sup.17, R.sup.18, R.sup.19, and R.sup.20 may be as
defined anywhere herein; at least one of R.sup.3, R.sup.4 and
R.sup.5 may be --N.sup.+R.sup.15R.sup.16R.sup.17 or
--P.sup.+R.sup.18R.sup.19R.sup.20; and at least one of R.sup.3,
R.sup.4, R.sup.5, R.sup.15, R.sup.16, R.sup.17, R.sup.18, R.sup.19,
and R.sup.20 may be a biomolecule, a linking group optionally
joined to a biomolecule, or a group that may be substituted with at
least one substituent that may be a biomolecule, or forms a group
that is substituted with at least one substituent that is a
biomolecule. In various embodiments, one of R.sup.3, R.sup.4 and
R.sup.5 may be --N.sup.+R.sup.15R.sup.16R.sup.17 or
--P.sup.+R.sup.18R.sup.19R.sup.20 and at least one of R.sup.3,
R.sup.4, R.sup.5, R.sup.15, R.sup.16, R.sup.17, R.sup.18, R.sup.19,
and R.sup.20 may be a biomolecule, a linking group optionally
joined to a biomolecule, or a group that may be substituted with at
least one substituent that may be a biomolecule, or forms a group
that is substituted with at least one substituent that is a
biomolecule.
[0133] In an embodiment, each of R.sup.3, R.sup.4, and R.sup.5 may
independently be H, D, --N.sup.+R.sup.15R.sup.16R.sup.17,
--S.sup.+R.sup.21R.sup.22, a biomolecule, a linking group
optionally joined to a biomolecule, a linear or branched
C.sub.1-C.sub.15 alkyl group, or a C.sub.3-C.sub.18 cycloalkyl
group, wherein each of the C.sub.1-C.sub.15 alkyl group and the
C.sub.3-C.sub.18 cycloalkyl group may be unsubstituted or
substituted and may be optionally intercepted with at least one
heteroatom selected from the group consisting of O, S, N and P;
each of the C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18
cycloalkyl group may be joined to the carbon atom of
--CR.sup.3R.sup.4R.sup.5 through a carbon atom; each of R.sup.1,
R.sup.16, R.sup.17, R.sup.21 and R.sup.22 may be as defined
anywhere herein; at least one of R.sup.3, R.sup.4 and R.sup.5 may
be --N.sup.+R.sup.15R.sup.16R.sup.17 or --S.sup.+R.sup.21R.sup.22;
and at least one of R.sup.3, R.sup.4, R.sup.5, R.sup.15, R.sup.16,
R.sup.17, R.sup.21, and R.sup.22 may be a biomolecule, a linking
group optionally joined to a biomolecule, or a group that may be
substituted with at least one substituent that may be a
biomolecule, or forms a group that is substituted with at least one
substituent that is a biomolecule. In various embodiments, one of
R.sup.3, R.sup.4 and R.sup.5 may be
--N.sup.+R.sup.15R.sup.16R.sup.17 or --S.sup.+R.sup.21R.sup.22 and
at least one of R.sup.3, R.sup.4, R.sup.5, R.sup.15, R.sup.16,
R.sup.17, R.sup.21, and R.sup.22 may be a biomolecule, a linking
group optionally joined to a biomolecule, or a group that may be
substituted with at least one substituent that may be a
biomolecule, or forms a group that is substituted with at least one
substituent that is a biomolecule.
[0134] In various embodiments, each of R.sup.3, R.sup.4, and
R.sup.5 may independently be H, D,
--N.sup.+R.sup.15R.sup.16R.sup.17, --NR.sup.23R.sup.24, a
biomolecule, a linking group optionally joined to a biomolecule, a
linear or branched C.sub.1-C.sub.15 alkyl group, or a
C.sub.3-C.sub.18 cycloalkyl group, wherein each of the
C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18 cycloalkyl
group may be unsubstituted or substituted and may be optionally
intercepted with at least one heteroatom selected from the group
consisting of O, S, N and P; each of the C.sub.1-C.sub.15 alkyl
group and the C.sub.3-C.sub.18 cycloalkyl group may be joined to
the carbon atom of --CR.sup.3R.sup.4R.sup.5 through a carbon atom;
each of R.sup.1, R.sup.16, R.sup.17, R.sup.23 and R.sup.24 may be
as defined anywhere herein; at least one of R.sup.3, R.sup.4 and
R.sup.5 may be --N.sup.+R.sup.15R.sup.16R.sup.17 or
--NR.sup.23R.sup.24; and at least one of R.sup.3, R.sup.4, R.sup.5,
R.sup.15, R.sup.16, R.sup.17, R.sup.23, and R.sup.24 may be a
biomolecule, a linking group optionally joined to a biomolecule, or
a group that may be substituted with at least one substituent that
may be a biomolecule, or forms a group that is substituted with at
least one substituent that is a biomolecule. In various
embodiments, one of R.sup.3, R.sup.4 and R.sup.5 may be
--N.sup.+R.sup.15R.sup.16R.sup.17 or --NR.sup.23R.sup.24; and at
least one of R.sup.3, R.sup.4, R.sup.5, R.sup.15, R.sup.16,
R.sup.17, R.sup.23, and R.sup.24 may be a biomolecule, a linking
group optionally joined to a biomolecule, or a group that may be
substituted with at least one substituent that may be a
biomolecule, or forms a group that is substituted with at least one
substituent that is a biomolecule.
[0135] In an embodiment, each of R.sup.3, R.sup.4, and R.sup.5 may
independently be H, D, --P.sup.+R.sup.18R.sup.19R.sup.20,
--S.sup.+R.sup.21R.sup.22, a biomolecule, a linking group
optionally joined to a biomolecule, a linear or branched
C.sub.1-C.sub.15 alkyl group, or a C.sub.3-C.sub.18 cycloalkyl
group, wherein each of the C.sub.1-C.sub.15 alkyl group and the
C.sub.3-C.sub.18 cycloalkyl group may be unsubstituted or
substituted and may be optionally intercepted with at least one
heteroatom selected from the group consisting of O, S, N and P;
each of the C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18
cycloalkyl group may be joined to the carbon atom of
--CR.sup.3R.sup.4R.sup.5 through a carbon atom; each of R.sup.18,
R.sup.19, R.sup.20, R.sup.21 and R.sup.22 may be as defined
anywhere herein; at least one of R.sup.3, R.sup.4 and R.sup.5 may
be --P.sup.+R.sup.18R.sup.19R.sup.20 or --S.sup.+R.sup.21R.sup.22;
and at least one of R.sup.3, R.sup.4, R.sup.5, R.sup.18, R.sup.19,
R.sup.20, R.sup.21, and R.sup.22 may be a biomolecule, a linking
group optionally joined to a biomolecule, or a group that may be
substituted with at least one substituent that may be a
biomolecule. In various embodiments, one of R.sup.3, R.sup.4 and
R.sup.5 may be --P.sup.+R.sup.18R.sup.19R.sup.20 or
--S.sup.+R.sup.21R.sup.22; and at least one of R.sup.3, R.sup.4,
R.sup.5, R.sup.18, R.sup.19, R.sup.20, R.sup.21, and R.sup.22 may
be a biomolecule, a linking group optionally joined to a
biomolecule, or a group that may be substituted with at least one
substituent that may be a biomolecule.
[0136] In an embodiment, each of R.sup.3, R.sup.4, and R.sup.5 may
independently be H, D, --P.sup.+R.sup.18R.sup.19R.sup.20,
--NR.sup.23R.sup.24, a biomolecule, a linking group optionally
joined to a biomolecule, a linear or branched C.sub.1-C.sub.15
alkyl group, or a C.sub.3-C.sub.18 cycloalkyl group, wherein each
of the C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18
cycloalkyl group may be unsubstituted or substituted and may be
optionally intercepted with at least one heteroatom selected from
the group consisting of O, S, N and P; each of the C.sub.1-C.sub.15
alkyl group and the C.sub.3-C.sub.18 cycloalkyl group may be joined
to the carbon atom of --CR.sup.3R.sup.4R.sup.5 through a carbon
atom; each of R.sup.18, R.sup.19, R.sup.20, R.sup.23, and R.sup.24
may be as defined anywhere herein; at least one of R.sup.3, R.sup.4
and R.sup.5 may be --P.sup.+R.sup.18R.sup.19R.sup.20 or
--NR.sup.23R.sup.24; and at least one of R.sup.3, R.sup.4, R.sup.5,
R.sup.18, R.sup.19, R.sup.20, R.sup.23, and R.sup.24 may be a
biomolecule, a linking group optionally joined to a biomolecule, or
a group that may be substituted with at least one substituent that
may be a biomolecule. In various embodiments, one of R.sup.3,
R.sup.4 and R.sup.5 may be --P.sup.+R.sup.18R.sup.19R.sup.20 or
--NR.sup.23R.sup.24; and at least one of R.sup.3, R.sup.4, R.sup.5,
R.sup.18, R.sup.19, R.sup.20, R.sup.23, and R.sup.24 may be a
biomolecule, a linking group optionally joined to a biomolecule, or
a group that may be substituted with at least one substituent that
may be a biomolecule.
[0137] In an embodiment, each of R.sup.3, R.sup.4, and R.sup.5 may
independently be H, D, --S.sup.+R.sup.21R.sup.22,
--NR.sup.23R.sup.24, a biomolecule, a linking group optionally
joined to a biomolecule, a linear or branched C.sub.1-C.sub.15
alkyl group, or a C.sub.3-C.sub.18 cycloalkyl group, wherein each
of the C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18
cycloalkyl group may be unsubstituted or substituted and may be
optionally intercepted with at least one heteroatom selected from
the group consisting of O, S, N and P; each of the C.sub.1-C.sub.15
alkyl group and the C.sub.3-C.sub.18 cycloalkyl group may be joined
to the carbon atom of --CR.sup.3R.sup.4R.sup.5 through a carbon
atom; each of R.sup.21, R.sup.22, R.sup.23 and R.sup.24 may be as
defined anywhere herein; at least one of R.sup.3, R.sup.4 and
R.sup.5 may be --S.sup.+R.sup.21R.sup.22 or --NR.sup.23R.sup.24;
and at least one of R.sup.3, R.sup.4, R.sup.5, R.sup.21, R.sup.22,
R.sup.23, and R.sup.24 may be a biomolecule, a linking group
optionally joined to a biomolecule, or a group that may be
substituted with at least one substituent that may be a
biomolecule. In various embodiments, one of R.sup.3, R.sup.4 and
R.sup.5 may be --S.sup.+R.sup.21R.sup.22 or --NR.sup.23R.sup.24 and
at least one of R.sup.3, R.sup.4, R.sup.5, R.sup.21, R.sup.22,
R.sup.23, and R.sup.24 may be a biomolecule, a linking group
optionally joined to a biomolecule, or a group that may be
substituted with at least one substituent that may be a
biomolecule.
[0138] In an embodiment, each of R.sup.3, R.sup.4, and R.sup.5 may
independently be H, D, F, Cl, Br, I, CX.sub.3,
--N.sup.+R.sup.15R.sup.16R.sup.17, a biomolecule, a linking group
optionally joined to a biomolecule, a linear or branched
C.sub.1-C.sub.15 alkyl group, or a C.sub.3-C.sub.18 cycloalkyl
group, wherein each of the C.sub.1-C.sub.15 alkyl group and the
C.sub.3-C.sub.18 cycloalkyl group may be unsubstituted or
substituted and may be optionally intercepted with at least one
heteroatom selected from the group consisting of O, S, N and P;
each of the C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18
cycloalkyl group may be joined to the carbon atom of
--CR.sup.3R.sup.4R.sup.5 through a carbon atom; each X may be the
same or different and may be F, Cl, Br, or I; each of R.sup.15,
R.sup.16 and R.sup.17 may be as defined anywhere herein; at least
one of R.sup.3, R.sup.4 and R.sup.5 may be F, Cl, Br, I, CX.sub.3,
or --N.sup.+R.sup.15R.sup.16R.sup.17; and at least one of R.sup.3,
R.sup.4, R.sup.5, R.sup.15, R.sup.16 and R.sup.17 may be a
biomolecule, a linking group optionally joined to a biomolecule, or
a group that may be substituted with at least one substituent that
may be a biomolecule, or forms a group that is substituted with at
least one substituent that is a biomolecule. In various
embodiments, at least two of R.sup.3, R.sup.4 and R.sup.5 may
independently be F, Cl, Br, I, or CX.sub.3, or at least one of
R.sup.3, R.sup.4 and R.sup.5 may be
--N.sup.+R.sup.15R.sup.16R.sup.17; and at least one of R.sup.3,
R.sup.4, R.sup.5, R.sup.15, R.sup.16 and R.sup.17 may be a
biomolecule, a linking group optionally joined to a biomolecule, or
a group that may be substituted with at least one substituent that
may be a biomolecule, or forms a group that is substituted with at
least one substituent that is a biomolecule. In various
embodiments, two of R.sup.3, R.sup.4 and R.sup.5 may independently
be F, Cl, Br, I, or CX.sub.3, or one of R.sup.3, R.sup.4 and
R.sup.5 may be --N.sup.+R.sup.15R.sup.16R.sup.17; and at least one
of R.sup.3, R.sup.4, R.sup.5, R.sup.15, R.sup.16 and R.sup.17 may
be a biomolecule, a linking group optionally joined to a
biomolecule, or a group that may be substituted with at least one
substituent that may be a biomolecule, or forms a group that is
substituted with at least one substituent that is a
biomolecule.
[0139] In various embodiments, the compound may be of the formula
(IV):
##STR00028##
wherein Q.sup.1 may be --CR.sup.3R.sup.4R.sup.5; and each of
R.sup.3, R.sup.4, and R.sup.5 may independently be H, D, F, Cl, Br,
I, CX.sub.3, a biomolecule, a linking group optionally joined to a
biomolecule, a linear or branched C.sub.1-C.sub.15 alkyl group, or
a C.sub.3-C.sub.18 cycloalkyl group, wherein each of the
C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18 cycloalkyl
group may be unsubstituted or substituted and may be optionally
intercepted with at least one heteroatom selected from the group
consisting of O, S, N and P; each of the C.sub.1-C.sub.15 alkyl
group and the C.sub.3-C.sub.18 cycloalkyl group may be joined to
the carbon atom of --CR.sup.3R.sup.4R.sup.5 through a carbon atom;
each X may be the same or different and may be F, Cl, Br, or I; at
least one of R.sup.3, R.sup.4 and R.sup.5 may be F, Cl, Br, I, or
CX.sub.3; and at least one of R.sup.3, R.sup.4 and R.sup.5 may be a
biomolecule, a linking group optionally joined to a biomolecule, or
a group that may be substituted with at least one substituent that
may be a biomolecule. In various embodiments, each of R.sup.3,
R.sup.4, and R.sup.5 may independently be F, Cl, Br, I, CX.sub.3, a
biomolecule, a linking group optionally joined to a biomolecule, a
linear or branched C.sub.1-C.sub.15 alkyl group, or a
C.sub.3-C.sub.18 cycloalkyl group, wherein each of the
C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18 cycloalkyl
group may be unsubstituted or substituted and may be optionally
intercepted with at least one heteroatom selected from the group
consisting of O, S, N and P; each of the C.sub.1-C.sub.15 alkyl
group and the C.sub.3-C.sub.18 cycloalkyl group may be joined to
the carbon atom of --CR.sup.3R.sup.4R.sup.5 through a carbon atom;
each X may be the same or different and may be F, Cl, Br, or I; two
of R.sup.3, R.sup.4 and R.sup.5 may be F, Cl, Br, I, or CX.sub.3;
and one of R.sup.3, R.sup.4 and R.sup.5 may be a biomolecule, a
linking group optionally joined to a biomolecule, or a group that
may be substituted with at least one substituent that may be a
biomolecule. In various embodiments, two of R.sup.3, R.sup.4, and
R.sup.5 may independently be F, Cl, Br, I, or CX.sub.3, and one of
R.sup.3, R.sup.4 and R.sup.5 may be a biomolecule or a linking
group optionally joined to a biomolecule. In various embodiments,
two of R.sup.3, R.sup.4, and R.sup.5 may independently be F, Cl,
Br, I, or CX.sub.3, and one of R.sup.3, R.sup.4 and R.sup.5 may be
a biomolecule. In various embodiments, two of R.sup.3, R.sup.4, and
R.sup.5 may independently be F, Cl, Br, CX.sub.3, and one of
R.sup.3, R.sup.4 and R.sup.5 may be a biomolecule or a linking
group optionally joined to a biomolecule. In various embodiments,
two of R.sup.3, R.sup.4, and R.sup.5 may independently be F, Cl,
Br, CX.sub.3, and one of R.sup.3, R.sup.4 and R.sup.5 may be a
biomolecule. In an embodiment, two of R.sup.3, R.sup.4, and R.sup.5
may independently be F, Br, I, or CX.sub.3, and one of R.sup.3,
R.sup.4 and R.sup.5 may be a biomolecule or a linking group
optionally joined to a biomolecule. In an embodiment, two of
R.sup.3, R.sup.4, and R.sup.5 may independently be F, Br, I, or
CX.sub.3, and one of R.sup.3, R.sup.4 and R.sup.5 may be a
biomolecule. In various embodiments, two of R.sup.3, R.sup.4, and
R.sup.5 may independently be F, Br, I, or CX.sub.3, and one of
R.sup.3, R.sup.4 and R.sup.5 may be a biomolecule or a linking
group optionally joined to a biomolecule. In an embodiment, two of
R.sup.3, R.sup.4, and R.sup.5 may independently be F, Br, I, or
CX.sub.3, and one of R.sup.3, R.sup.4 and R.sup.5 may be a
biomolecule. In an embodiment, two of R.sup.3, R.sup.4, and R.sup.5
may independently be Cl, Br, I, or CX.sub.3, and one of R.sup.3,
R.sup.4 and R.sup.5 may be a biomolecule or a linking group
optionally joined to a biomolecule. In various embodiments, two of
R.sup.3, R.sup.4, and R.sup.5 may independently be Cl, Br, I, or
CX.sub.3, and one of R.sup.3, R.sup.4 and R.sup.5 may be a
biomolecule. In an embodiment, two of R.sup.3, R.sup.4, and R.sup.5
may independently be F, Cl, or I, and one of R.sup.3, R.sup.4 and
R.sup.5 may be a biomolecule or a linking group optionally joined
to a biomolecule. In an embodiment, two of R.sup.3, R.sup.4, and
R.sup.5 may independently be F, Cl, or I, and one of R.sup.3,
R.sup.4 and R.sup.5 may be a biomolecule. In an embodiment, two of
R.sup.3, R.sup.4, and R.sup.5 may independently be F, Cl, or
CX.sub.3, and one of R.sup.3, R.sup.4 and R.sup.5 may be a
biomolecule or a linking group optionally joined to a biomolecule.
In an embodiment, two of R.sup.3, R.sup.4, and R.sup.5 may
independently be F, Cl, or CX.sub.3, and one of R.sup.3, R.sup.4
and R.sup.5 may be a biomolecule. In various embodiments, two of
R.sup.3, R.sup.4, and R.sup.5 may independently be F, Br, or I, and
one of R.sup.3, R.sup.4 and R.sup.5 may be a biomolecule or a
linking group optionally joined to a biomolecule. In an embodiment,
two of R.sup.3, R.sup.4, and R.sup.5 may independently be F, Br, or
I, and one of R.sup.3, R.sup.4 and R.sup.5 may be a biomolecule. In
various embodiments, two of R.sup.3, R.sup.4, and R.sup.5 may
independently be F, Br, or CX.sub.3, and one of R.sup.3, R.sup.4
and R.sup.5 may be a biomolecule or a linking group optionally
joined to a biomolecule. In an embodiment, two of R.sup.3, R.sup.4,
and R.sup.5 may independently be F, Br, or CX.sub.3, and one of
R.sup.3, R.sup.4 and R.sup.5 may be a biomolecule. In various
embodiments, two of R.sup.3, R.sup.4, and R.sup.5 may independently
be F, I, or CX.sub.3, and one of R.sup.3, R.sup.4 and R.sup.5 may
be a biomolecule or a linking group optionally joined to a
biomolecule. In an embodiment, two of R.sup.3, R.sup.4, and RI may
independently be F, I, or CX.sub.3, and one of R.sup.3, R.sup.4 and
R.sup.5 may be a biomolecule. In various embodiments, two of
R.sup.3, R.sup.4, and R.sup.5 may independently be Cl, Br, or I,
and one of R.sup.3, R.sup.4 and R.sup.5 may be a biomolecule or a
linking group optionally joined to a biomolecule. In an embodiment,
two of R.sup.3, R.sup.4, and R.sup.5 may independently be Cl, Br,
or I, and one of R.sup.3, R.sup.4 and R.sup.5 may be a biomolecule.
In an embodiment, two of R.sup.3, R.sup.4, and R.sup.5 may
independently be Cl, Br, or CX.sub.3, and one of R.sup.3, R.sup.4
and R.sup.5 may be a biomolecule or a linking group optionally
joined to a biomolecule. In an embodiment, two of R.sup.3, R.sup.4,
and R.sup.5 may independently be Cl, Br, or CX.sub.3, and one of
R.sup.3, R.sup.4 and R.sup.5 may be a biomolecule. In an
embodiment, two of R.sup.3, R.sup.4, and R.sup.5 may independently
be Cl, I, or CX.sub.3, and one of R.sup.3, R.sup.4 and R.sup.5 may
be a biomolecule or a linking group optionally joined to a
biomolecule. In an embodiment, two of R.sup.3, R.sup.4, and R.sup.5
may independently be Cl, I, or CX.sub.3, and one of R.sup.3,
R.sup.4 and R.sup.5 may be a biomolecule. In an embodiment, two of
R.sup.3, R.sup.4, and R.sup.5 may independently be Br, I, or
CX.sub.3, and one of R.sup.3, R.sup.4 and R.sup.5 may be a
biomolecule or a linking group optionally joined to a biomolecule.
In an embodiment, two of R.sup.3, R.sup.4, and R.sup.5 may
independently be Br, I, or CX.sub.3, and one of R.sup.3, R.sup.4
and R.sup.5 may be a biomolecule. In an embodiment, two of R.sup.3,
R.sup.4, and R.sup.5 may independently be F or Br, and one of
R.sup.3, R.sup.4 and R.sup.5 may be a biomolecule or a linking
group optionally joined to a biomolecule. In an embodiment, two of
R.sup.3, R.sup.4, and R.sup.5 may independently be F or Br, and one
of R.sup.3, R.sup.4 and R.sup.5 may be a biomolecule. In an
embodiment, two of R.sup.3, R.sup.4, and R.sup.5 may independently
be F or I, and one of R.sup.3, R.sup.4 and R.sup.5 may be a
biomolecule or a linking group optionally joined to a biomolecule.
In an embodiment, two of R.sup.3, R.sup.4, and R.sup.5 may
independently be F or I, and one of R.sup.3, R.sup.4 and R.sup.5
may be a biomolecule. In an embodiment, two of R.sup.3, R.sup.4,
and R.sup.5 may independently be F or CX.sub.3, and one of R.sup.3,
R.sup.4 and R.sup.5 may be a biomolecule or a linking group
optionally joined to a biomolecule. In an embodiment, two of
R.sup.3, R.sup.4, and R.sup.5 may independently be F or CX.sub.3,
and one of R.sup.3, R.sup.4 and R.sup.5 may be a biomolecule. In an
embodiment, two of R.sup.3, R.sup.4, and R.sup.5 may independently
be Cl or Br, and one of R.sup.3, R.sup.4 and R.sup.5 may be a
biomolecule or a linking group optionally joined to a biomolecule.
In an embodiment, two of R.sup.3, R.sup.4, and R.sup.5 may
independently be Cl or Br, and one of R.sup.3, R.sup.4 and R.sup.5
may be a biomolecule. In an embodiment, two of R.sup.3, R.sup.4,
and R.sup.5 may independently be Cl or I, and one of R.sup.3,
R.sup.4 and R.sup.5 may be a biomolecule or a linking group
optionally joined to a biomolecule. In an embodiment, two of
R.sup.3, R.sup.4, and R.sup.5 may independently be Cl or I, and one
of R.sup.3, R.sup.4 and R.sup.5 may be a biomolecule. In an
embodiment, two of R.sup.3, R.sup.4, and R.sup.5 may independently
be Cl or CX.sub.3, and one of R.sup.3, R.sup.4 and R.sup.5 may be a
biomolecule or a linking group optionally joined to a biomolecule.
In an embodiment, two of R.sup.3, R.sup.4, and R.sup.5 may
independently be Cl or CX.sub.3, and one of R.sup.3, R.sup.4 and
R.sup.5 may be a biomolecule. In an embodiment, two of R.sup.3,
R.sup.4, and R.sup.5 may independently be Br or I, and one of
R.sup.3, R.sup.4 and R.sup.5 may be a biomolecule or a linking
group optionally joined to a biomolecule. In an embodiment, two of
R.sup.3, R.sup.4, and R.sup.5 may independently be Br or I, and one
of R.sup.3, R.sup.4 and R.sup.5 may be a biomolecule. In an
embodiment, two of R.sup.3, R.sup.4, and R.sup.5 may independently
be Br or CX.sub.3, and one of R.sup.3, R.sup.4 and R.sup.5 may be a
biomolecule or a linking group optionally joined to a biomolecule.
In an embodiment, two of R.sup.3, R.sup.4, and R.sup.5 may
independently be Br or CX.sub.3, and one of R.sup.3, R.sup.4 and
R.sup.5 may be a biomolecule. In an embodiment, two of R.sup.3,
R.sup.4, and R.sup.5 may independently be I or CX.sub.3, and one of
R.sup.3, R.sup.4 and R.sup.5 may be a biomolecule or a linking
group optionally joined to a biomolecule. In an embodiment, two of
R.sup.3, R.sup.4, and R.sup.5 may independently be I or CX.sub.3,
and one of R.sup.3, R.sup.4 and R.sup.5 may be a biomolecule. In an
embodiment, two of R.sup.3, R.sup.4, and R.sup.5 may be CX.sub.3,
and one of R.sup.3, R.sup.4 and R.sup.5 may be a biomolecule or a
linking group optionally joined to a biomolecule. In an embodiment,
two of R.sup.3, R.sup.4, and R.sup.5 may be CX.sub.3, and one of
R.sup.3, R.sup.4 and R.sup.5 may be a biomolecule. In an
embodiment, two of R.sup.3, R.sup.4, and R.sup.5 may be Cl, and one
of R.sup.3, R.sup.4 and R.sup.5 may be a biomolecule or a linking
group optionally joined to a biomolecule. In an embodiment, two of
R.sup.3, R.sup.4, and R.sup.5 may be Cl, and one of R.sup.3,
R.sup.4 and R.sup.5 may be a biomolecule. In an embodiment, two of
R.sup.3, R.sup.4, and R.sup.5 may be Br, and one of R.sup.3,
R.sup.4 and R.sup.5 may be a biomolecule or a linking group
optionally joined to a biomolecule. In an embodiment, two of
R.sup.3, R.sup.4, and R.sup.5 may be Br, and one of R.sup.3,
R.sup.4 and R.sup.5 may be a biomolecule. In an embodiment, two of
R.sup.3, R.sup.4, and R.sup.5 may be I, and one of R.sup.3, R.sup.4
and R.sup.5 may be a biomolecule or a linking group optionally
joined to a biomolecule. In an embodiment, two of R.sup.3, R.sup.4,
and R.sup.5 may be I, and one of R.sup.3, R.sup.4 and R.sup.5 may
be a biomolecule. In various embodiments, two of R.sup.3, R.sup.4,
and R.sup.5 may independently be F, Cl, Br, or I, and one of
R.sup.3, R.sup.4 and R.sup.5 may be a biomolecule or a linking
group optionally joined to a biomolecule. In various embodiments,
two of R.sup.3, R.sup.4, and R.sup.5 may independently be F, Cl,
Br, or I, and one of R.sup.3, R.sup.4 and R.sup.5 may be a
biomolecule. In an embodiment, two of R.sup.3, R.sup.4, and R.sup.5
may independently be F, Cl, or Br, and one of R.sup.3, R.sup.4 and
R.sup.5 may be a biomolecule or a linking group optionally joined
to a biomolecule. In an embodiment, two of R.sup.3, R.sup.4, and
R.sup.5 may independently be F, Cl, or Br, and one of R.sup.3,
R.sup.4 and R.sup.5 may be a biomolecule. In an embodiment, two of
R.sup.3, R.sup.4, and R.sup.5 may independently be F or Cl, and one
of R.sup.3, R.sup.4 and R.sup.5 may be a biomolecule or a linking
group optionally joined to a biomolecule. In an embodiment, two of
R.sup.3, R.sup.4, and R.sup.5 may independently be F or Cl, and one
of R.sup.3, R.sup.4 and R.sup.5 may be a biomolecule. In an
embodiment, two of R.sup.3, R.sup.4, and R.sup.5 may be F, and one
of R.sup.3, R.sup.4 and R.sup.5 may be a biomolecule or a linking
group optionally joined to a biomolecule. In an embodiment, two of
R.sup.3, R.sup.4, and R.sup.5 may be F, and one of R.sup.3, R.sup.4
and R.sup.5 may be a biomolecule. In an embodiment, each X may be
the same or different and may be F, Cl, Br, or I. In various
embodiments, each X may be the same or different and may be F, Cl,
or I. In various embodiments, each X may be the same or different
and may be F, Br, or I. In an embodiment, each X may be the same or
different and may be Cl, Br, or I. In an embodiment, each X may be
the same or different and may be F or Br. In an embodiment, each X
may be the same or different and may be F or I. In an embodiment,
each X may be the same or different and may be Cl or Br. In an
embodiment, each X may be the same or different and may be Cl or I.
In an embodiment, each X may be the same or different and may be Br
or I. In an embodiment, each X may be Cl. In an embodiment, each X
may be Br. In an embodiment, each X may be I. In various
embodiments, each X may be the same or different and may be F, Cl,
Br. In an embodiment, each X may be the same or different and may
be F or Cl. In an embodiment, each X may be F.
[0140] In various embodiments, the compound may be of the formula
(IV):
##STR00029##
wherein Q.sup.1 may be --CR.sup.3R.sup.4R.sup.5; and each of
R.sup.3, R.sup.4, and R.sup.5 may independently be H, D,
--N.sup.+R.sup.15R.sup.16R.sup.17, a biomolecule, a linking group
optionally joined to a biomolecule, a linear or branched
C.sub.1-C.sub.15 alkyl group, or a C.sub.3-C.sub.18 cycloalkyl
group, wherein each of the C.sub.1-C.sub.15 alkyl group and the
C.sub.3-C.sub.18 cycloalkyl group may be unsubstituted or
substituted and may be optionally intercepted with at least one
heteroatom selected from the group consisting of O, S, N and P;
each of the C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18
cycloalkyl group may be joined to the carbon atom of
--CR.sup.3R.sup.4R.sup.5 through a carbon atom; each of R.sup.15,
R.sup.16 and R.sup.17 may independently be H, D, a biomolecule, a
linking group optionally joined to a biomolecule, a linear or
branched C.sub.1-C.sub.15 alkyl group, or a C.sub.3-C.sub.18
cycloalkyl group, wherein each of the C.sub.1-C.sub.15 alkyl group
and the C.sub.3-C.sub.18 cycloalkyl group may be unsubstituted or
substituted and may be optionally intercepted with at least one
heteroatom selected from the group consisting of O, S, N and P,
each of the C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18
cycloalkyl group may be joined to the nitrogen atom of
--N.sup.+R.sup.15R.sup.16R.sup.17 through a carbon atom, or R.sup.5
may be absent and R.sup.16 and R.sup.17 may be joined so that
--N.sup.+R.sup.15R.sup.16R.sup.17 forms a positively charged
nitrogen containing heterocyclic group which may be substituted or
unsubstituted; at least one of R.sup.3, R.sup.4 and R.sup.5 may be
--N.sup.+R.sup.15R.sup.16R.sup.17; and at least one of R.sup.3,
R.sup.4, R.sup.5, R.sup.15, R.sup.16, and R.sup.17 may be a
biomolecule, a linking group optionally joined to a biomolecule, or
a group that may be substituted with at least one substituent that
may be a biomolecule, or forms a group that is substituted with at
least one substituent that is a biomolecule. In various
embodiments, R.sup.3 may be --N.sup.+R.sup.15R.sup.16R.sup.17; each
of each of R.sup.4 and R.sup.5 may independently be H, D, a
biomolecule, a linking group optionally joined to a biomolecule, a
linear or branched C.sub.1-C.sub.15 alkyl group, or a
C.sub.3-C.sub.18 cycloalkyl group, wherein each of the
C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18 cycloalkyl
group may be unsubstituted or substituted and may be optionally
intercepted with at least one heteroatom selected from the group
consisting of O, S, N and P; each of the C.sub.1-C.sub.15 alkyl
group and the C.sub.3-C.sub.18 cycloalkyl group may be joined to
the carbon atom of --CR.sup.3R.sup.4R.sup.5 through a carbon atom;
each of R.sup.15, R.sup.16 and R.sup.17 may independently be H, D,
a biomolecule, a linking group optionally joined to a biomolecule,
a linear or branched C.sub.1-C.sub.15 alkyl group, or a
C.sub.3-C.sub.18 cycloalkyl group, wherein each of the
C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18 cycloalkyl
group may be unsubstituted or substituted and may be optionally
intercepted with at least one heteroatom selected from the group
consisting of O, S, N and P, each of the C.sub.1-C.sub.15 alkyl
group and the C.sub.3-C.sub.18 cycloalkyl group may be joined to
the nitrogen atom of --N.sup.+R.sup.15R.sup.16R.sup.17 through a
carbon atom, or R.sup.5 may be absent and R.sup.16 and R.sup.17 may
be joined so that --N.sup.+R.sup.15R.sup.16R.sup.17 forms a
positively charged nitrogen containing heterocyclic group which may
be substituted or unsubstituted; and at least one of R.sup.4,
R.sup.5, R.sup.15, R.sup.16 and R.sup.17 may be a biomolecule, a
linking group optionally joined to a biomolecule, or a group that
may be substituted with at least one substituent that may be a
biomolecule, or forms a group that is substituted with at least one
substituent that is a biomolecule. In an embodiment, each of
R.sup.15, R.sup.16 and R.sup.17 may independently be H, D, a
biomolecule, a linking group optionally joined to a biomolecule, a
linear or branched C.sub.1-C.sub.15 alkyl group, or a
C.sub.3-C.sub.18 cycloalkyl group, wherein each of the
C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18 cycloalkyl
group may be unsubstituted or substituted and may be optionally
intercepted with at least one heteroatom selected from the group
consisting of O, S, N and P, and each of the C.sub.1-C.sub.15 alkyl
group and the C.sub.3-C.sub.18 cycloalkyl group may be joined to
the nitrogen atom of --N.sup.+R.sup.15R.sup.16R.sup.17 through a
carbon atom. In various embodiments, R.sup.15 may be absent and
R.sup.16 and R.sup.17 may be joined so that
--N.sup.+R.sup.15R.sup.16R.sup.17 forms a positively charged
nitrogen containing heterocyclic group which may be substituted or
unsubstituted. In various embodiments, R.sup.15 may be absent and
R.sup.16 and R.sup.17 may be joined so that
--N.sup.+R.sup.15R.sup.16R.sup.17 forms a positively charged 4 to
6-membered nitrogen containing heterocyclic group which may be
substituted or unsubstituted. In an embodiment, the positively
charged 4 to 6-membered nitrogen containing heterocyclic group may
be a pyridinium group, an imidazolium group, a pyrazinium group, a
pyrimidinium group or a pyridazinium group, each of which may be
substituted or unsubstituted. In various embodiments, the
positively charged nitrogen containing heterocyclic group may be
unsubstituted. In various embodiments, the positively charged
nitrogen containing heterocyclic group which may be substituted
with one or more substituents that are selected from the group
consisting of a C.sub.1-C.sub.15 alkyl group, a biomolecule, a
linking group optionally joined to a biomolecule. In various
embodiments, the C.sub.1-C.sub.15 alkyl group may be a
C.sub.1-C.sub.6 alkyl group. In various embodiments, the
C.sub.3-C.sub.18 cycloalkyl group may be a C.sub.4-C.sub.8
cycloalkyl group.
[0141] In various embodiments, the compound may be of the formula
(IV):
##STR00030##
wherein Q.sup.1 may be --CR.sup.3R.sup.4R.sup.5; and each of
R.sup.3, R.sup.4, and R.sup.5 may independently be H, D,
--P.sup.+R.sup.18R.sup.19R.sup.20, a biomolecule, a linking group
optionally joined to a biomolecule, a linear or branched
C.sub.1-C.sub.15 alkyl group, or a C.sub.3-C.sub.18 cycloalkyl
group, wherein each of the C.sub.1-C.sub.15 alkyl group and the
C.sub.3-C.sub.18 cycloalkyl group may be unsubstituted or
substituted and may be optionally intercepted with at least one
heteroatom selected from the group consisting of O, S, N and P;
each of the C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18
cycloalkyl group may be joined to the carbon atom of
--CR.sup.3R.sup.4R.sup.5 through a carbon atom; each of R.sup.18,
R.sup.19, and R.sup.20 may independently be H, D, a biomolecule, a
linking group optionally joined to a biomolecule, a linear or
branched C.sub.1-C.sub.15 alkyl group, or a C.sub.3-C.sub.18
cycloalkyl group, wherein each of the C.sub.1-C.sub.15 alkyl group
and the C.sub.3-C.sub.18 cycloalkyl group may be unsubstituted or
substituted and may be optionally intercepted with at least one
heteroatom selected from the group consisting of O, S, N and P;
each of the C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18
cycloalkyl group may be joined to the phosphorus atom of
--P.sup.+R.sup.18R.sup.19R.sup.20 through a carbon atom; at least
one of R.sup.3, R.sup.4 and R.sup.5 may be
--P.sup.+R.sup.18R.sup.19R.sup.20; and at least one of R.sup.3,
R.sup.4, R.sup.5, R.sup.18, R.sup.19, and R.sup.20 may be a
biomolecule, a linking group optionally joined to a biomolecule, or
a group that may be substituted with at least one substituent that
may be a biomolecule. In various embodiments, R.sup.3 may be
--P.sup.+R.sup.18R.sup.19R.sup.20; each of R.sup.4 and R.sup.5 may
independently be H, D, a biomolecule, a linking group optionally
joined to a biomolecule, a linear or branched C.sub.1-C.sub.15
alkyl group, or a C.sub.3-C.sub.18 cycloalkyl group, wherein each
of the C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18
cycloalkyl group may be unsubstituted or substituted and may be
optionally intercepted with at least one heteroatom selected from
the group consisting of O, S, N and P; each of the C.sub.1-C.sub.15
alkyl group and the C.sub.3-C.sub.18 cycloalkyl group may be joined
to the carbon atom of --CR.sup.3R.sup.4R.sup.5 through a carbon
atom; each of R.sup.18, R.sup.19, and R.sup.20 may independently be
H, D, a biomolecule, a linking group optionally joined to a
biomolecule, a linear or branched C.sub.1-C.sub.15 alkyl group, or
a C.sub.3-C.sub.18 cycloalkyl group, wherein each of the
C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18 cycloalkyl
group may be unsubstituted or substituted and may be optionally
intercepted with at least one heteroatom selected from the group
consisting of O, S, N and P; each of the C.sub.1-C.sub.15 alkyl
group and the C.sub.3-C.sub.18 cycloalkyl group may be joined to
the phosphorus atom of --P.sup.+R.sup.18R.sup.19R.sup.20 through a
carbon atom; and at least one of R.sup.4, R.sup.5, R.sup.18,
R.sup.19, and R.sup.20 may be a biomolecule, a linking group
optionally joined to a biomolecule, or a group that may be
substituted with at least one substituent that may be a
biomolecule. In various embodiments, the C.sub.1-C.sub.15 alkyl
group may be a C.sub.1-C.sub.6 alkyl group. In various embodiments,
the C.sub.3-C.sub.18 cycloalkyl group may be a C.sub.4-C.sub.8
cycloalkyl group.
[0142] In various embodiments, the compound may be of the formula
(IV):
##STR00031##
wherein Q.sup.1 may be --CR.sup.3R.sup.4R.sup.5; and each of
R.sup.3, R.sup.4, and R.sup.5 may independently be H, D,
--S*R.sup.21R.sup.22, a biomolecule, a linking group optionally
joined to a biomolecule, a linear or branched C.sub.1-C.sub.15
alkyl group, or a C.sub.3-C.sub.18 cycloalkyl group, wherein each
of the C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18
cycloalkyl group may be unsubstituted or substituted and may be
optionally intercepted with at least one heteroatom selected from
the group consisting of O, S, N and P; each of the C.sub.1-C.sub.15
alkyl group and the C.sub.3-C.sub.18 cycloalkyl group may be joined
to the carbon atom of --CR.sup.3R.sup.4R.sup.5 through a carbon
atom; each of R.sup.21 and R.sup.22 may independently be H, D, a
biomolecule, a linking group optionally joined to a biomolecule, a
linear or branched C.sub.1-C.sub.15 alkyl group, or a
C.sub.3-C.sub.18 cycloalkyl group, wherein each of the
C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18 cycloalkyl
group may be unsubstituted or substituted and may be optionally
intercepted with at least one heteroatom selected from the group
consisting of O, S, N and P; each of the C.sub.1-C.sub.15 alkyl
group and the C.sub.3-C.sub.18 cycloalkyl group may be joined to
the sulfur atom of --S.sup.+R.sup.21R.sup.22 through a carbon atom;
at least one of R.sup.3, R.sup.4 and R.sup.5 may be
--S.sup.+R.sup.21R.sup.22; and at least one of R.sup.3, R.sup.4,
R.sup.5, R.sup.21, and R.sup.22 may be a biomolecule, a linking
group optionally joined to a biomolecule, or a group that may be
substituted with at least one substituent that may be a
biomolecule. In various embodiments, R.sup.3 may be
--S.sup.+R.sup.21R.sup.22; each of R.sup.4 and R.sup.5 may
independently be H, D, a biomolecule, a linking group optionally
joined to a biomolecule, a linear or branched C.sub.1-C.sub.15
alkyl group, or a C.sub.3-C.sub.18 cycloalkyl group, wherein each
of the C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18
cycloalkyl group may be unsubstituted or substituted and may be
optionally intercepted with at least one heteroatom selected from
the group consisting of O, S, N and P; each of the C.sub.1-C.sub.15
alkyl group and the C.sub.3-C.sub.18 cycloalkyl group may be joined
to the carbon atom of --CR.sup.3R.sup.4R.sup.5 through a carbon
atom; each of R.sup.21 and R.sup.22 may independently be H, D, a
biomolecule, a linking group optionally joined to a biomolecule, a
linear or branched C.sub.1-C.sub.15 alkyl group, or a
C.sub.3-C.sub.18 cycloalkyl group, wherein each of the
C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18 cycloalkyl
group may be unsubstituted or substituted and may be optionally
intercepted with at least one heteroatom selected from the group
consisting of O, S, N and P; each of the C.sub.1-C.sub.15 alkyl
group and the C.sub.3-C.sub.18 cycloalkyl group may be joined to
the sulfur atom of --S.sup.+R.sup.21R.sup.22 through a carbon atom;
and at least one of R.sup.4, R.sup.5, R.sup.21, and R.sup.22 may be
a biomolecule, a linking group optionally joined to a biomolecule,
or a group that may be substituted with at least one substituent
that may be a biomolecule. In various embodiments, the
C.sub.1-C.sub.15 alkyl group may be a C.sub.1-C.sub.6 alkyl group.
In various embodiments, the C.sub.3-C.sub.18 cycloalkyl group may
be a C.sub.4-C.sub.8 cycloalkyl group.
[0143] In various embodiments, the compound may be of the formula
(IV):
##STR00032##
wherein Q.sup.1 may be --CR.sup.3R.sup.4R.sup.5; and each of
R.sup.3, R.sup.4, and R.sup.5 may independently be H, D,
--NR.sup.23R.sup.24, a biomolecule, a linking group optionally
joined to a biomolecule, a linear or branched C.sub.1-C.sub.15
alkyl group, or a C.sub.3-C.sub.18 cycloalkyl group, wherein each
of the C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18
cycloalkyl group may be unsubstituted or substituted and may be
optionally intercepted with at least one heteroatom selected from
the group consisting of O, S, N and P; each of the C.sub.1-C.sub.15
alkyl group and the C.sub.3-C.sub.18 cycloalkyl group may be joined
to the carbon atom of --CR.sup.3R.sup.4R.sup.5 through a carbon
atom; each of R.sup.23 and R.sup.24 may independently be H, D, a
biomolecule, a linking group optionally joined to a biomolecule, a
linear or branched C.sub.1-C.sub.15 alkyl group, or a
C.sub.3-C.sub.18 cycloalkyl group, wherein each of the
C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18 cycloalkyl
group may be unsubstituted or substituted and may be optionally
intercepted with at least one heteroatom selected from the group
consisting of O, S, N and P; each of the C.sub.1-C.sub.15 alkyl
group and the C.sub.3-C.sub.18 cycloalkyl group may be joined to
the nitrogen atom of --NR.sup.23R.sup.24 through a carbon atom; at
least one of R.sup.3, R.sup.4 and R.sup.5 may be
--NR.sup.23R.sup.24; and at least one of R.sup.3, R.sup.4, R.sup.5,
R.sup.23, and R.sup.24 may be a biomolecule, a linking group
optionally joined to a biomolecule, or a group that may be
substituted with at least one substituent that may be a
biomolecule. In various embodiments, R.sup.3 may be
--NR.sup.23R.sup.24; each of R.sup.4 and R.sup.5 may independently
be H, D, a biomolecule, a linking group optionally joined to a
biomolecule, a linear or branched C.sub.1-C.sub.15 alkyl group, or
a C.sub.3-C.sub.18 cycloalkyl group, wherein each of the
C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18 cycloalkyl
group may be unsubstituted or substituted and may be optionally
intercepted with at least one heteroatom selected from the group
consisting of O, S, N and P; each of the C.sub.1-C.sub.15 alkyl
group and the C.sub.3-C.sub.18 cycloalkyl group may be joined to
the carbon atom of --CR.sup.3R.sup.4R.sup.5 through a carbon atom;
each of R.sup.23 and R.sup.24 may independently be H, D, a
biomolecule, a linking group optionally joined to a biomolecule, a
linear or branched C.sub.1-C.sub.15 alkyl group, or a
C.sub.3-C.sub.18 cycloalkyl group, wherein each of the
C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18 cycloalkyl
group may be unsubstituted or substituted and may be optionally
intercepted with at least one heteroatom selected from the group
consisting of O, S, N and P; each of the C.sub.1-C.sub.15 alkyl
group and the C.sub.3-C.sub.18 cycloalkyl group may be joined to
the nitrogen atom of --NR.sup.23R.sup.24 through a carbon atom; and
at least one of R.sup.4, R.sup.5, R.sup.23, and R.sup.24 may be a
biomolecule, a linking group optionally joined to a biomolecule, or
a group that may be substituted with at least one substituent that
may be a biomolecule. In various embodiments, the C.sub.1-C.sub.15
alkyl group may be a C.sub.1-C.sub.6 alkyl group. In various
embodiments, the C.sub.3-C.sub.18 cycloalkyl group may be a
C.sub.4-C.sub.8 cycloalkyl group.
[0144] In various embodiments, the compound may be of the formula
(IV):
##STR00033##
wherein Q.sup.1 may be --C.ident.CR.sup.8; and R.sup.B may be as
defined anywhere herein.
[0145] In an embodiment, R.sup.8 may be
--N.sup.+R.sup.25R.sup.26R.sup.27,
--P.sup.+R.sup.28R.sup.29R.sup.30, --S.sup.+R.sup.31R.sup.32,
--NR.sup.33R.sup.34,
##STR00034##
a biomolecule, a linking group optionally joined to a biomolecule,
a linear or branched C.sub.1-C.sub.15 alkyl group or a
C.sub.3-C.sub.18 cycloalkyl group, wherein each of the
C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18 cycloalkyl
group may be substituted with at least one substituent that may be
a biomolecule and may be optionally intercepted with at least one
heteroatom selected from the group consisting of O, S, N and P;
each of the C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18
cycloalkyl group may be joined to the carbon atom of
--C.ident.CR.sup.8 through a carbon atom; each of R.sup.25,
R.sup.26, R.sup.27, R.sup.28, R.sup.29, R.sup.30, R.sup.31,
R.sup.32, R.sup.33, R.sup.34, and R.sup.35 may be as defined
anywhere herein; and at least one of R.sup.8, R.sup.25, R.sup.26,
R.sup.27, R.sup.28, R.sup.29, R.sup.30, R.sup.31, R.sup.32,
R.sup.33, R.sup.34, and R.sup.35 may be a biomolecule, a linking
group optionally joined to a biomolecule, or a group that may be
substituted with at least one substituent that may be a
biomolecule, or forms a group that is substituted with at least one
substituent that is a biomolecule.
[0146] In various embodiments, R.sup.B may be
--N.sup.+R.sup.25R.sup.26R.sup.27; each of R.sup.25, R.sup.26 and
R.sup.27 may independently be H, D, a biomolecule, a linking group
optionally joined to a biomolecule, a linear or branched
C.sub.1-C.sub.15 alkyl group, or a C.sub.3-C.sub.18 cycloalkyl
group, wherein each of the C.sub.1-C.sub.15 alkyl group and the
C.sub.3-C.sub.18 cycloalkyl group may be unsubstituted or
substituted and may be optionally intercepted with at least one
heteroatom selected from the group consisting of O, S, N and P;
each of the C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18
cycloalkyl group may be joined to the nitrogen atom of
--NR.sup.25R.sup.26R.sup.27 through a carbon atom, or R.sup.2 may
be absent and R.sup.26 and R.sup.27 may be joined so that
--N.sup.+R.sup.25R.sup.26R.sup.27 forms a positively charged
nitrogen containing heterocyclic group which may be unsubstituted
or substituted; and at least one of R.sup.25, R.sup.26 and R.sup.27
may be a biomolecule, a linking group optionally joined to a
biomolecule, or a group that may be substituted with at least one
substituent that may be a biomolecule, or forms a group that is
substituted with at least one substituent that is a biomolecule. In
an embodiment, the positively charged 4 to 6-membered nitrogen
containing heterocyclic group may be a pyridinium group, an
imidazolium group, a pyrazinium group, a pyrimidinium group or a
pyridazinium group, each of which may be substituted or
unsubstituted. In various embodiments, the positively charged
nitrogen containing heterocyclic group may be unsubstituted. In
various embodiments, the C.sub.1-C.sub.15 alkyl group may be a
C.sub.1-C.sub.6 alkyl group. In various embodiments, the
C.sub.3-C.sub.18 cycloalkyl group may be a C.sub.4-C.sub.8
cycloalkyl group.
[0147] In various embodiments, R.sup.8 may be
--P.sup.+R.sup.28R.sup.29R.sup.30; each of R.sup.28, R.sup.29, and
R.sup.30 may independently be H, D, a biomolecule, a linking group
optionally joined to a biomolecule, a linear or branched
C.sub.1-C.sub.15 alkyl group, or a C.sub.3-C.sub.18 cycloalkyl
group, wherein each of the C.sub.1-C.sub.15 alkyl group and the
C.sub.3-C.sub.18 cycloalkyl group may be unsubstituted or
substituted and may be optionally intercepted with at least one
heteroatom selected from the group consisting of O, S, N and P;
each of the C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18
cycloalkyl group may be joined to the phosphorus atom of
--P.sup.+R.sup.28R.sup.29R.sup.30 through a carbon atom; and at
least one of R.sup.28, R.sup.29 and R.sup.30 may be a biomolecule,
a linking group optionally joined to a biomolecule, or a group that
may be substituted with at least one substituent that may be a
biomolecule. In various embodiments, the C.sub.1-C.sub.15 alkyl
group may be a C.sub.1-C.sub.6 alkyl group. In various embodiments,
the C.sub.3-C.sub.18 cycloalkyl group may be a C.sub.4-C.sub.8
cycloalkyl group.
[0148] In various embodiments, R.sup.8 may be
--S.sup.+R.sup.31R.sup.32; each of R.sup.31 and R.sup.32 may
independently be H, D, a biomolecule, a linking group optionally
joined to a biomolecule, a linear or branched C.sub.1-C.sub.15
alkyl group, or a C.sub.3-C.sub.18 cycloalkyl group, wherein each
of the C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18
cycloalkyl group may be unsubstituted or substituted and may be
optionally intercepted with at least one heteroatom selected from
the group consisting of O, S, N and P; each of the C.sub.1-C.sub.15
alkyl group and the C.sub.3-C.sub.18 cycloalkyl group may be joined
to the sulfur atom of --S.sup.+R.sup.31R.sup.32 through a carbon
atom; and at least one of R.sup.31 and R.sup.32 may be a
biomolecule, a linking group optionally joined to a biomolecule, or
a group that may be substituted with at least one substituent that
may be a biomolecule. In various embodiments, the C.sub.1-C.sub.15
alkyl group may be a C.sub.1-C.sub.6 alkyl group. In various
embodiments, the C.sub.3-C.sub.18 cycloalkyl group may be a
C.sub.4-C.sub.8 cycloalkyl group.
[0149] In an embodiment, R.sup.8 may be --NR.sup.33R.sup.34; each
of R.sup.33 and R.sup.34 may independently be H, D, a biomolecule,
a linking group optionally joined to a biomolecule, a linear or
branched C.sub.1-C.sub.15 alkyl group, or a C.sub.3-C.sub.18
cycloalkyl group, wherein each of the C.sub.1-C.sub.15 alkyl group
and the C.sub.3-C.sub.18 cycloalkyl group may be unsubstituted or
substituted and may be optionally intercepted with at least one
heteroatom selected from the group consisting of O, S, N and P;
each of the C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18
cycloalkyl group may be joined to the nitrogen atom of
--NR.sup.33R.sup.34 through a carbon atom; and at least one of
R.sup.33 and R.sup.34 may be a biomolecule, a linking group
optionally joined to a biomolecule, or a group that may be
substituted with at least one substituent that may be a
biomolecule. In various embodiments, the C.sub.1-C.sub.15 alkyl
group may be a C.sub.1-C.sub.6 alkyl group. In various embodiments,
the C.sub.3-C.sub.18 cycloalkyl group may be a C.sub.4-C.sub.8
cycloalkyl group.
[0150] In an embodiment, R.sup.8 may be
##STR00035##
and R.sup.35 may be a biomolecule, a linking group optionally
joined to a biomolecule, a linear or branched C.sub.1-C.sub.15
alkyl group or a C.sub.3-C.sub.18 cycloalkyl group, wherein each of
the C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18
cycloalkyl group may be substituted with at least one substituent
that may be a biomolecule and may be optionally intercepted with at
least one heteroatom selected from the group consisting of O, S, N
and P; and each of the C.sub.1-C.sub.15 alkyl group and the
C.sub.3-C.sub.18 cycloalkyl group may be joined to the carbon atom
of
##STR00036##
through a carbon atom. In various embodiments, the C.sub.1-C.sub.15
alkyl group may be a C.sub.1-C.sub.6 alkyl group. In various
embodiments, the C.sub.3-C.sub.18 cycloalkyl group may be a
C.sub.4-C.sub.8 cycloalkyl group.
[0151] In various embodiments, R.sup.8 may be a biomolecule, a
linking group optionally joined to a biomolecule, a linear or
branched C.sub.1-C.sub.15 alkyl group, or a C.sub.3-C.sub.18
cycloalkyl group, wherein each of the C.sub.1-C.sub.15 alkyl group
and the C.sub.3-C.sub.18 cycloalkyl group may be substituted with
at least one substituent that may be a biomolecule and may be
optionally intercepted with at least one heteroatom selected from
the group consisting of O, S, N and P; and each of the
C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18 cycloalkyl
group may be joined to the carbon atom of --C.ident.CR.sup.8
through a carbon atom. In various embodiments, R.sup.8 may be a
linear or branched C.sub.1-C.sub.15 alkyl group or a
C.sub.3-C.sub.18 cycloalkyl group, wherein each of the
C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18 cycloalkyl
group may be substituted with at least one substituent that may be
a biomolecule and may be optionally intercepted with at least one
heteroatom selected from the group consisting of O, S, N and P; and
each of the C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18
cycloalkyl group may be joined to the carbon atom of
--C.ident.CR.sup.8 through a carbon atom. In various embodiments,
R.sup.8 may be a biomolecule or a linking group optionally joined
to a biomolecule. In various embodiments, the C.sub.1-C.sub.15
alkyl group may be a C.sub.1-C.sub.6 alkyl group. In various
embodiments, the C.sub.3-C.sub.18 cycloalkyl group may be a
C.sub.4-C.sub.8 cycloalkyl group.
[0152] In an embodiment, the compound may be of the formula
(IV):
##STR00037##
wherein Q.sup.1 may be
##STR00038##
and R.sup.9 may be as defined anywhere herein.
[0153] In various embodiments, R.sup.9 may be
--NR.sup.38R.sup.39,
##STR00039##
a biomolecule, a linking group optionally joined to a biomolecule,
a linear or branched C.sub.1-C.sub.15 alkyl group, or a
C.sub.3-C.sub.18 cycloalkyl group, wherein each of the
C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18 cycloalkyl
group may be substituted with at least one substituent that may be
a biomolecule and may be optionally intercepted with at least one
heteroatom selected from the group consisting of O, S, N and P;
each of the C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18
cycloalkyl group may be joined to the carbon atom of
##STR00040##
through a carbon atom; each of R.sup.38, R.sup.39, and R.sup.40 may
be as defined anywhere herein; and at least one of R.sup.9,
R.sup.38, R.sup.39, and R.sup.40 may be a biomolecule, a linking
group optionally joined to a biomolecule, or a group that may be
substituted with at least one substituent that may be a
biomolecule. In various embodiments, the C.sub.1-C.sub.15 alkyl
group may be a C.sub.1-C.sub.6 alkyl group. In various embodiments,
the C.sub.3-C.sub.18 cycloalkyl group may be a C.sub.4-C.sub.8
cycloalkyl group.
[0154] In various embodiments, R.sup.9 may be --NR.sup.38R.sup.39;
each of R.sup.38 and R.sup.39 may independently be H, D, a
biomolecule, a linking group optionally joined to a biomolecule, a
linear or branched C.sub.1-C.sub.15 alkyl group, or a
C.sub.3-C.sub.18 cycloalkyl group, wherein each of the
C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18 cycloalkyl
group may be unsubstituted or substituted and may be optionally
intercepted with at least one heteroatom selected from the group
consisting of O, S, N and P; each of the C.sub.1-C.sub.15 alkyl
group and the C.sub.3-C.sub.18 cycloalkyl group may be joined to
the nitrogen atom of --NR.sup.38R.sup.39 through a carbon atom; and
at least one of R.sup.38 and R.sup.39 may be a biomolecule, a
linking group optionally joined to a biomolecule, or a group that
may be substituted with at least one substituent that may be a
biomolecule. In various embodiments, the C.sub.1-C.sub.15 alkyl
group may be a C.sub.1-C.sub.6 alkyl group. In various embodiments,
the C.sub.3-C.sub.18 cycloalkyl group may be a C.sub.4-C.sub.8
cycloalkyl group.
[0155] In an embodiment, R.sup.9 may be
##STR00041##
and R.sup.40 may be a biomolecule, a linking group optionally
joined to a biomolecule, a linear or branched C.sub.1-C.sub.15
alkyl group, or a C.sub.3-C.sub.18 cycloalkyl group, wherein each
of the C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18
cycloalkyl group may be substituted with at least one substituent
that may be a biomolecule and may be optionally intercepted with at
least one heteroatom selected from the group consisting of O, S, N
and P; and each of the C.sub.1-C.sub.15 alkyl group and the
C.sub.3-C.sub.18 cycloalkyl group may be joined to the carbon atom
of
##STR00042##
through a carbon atom. In various embodiments, the C.sub.1-C.sub.15
alkyl group may be a C.sub.1-C.sub.6 alkyl group. In various
embodiments, the C.sub.3-C.sub.18 cycloalkyl group may be a
C.sub.4-C.sub.8 cycloalkyl group.
[0156] In various embodiments, R.sup.9 may be a biomolecule, a
linking group optionally joined to a biomolecule, a linear or
branched C.sub.1-C.sub.15 alkyl group, or a C.sub.3-C.sub.18
cycloalkyl group, wherein each of the C.sub.1-C.sub.15 alkyl group
and the C.sub.3-C.sub.18 cycloalkyl group may be substituted with
at least one substituent that may be a biomolecule and may be
optionally intercepted with at least one heteroatom selected from
the group consisting of O, S, N and P; and each of the
C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18 cycloalkyl
group may be joined to the carbon atom of
##STR00043##
through a carbon atom. In an embodiment, R.sup.9 may be a linear or
branched C.sub.1-C.sub.15 alkyl group, or a C.sub.3-C.sub.18
cycloalkyl group, wherein each of the C.sub.1-C.sub.15 alkyl group
and the C.sub.3-C.sub.18 cycloalkyl group may be substituted with
at least one substituent that may be a biomolecule and may be
optionally intercepted with at least one heteroatom selected from
the group consisting of O, S, N and P; and each of the
C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18 cycloalkyl
group may be joined to the carbon atom of
##STR00044##
through a carbon atom. In an embodiment, R.sup.9 may be a
biomolecule or a linking group optionally joined to a biomolecule.
In various embodiments, the C.sub.1-C.sub.15 alkyl group may be a
C.sub.1-C.sub.6 alkyl group. In various embodiments, the
C.sub.3-C.sub.18 cycloalkyl group may be a C.sub.4-C.sub.8
cycloalkyl group.
[0157] In various embodiments, the compound may be of the formula
(IV):
##STR00045##
wherein Q.sup.1 may be --R.sup.10C.dbd.CR.sup.11R.sup.12; and each
of R.sup.10, R.sup.11, and R.sup.12 may be as defined anywhere
herein.
[0158] In various embodiments, each of R.sup.10, R.sup.11, and
R.sup.12 may independently be H, D, F, Cl, Br, I, CX.sub.3,
--N.sup.+R.sup.41R.sup.42R.sup.43,
--P.sup.+R.sup.44R.sup.45R.sup.46, --S.sup.+R.sup.47R.sup.48, a
biomolecule, a linking group optionally joined to a biomolecule, a
linear or branched C.sub.1-C.sub.15 alkyl group, or a
C.sub.3-C.sub.18 cycloalkyl group, wherein each of the
C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18 cycloalkyl
group is unsubstituted or substituted and is optionally intercepted
with at least one heteroatom selected from the group consisting of
O, S, N and P; each of the C.sub.1-C.sub.15 alkyl group and the
C.sub.3-C.sub.18 cycloalkyl group is joined to the carbon atom of
--R.sup.10C.dbd.CR.sup.11R.sup.12 through a carbon atom, and each X
is the same or different and is F, Cl, Br, or I; each of R.sup.41,
R.sup.42, R.sup.43, R.sup.44, R.sup.45, R.sup.46, R.sup.47, and
R.sup.48 may be as defined anywhere herein; at least one of
R.sup.10, R.sup.11, and R.sup.12 may independently be F, Cl, Br, I,
CX.sub.3, --N.sup.+R.sup.41R.sup.42R.sup.43,
--P.sup.+R.sup.44R.sup.45R.sup.46, or --S.sup.+R.sup.47R.sup.48;
and at least one of R.sup.10, R.sup.11, R.sup.12, R.sup.41,
R.sup.42, R.sup.43, R.sup.44, R.sup.45, R.sup.46, R.sup.47, and
R.sup.48 may be a biomolecule, a linking group optionally joined to
a biomolecule, or a group that is substituted with at least one
substituent that may be a biomolecule, or forms a group that is
substituted with at least one substituent that is a biomolecule. In
various embodiments, at least two of R.sup.10, R.sup.11, and
R.sup.12 may independently be F, Cl, Br, I, or CX.sub.3, or at
least one of R.sup.10, R.sup.11, and R.sup.12 may be
--N.sup.+R.sup.41R.sup.42R.sup.43,
--P.sup.+R.sup.44R.sup.45R.sup.46, or --S.sup.+R.sup.47R.sup.48;
and at least one of R.sup.10, R.sup.11, R.sup.12, R.sup.41,
R.sup.42, R.sup.43, R.sup.44, R.sup.45, R.sup.46, R.sup.47, and
R.sup.48 may be a biomolecule, a linking group optionally joined to
a biomolecule, or a group that is substituted with at least one
substituent that may be a biomolecule, or forms a group that is
substituted with at least one substituent that is a biomolecule. In
various embodiments, two of R.sup.10, R.sup.11, and R.sup.12 may
independently be F, Cl, Br, I, or CX.sub.3, or one of R.sup.10,
R.sup.11, and R.sup.12 may be --N.sup.+R.sup.41R.sup.42R.sup.43,
--P.sup.+R.sup.44R.sup.45R.sup.46, or --S.sup.+R.sup.47R.sup.48;
and at least one of R.sup.10, R.sup.11, R.sup.12, R.sup.41,
R.sup.42, R.sup.43, R.sup.44, R.sup.45, R.sup.46, R.sup.47, and
R.sup.48 may be a biomolecule, a linking group optionally joined to
a biomolecule, or a group that is substituted with at least one
substituent that may be a biomolecule, or forms a group that is
substituted with at least one substituent that is a biomolecule. In
various embodiments, the C.sub.1-C.sub.15 alkyl group may be a
C.sub.1-C.sub.6 alkyl group. In various embodiments, the
C.sub.3-C.sub.18 cycloalkyl group may be a C.sub.4-C.sub.8
cycloalkyl group.
[0159] In various embodiments, each of R.sup.10, R.sup.11, and
R.sup.12 may independently be H, D, F, Cl, Br, I, CX.sub.3,
--N.sup.+R.sup.41R.sup.42R.sup.43,
--P.sup.+R.sup.44R.sup.45R.sup.46, a biomolecule, a linking group
optionally joined to a biomolecule, a linear or branched
C.sub.1-C.sub.15 alkyl group, or a C.sub.3-C.sub.18 cycloalkyl
group, wherein each of the C.sub.1-C.sub.15 alkyl group and the
C.sub.3-C.sub.18 cycloalkyl group is unsubstituted or substituted
and is optionally intercepted with at least one heteroatom selected
from the group consisting of O, S, N and P; each of the
C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18 cycloalkyl
group is joined to the carbon atom of
--R.sup.10C.dbd.CR.sup.11R.sup.12 through a carbon atom, and each X
is the same or different and is F, Cl, Br, or I; each of R.sup.41,
R.sup.42, R.sup.43, R.sup.44, R.sup.45, R.sup.46, R.sup.47, and
R.sup.48 may be as defined anywhere herein; at least one of
R.sup.10, R.sup.11, and R.sup.12 may independently be F, Cl, Br, I,
CX.sub.3, --N.sup.+R.sup.41R.sup.42R.sup.43, or
--P.sup.+R.sup.44R.sup.45R.sup.46; and at least one of R.sup.10,
R.sup.11, R.sup.12, R.sup.41, R.sup.42, R.sup.43, R.sup.44,
R.sup.45, and R.sup.46 may be a biomolecule, a linking group
optionally joined to a biomolecule, or a group that is substituted
with at least one substituent that may be a biomolecule, or forms a
group that is substituted with at least one substituent that is a
biomolecule. In various embodiments, at least two of R.sup.10,
R.sup.11, and R.sup.12 may independently be F, Cl, Br, I, or
CX.sub.3, or at least one of R.sup.10, R.sup.11, and R.sup.12 may
be --N.sup.+R.sup.41R.sup.42R.sup.43, or
--P.sup.+R.sup.44R.sup.45R.sup.46; and at least one of R.sup.10,
R.sup.11, R.sup.12, R.sup.41, R.sup.42, R.sup.43, R.sup.44,
R.sup.45, and R.sup.46 may be a biomolecule, a linking group
optionally joined to a biomolecule, or a group that is substituted
with at least one substituent that may be a biomolecule, or forms a
group that is substituted with at least one substituent that is a
biomolecule. In various embodiments, two of R.sup.10, R.sup.11 and
R.sup.12 may independently be F, Cl, Br, I, or CX.sub.3, or one of
R.sup.10, R.sup.11 and R.sup.12 may be
--N.sup.+R.sup.41R.sup.42R.sup.43, or
--P.sup.+R.sup.44R.sup.45R.sup.46; and at least one of R.sup.10,
R.sup.11, R.sup.12, R.sup.41, R.sup.42, R.sup.43, R.sup.44,
R.sup.45, and R.sup.46 may be a biomolecule, a linking group
optionally joined to a biomolecule, or a group that is substituted
with at least one substituent that may be a biomolecule, or forms a
group that is substituted with at least one substituent that is a
biomolecule. In various embodiments, the C.sub.1-C.sub.15 alkyl
group may be a C.sub.1-C.sub.6 alkyl group. In various embodiments,
the C.sub.3-C.sub.18 cycloalkyl group may be a C.sub.4-C.sub.8
cycloalkyl group.
[0160] In various embodiments, each of R.sup.10, R.sup.11 and
R.sup.12 may independently be H, D, F, Cl, Br, I, CX.sub.3,
--N.sup.+R.sup.41R.sup.42R.sup.43, --S.sup.+R.sup.47R.sup.48, a
biomolecule, a linking group optionally joined to a biomolecule, a
linear or branched C.sub.1-C.sub.15 alkyl group, or a
C.sub.3-C.sub.18 cycloalkyl group, wherein each of the
C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18 cycloalkyl
group is unsubstituted or substituted and is optionally intercepted
with at least one heteroatom selected from the group consisting of
O, S, N and P; each of the C.sub.1-C.sub.15 alkyl group and the
C.sub.3-C.sub.18 cycloalkyl group is joined to the carbon atom of
--R.sup.10C.dbd.CR.sup.11R.sup.12 through a carbon atom, and each X
is the same or different and is F, Cl, Br, or I; each of R.sup.41,
R.sup.42, R.sup.43, R.sup.47, and R.sup.48 may be as defined
anywhere herein; at least one of R.sup.10, R.sup.11 and R.sup.12
may independently be F, Cl, Br, I, CX.sub.3,
--N.sup.+R.sup.41R.sup.42R.sup.43, or --S.sup.+R.sup.47R.sup.48;
and at least one of R.sup.10, R.sup.11, R.sup.12, R.sup.41,
R.sup.42, R.sup.43, R.sup.47, and R.sup.48 may be a biomolecule, a
linking group optionally joined to a biomolecule, or a group that
is substituted with at least one substituent that may be a
biomolecule, or forms a group that is substituted with at least one
substituent that is a biomolecule. In various embodiments, at least
two of R.sup.10, R.sup.11, and R.sup.12 may independently be F, Cl,
Br, I, or CX.sub.3, or at least one of R.sup.10, R.sup.11 and
R.sup.12 may be --N.sup.+R.sup.41R.sup.42R.sup.43 or
--S.sup.+R.sup.47R.sup.48; and at least one of R.sup.10, R.sup.11,
R.sup.1, R.sup.41, R.sup.42, R.sup.43, R.sup.47, and R.sup.48 may
be a biomolecule, a linking group optionally joined to a
biomolecule, or a group that is substituted with at least one
substituent that may be a biomolecule, or forms a group that is
substituted with at least one substituent that is a biomolecule. In
various embodiments, two of R.sup.10, R.sup.11, and R.sup.12 may
independently be F, Cl, Br, I, or CX.sub.3, or one of R.sup.10,
R.sup.11, and R.sup.12 may be --N.sup.+R.sup.41R.sup.42R.sup.43 or
--S.sup.+R.sup.47R.sup.48; and at least one of R.sup.10, R.sup.11,
R.sup.1, R.sup.41, R.sup.42, R.sup.43, R.sup.47, and R.sup.48 may
be a biomolecule, a linking group optionally joined to a
biomolecule, or a group that is substituted with at least one
substituent that may be a biomolecule, or forms a group that is
substituted with at least one substituent that is a biomolecule. In
various embodiments, the C.sub.1-C.sub.15 alkyl group may be a
C.sub.1-C.sub.6 alkyl group. In various embodiments, the
C.sub.3-C.sub.18 cycloalkyl group may be a C.sub.4-C.sub.8
cycloalkyl group.
[0161] In various embodiments, each of R.sup.10, R.sup.11, and
R.sup.12 may independently be H, D, F, Cl, Br, I, CX.sub.3,
--P.sup.+R.sup.44R.sup.45R.sup.46, --S.sup.+R.sup.47R.sup.48, a
biomolecule, a linking group optionally joined to a biomolecule, a
linear or branched C.sub.1-C.sub.15 alkyl group, or a
C.sub.3-C.sub.18 cycloalkyl group, wherein each of the
C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18 cycloalkyl
group is unsubstituted or substituted and is optionally intercepted
with at least one heteroatom selected from the group consisting of
O, S, N and P; each of the C.sub.1-C.sub.15 alkyl group and the
C.sub.3-C.sub.18 cycloalkyl group is joined to the carbon atom of
--R.sup.10C.dbd.CR.sup.11R.sup.12 through a carbon atom, and each X
is the same or different and is F, Cl, Br, or I; each of R.sup.44,
R.sup.45, R.sup.46, R.sup.47, and R.sup.48 may be as defined
anywhere herein; at least one of R.sup.10, R.sup.11, and R.sup.12
may independently be F, Cl, Br, I, CX.sub.3,
--P.sup.+R.sup.44R.sup.45R.sup.46, or --S.sup.+R.sup.47R.sup.48;
and at least one of R.sup.10, R.sup.11, R.sup.12, R.sup.44,
R.sup.45, R.sup.46, R.sup.47, and R.sup.48 may be a biomolecule, a
linking group optionally joined to a biomolecule, or a group that
is substituted with at least one substituent that may be a
biomolecule, or forms a group that is substituted with at least one
substituent that is a biomolecule. In various embodiments, at least
two of R.sup.10, R.sup.11, and R.sup.12 may independently be F, Cl,
Br, I, or CX.sub.3, or at least one of R.sup.10, R.sup.11, and
R.sup.12 may be --P.sup.+R.sup.44R.sup.45R.sup.46 or
--S.sup.+R.sup.47R.sup.48; and at least one of R.sup.10, R.sup.11,
R.sup.12, R.sup.44, R.sup.45, R.sup.46, R.sup.47, and R.sup.48 may
be a biomolecule, a linking group optionally joined to a
biomolecule, or a group that is substituted with at least one
substituent that may be a biomolecule, or forms a group that is
substituted with at least one substituent that is a biomolecule. In
various embodiments, two of R.sup.10, R.sup.11, and R.sup.12 may
independently be F, Cl, Br, I, or CX.sub.3, or one of R.sup.10,
R.sup.11, and R.sup.12 may be --P.sup.+R.sup.44R.sup.45R.sup.46 or
--S.sup.+R.sup.47R.sup.48; and at least one of R.sup.10, R.sup.11,
R.sup.12, R.sup.44, R.sup.45, R.sup.46, R.sup.47, and R.sup.48 may
be a biomolecule, a linking group optionally joined to a
biomolecule, or a group that is substituted with at least one
substituent that may be a biomolecule, or forms a group that is
substituted with at least one substituent that is a biomolecule. In
various embodiments, the C.sub.1-C.sub.15 alkyl group may be a
C.sub.1-C.sub.6 alkyl group. In various embodiments, the
C.sub.3-C.sub.18 cycloalkyl group may be a C.sub.4-C.sub.8
cycloalkyl group.
[0162] In various embodiments, each of R.sup.10, R.sup.11, and
R.sup.12 may independently be H, D,
--N.sup.+R.sup.41R.sup.42R.sup.43,
--P.sup.+R.sup.44R.sup.45R.sup.46, --S.sup.+R.sup.47R.sup.48, a
biomolecule, a linking group optionally joined to a biomolecule, a
linear or branched C.sub.1-C.sub.15 alkyl group, or a
C.sub.3-C.sub.18 cycloalkyl group, wherein each of the
C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18 cycloalkyl
group is unsubstituted or substituted and is optionally intercepted
with at least one heteroatom selected from the group consisting of
O, S, N and P; each of the C.sub.1-C.sub.15 alkyl group and the
C.sub.3-C.sub.18 cycloalkyl group is joined to the carbon atom of
--R.sup.10C.dbd.CR.sup.11R.sup.12 through a carbon atom; each of
R.sup.41, R.sup.42, R.sup.43, R.sup.44, R.sup.45, R.sup.46,
R.sup.47, and R.sup.48 may be as defined anywhere herein; at least
one of R.sup.10, R.sup.11, and R.sup.12 may independently be
--N.sup.+R.sup.41R.sup.42R.sup.43,
--P.sup.+R.sup.44R.sup.45R.sup.46, or --S.sup.+R.sup.47R.sup.48;
and at least one of R.sup.10, R.sup.11, R.sup.12, R.sup.41,
R.sup.42, R.sup.43, R.sup.44, R.sup.45, R.sup.46, R.sup.47, and
R.sup.48 may be a biomolecule, a linking group optionally joined to
a biomolecule, or a group that is substituted with at least one
substituent that may be a biomolecule, or forms a group that is
substituted with at least one substituent that is a biomolecule. In
various embodiments, one of R.sup.10, R.sup.11, and R.sup.12 may be
--N.sup.+R.sup.41R.sup.42R.sup.43,
--P.sup.+R.sup.44R.sup.45R.sup.46, or --S.sup.+R.sup.47R.sup.48;
and at least one of R.sup.10, R.sup.11, R.sup.12, R.sup.41,
R.sup.42, R.sup.43, R.sup.44, R.sup.45, R.sup.46, R.sup.47, and
R.sup.48 may be a biomolecule, a linking group optionally joined to
a biomolecule, or a group that is substituted with at least one
substituent that may be a biomolecule, or forms a group that is
substituted with at least one substituent that is a biomolecule. In
various embodiments, the C.sub.1-C.sub.15 alkyl group may be a
C.sub.1-C.sub.6 alkyl group. In various embodiments, the
C.sub.3-C.sub.18 cycloalkyl group may be a C.sub.4-C.sub.8
cycloalkyl group.
[0163] In various embodiments, each of R.sup.10, R.sup.11, and
R.sup.12 may independently be H, D, F, Cl, Br, I, CX.sub.3,
--N.sup.+R.sup.41R.sup.42R.sup.43, a biomolecule, a linking group
optionally joined to a biomolecule, a linear or branched
C.sub.1-C.sub.15 alkyl group, or a C.sub.3-C.sub.18 cycloalkyl
group, wherein each of the C.sub.1-C.sub.15 alkyl group and the
C.sub.3-C.sub.18 cycloalkyl group is unsubstituted or substituted
and is optionally intercepted with at least one heteroatom selected
from the group consisting of O, S, N and P; each of the
C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18 cycloalkyl
group is joined to the carbon atom of
--R.sup.10C.dbd.CR.sup.11R.sup.12 through a carbon atom, and each X
is the same or different and is F, Cl, Br, or I; each of R.sup.41,
R.sup.42, and R.sup.43 may be as defined anywhere herein; at least
one of R.sup.10, R.sup.11, and R.sup.12 may independently be F, Cl,
Br, I, CX.sub.3, or --N.sup.+R.sup.41R.sup.42R.sup.43; and at least
one of R.sup.10, R.sup.11, R.sup.12, R.sup.41, R.sup.42, and
R.sup.43 may be a biomolecule, a linking group optionally joined to
a biomolecule, or a group that is substituted with at least one
substituent that may be a biomolecule, or forms a group that is
substituted with at least one substituent that is a biomolecule. In
various embodiments, at least two of R.sup.10, R.sup.11, and
R.sup.12 may independently be F, Cl, Br, I, or CX.sub.3, or at
least one of R.sup.10, R.sup.11, and R.sup.12 may be
--N.sup.+R.sup.41R.sup.42R.sup.43; and at least one of R.sup.10,
R.sup.11, R.sup.12, R.sup.41, R.sup.42, and R.sup.43 may be a
biomolecule, a linking group optionally joined to a biomolecule, or
a group that is substituted with at least one substituent that may
be a biomolecule, or forms a group that is substituted with at
least one substituent that is a biomolecule. In various
embodiments, two of R.sup.10, R.sup.11, and R.sup.12 may
independently be F, Cl, Br, I, or CX.sub.3, or one of R.sup.10,
R.sup.11, and R.sup.12 may be --N.sup.+R.sup.41R.sup.42R.sup.43;
and at least one of R.sup.10, R.sup.11, R.sup.12, R.sup.41,
R.sup.42, and R.sup.43 may be a biomolecule, a linking group
optionally joined to a biomolecule, or a group that is substituted
with at least one substituent that may be a biomolecule, or forms a
group that is substituted with at least one substituent that is a
biomolecule. In various embodiments, the C.sub.1-C.sub.15 alkyl
group may be a C.sub.1-C.sub.6 alkyl group. In various embodiments,
the C.sub.3-C.sub.18 cycloalkyl group may be a C.sub.4-C.sub.8
cycloalkyl group.
[0164] In various embodiments, each of R.sup.10, R.sup.11, and
R.sup.12 may independently be H, D, F, Cl, Br, I, CX.sub.3,
--P.sup.+R.sup.44R.sup.45R.sup.46, a biomolecule, a linking group
optionally joined to a biomolecule, a linear or branched
C.sub.1-C.sub.15 alkyl group, or a C.sub.3-C.sub.18 cycloalkyl
group, wherein each of the C.sub.1-C.sub.15 alkyl group and the
C.sub.3-C.sub.18 cycloalkyl group is unsubstituted or substituted
and is optionally intercepted with at least one heteroatom selected
from the group consisting of O, S, N and P; each of the
C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18 cycloalkyl
group is joined to the carbon atom of
--R.sup.10C.dbd.CR.sup.11R.sup.12 through a carbon atom, and each X
is the same or different and is F, Cl, Br, or I; each of R.sup.44,
R.sup.45, and R.sup.46 may be as defined anywhere herein; at least
one of R.sup.10, R.sup.11, and R.sup.12 may independently be F, Cl,
Br, I, CX.sub.3, or --P.sup.+R.sup.44R.sup.45R.sup.46; and at least
one of R.sup.10, R.sup.11, R.sup.12, R.sup.44, R.sup.45, and
R.sup.46 may be a biomolecule, a linking group optionally joined to
a biomolecule, or a group that is substituted with at least one
substituent that may be a biomolecule. In various embodiments, at
least two of R.sup.10, R.sup.11, and R.sup.12 may independently be
F, Cl, Br, I, or CX.sub.3, or at least one of R.sup.10, R.sup.11,
and R.sup.12 may be --P.sup.+R.sup.44R.sup.45R.sup.46; and at least
one of R.sup.10, R.sup.11, R.sup.12, R.sup.44, R.sup.45, and
R.sup.46 may be a biomolecule, a linking group optionally joined to
a biomolecule, or a group that is substituted with at least one
substituent that may be a biomolecule. In various embodiments, two
of R.sup.10, R.sup.11, and R.sup.12 may independently be F, Cl, Br,
I, or CX.sub.3, or one of R.sup.10, R.sup.11, and R.sup.12 may be
--P.sup.+R.sup.44R.sup.45R.sup.46; and at least one of R.sup.10,
R.sup.11, R.sup.12, R.sup.44, R.sup.45, and R.sup.46 may be a
biomolecule, a linking group optionally joined to a biomolecule, or
a group that is substituted with at least one substituent that may
be a biomolecule. In various embodiments, the C.sub.1-C.sub.15
alkyl group may be a C.sub.1-C.sub.6 alkyl group. In various
embodiments, the C.sub.3-C.sub.18 cycloalkyl group may be a
C.sub.4-C.sub.8 cycloalkyl group.
[0165] In various embodiments, each of R.sup.10, R.sup.11, and
R.sup.12 may independently be H, D, F, Cl, Br, I, CX.sub.3,
--S.sup.+R.sup.47R.sup.48, a biomolecule, a linking group
optionally joined to a biomolecule, a linear or branched
C.sub.1-C.sub.15 alkyl group, or a C.sub.3-C.sub.18 cycloalkyl
group, wherein each of the C.sub.1-C.sub.15 alkyl group and the
C.sub.3-C.sub.18 cycloalkyl group is unsubstituted or substituted
and is optionally intercepted with at least one heteroatom selected
from the group consisting of O, S, N and P; each of the
C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18 cycloalkyl
group is joined to the carbon atom of
--R.sup.10C.dbd.CR.sup.11R.sup.12 through a carbon atom, and each X
is the same or different and is F, Cl, Br, or I; each of R.sup.47
and R.sup.48 may be as defined anywhere herein; at least one of
R.sup.10, R.sup.11, and R.sup.12 may independently be F, Cl, Br, I,
CX.sub.3, or --S.sup.+R.sup.47R.sup.48; and at least one of
R.sup.10, R.sup.11, R.sup.12, R.sup.47, and R.sup.48 may be a
biomolecule, a linking group optionally joined to a biomolecule, or
a group that is substituted with at least one substituent that may
be a biomolecule. In various embodiments, at least two of R.sup.10,
R.sup.11, and R.sup.12 may independently be F, Cl, Br, I, or
CX.sub.3, or at least one of R.sup.10, R.sup.11, and R.sup.12 may
be --S.sup.+R.sup.47R.sup.48; and at least one of R.sup.10,
R.sup.11, R.sup.12, R.sup.47, and R.sup.48 may be a biomolecule, a
linking group optionally joined to a biomolecule, or a group that
is substituted with at least one substituent that may be a
biomolecule. In various embodiments, at two of R.sup.10, R.sup.11,
and R.sup.12 may independently be F, Cl, Br, I, or CX.sub.3, or one
of R.sup.10, R.sup.11, and R.sup.12 may be
--S.sup.+R.sup.47R.sup.48; and at least one of R.sup.10, R.sup.11,
R.sup.12, R.sup.47, and R.sup.48 may be a biomolecule, a linking
group optionally joined to a biomolecule, or a group that is
substituted with at least one substituent that may be a
biomolecule. In various embodiments, the C.sub.1-C.sub.15 alkyl
group may be a C.sub.1-C.sub.6 alkyl group. In various embodiments,
the C.sub.3-C.sub.18 cycloalkyl group may be a C.sub.4-C.sub.8
cycloalkyl group.
[0166] In various embodiments, each of R.sup.10, R.sup.11, and
R.sup.12 may independently be H, D,
--N.sup.+R.sup.41R.sup.42R.sup.43,
--P.sup.+R.sup.44R.sup.45R.sup.46, a biomolecule, a linking group
optionally joined to a biomolecule, a linear or branched
C.sub.1-C.sub.15 alkyl group, or a C.sub.3-C.sub.18 cycloalkyl
group, wherein each of the C.sub.1-C.sub.15 alkyl group and the
C.sub.3-C.sub.18 cycloalkyl group is unsubstituted or substituted
and is optionally intercepted with at least one heteroatom selected
from the group consisting of O, S, N and P; each of the
C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18 cycloalkyl
group is joined to the carbon atom of
--R.sup.10C.dbd.CR.sup.11R.sup.12 through a carbon atom; each of
R.sup.41, R.sup.42, R.sup.43, R.sup.44, R.sup.45, and R.sup.46 may
be as defined anywhere herein; at least one of R.sup.10, R.sup.11,
and R.sup.12 may independently be --N.sup.+R.sup.41R.sup.42R.sup.43
or --P.sup.+R.sup.44R.sup.45R.sup.46; and at least one of R.sup.10,
R.sup.11, R.sup.12, R.sup.41, R.sup.42, R.sup.43, R.sup.44,
R.sup.45, and R.sup.46 may be a biomolecule, a linking group
optionally joined to a biomolecule, or a group that is substituted
with at least one substituent that may be a biomolecule, or forms a
group that is substituted with at least one substituent that is a
biomolecule. In various embodiments, one of R.sup.10, R.sup.11, and
R.sup.12 may be --N.sup.+R.sup.41R.sup.42R.sup.43 or
--P.sup.+R.sup.44R.sup.45R.sup.46; and at least one of R.sup.10,
R.sup.11, R.sup.12, R.sup.41, R.sup.42, R.sup.43, R.sup.44,
R.sup.45, and R.sup.46 may be a biomolecule, a linking group
optionally joined to a biomolecule, or a group that is substituted
with at least one substituent that may be a biomolecule, or forms a
group that is substituted with at least one substituent that is a
biomolecule. In various embodiments, the C.sub.1-C.sub.15 alkyl
group may be a C.sub.1-C.sub.6 alkyl group. In various embodiments,
the C.sub.3-C.sub.18 cycloalkyl group may be a C.sub.4-C.sub.8
cycloalkyl group.
[0167] In various embodiments, each of R.sup.10, R.sup.11, and
R.sup.12 may independently be H, D,
--N.sup.+R.sup.41R.sup.42R.sup.43, --S.sup.+R.sup.47R.sup.48, a
biomolecule, a linking group optionally joined to a biomolecule, a
linear or branched C.sub.1-C.sub.15 alkyl group, or a
C.sub.3-C.sub.18 cycloalkyl group, wherein each of the
C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18 cycloalkyl
group is unsubstituted or substituted and is optionally intercepted
with at least one heteroatom selected from the group consisting of
O, S, N and P; each of the C.sub.1-C.sub.15 alkyl group and the
C.sub.3-C.sub.18 cycloalkyl group is joined to the carbon atom of
--R.sup.10C.dbd.CR.sup.11R.sup.12 through a carbon atom; each of
R.sup.41, R.sup.42, R.sup.43, R.sup.47, and R.sup.48 may be as
defined anywhere herein; at least one of R.sup.10, R.sup.11, and
R.sup.12 may independently be --N.sup.+R.sup.41R.sup.42R.sup.43 or
--S.sup.+R.sup.47R.sup.48; and at least one of R.sup.10, R.sup.11,
R.sup.12, R.sup.41, R.sup.42, R.sup.43, R.sup.47, and R.sup.48 may
be a biomolecule, a linking group optionally joined to a
biomolecule, or a group that is substituted with at least one
substituent that may be a biomolecule, or forms a group that is
substituted with at least one substituent that is a biomolecule. In
various embodiments, one of R.sup.10, R.sup.11, and R.sup.12 may be
--N.sup.+R.sup.41R.sup.42R.sup.43 or --S.sup.+R.sup.47R.sup.48; and
at least one of R.sup.10, R.sup.11, R.sup.12, R.sup.41, R.sup.42,
R.sup.43, R.sup.47, and R.sup.48 may be a biomolecule, a linking
group optionally joined to a biomolecule, or a group that is
substituted with at least one substituent that may be a
biomolecule, or forms a group that is substituted with at least one
substituent that is a biomolecule. In various embodiments, the
C.sub.1-C.sub.15 alkyl group may be a C.sub.1-C.sub.6 alkyl group.
In various embodiments, the C.sub.3-C.sub.18 cycloalkyl group may
be a C.sub.4-C.sub.8 cycloalkyl group.
[0168] In various embodiments, each of R.sup.10, R.sup.11, and
R.sup.12 may independently be H, D,
--P.sup.+R.sup.44R.sup.45R.sup.46, --S.sup.+R.sup.47R.sup.48, a
biomolecule, a linking group optionally joined to a biomolecule, a
linear or branched C.sub.1-C.sub.15 alkyl group, or a
C.sub.3-C.sub.18 cycloalkyl group, wherein each of the
C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18 cycloalkyl
group is unsubstituted or substituted and is optionally intercepted
with at least one heteroatom selected from the group consisting of
O, S, N and P; each of the C.sub.1-C.sub.15 alkyl group and the
C.sub.3-C.sub.18 cycloalkyl group is joined to the carbon atom of
--R.sup.10C.dbd.CR.sup.11R.sup.12 through a carbon atom; each of
R.sup.44, R.sup.45, R.sup.46, R.sup.47, and R.sup.48 may be as
defined anywhere herein; at least one of R.sup.10, R.sup.11, and
R.sup.12 may independently be --P.sup.+R.sup.44R.sup.45R.sup.46 or
--S.sup.+R.sup.47R.sup.48; and at least one of R.sup.10, R.sup.11,
R.sup.12, R.sup.44, R.sup.45, R.sup.46, R.sup.47, and R.sup.48 may
be a biomolecule, a linking group optionally joined to a
biomolecule, or a group that is substituted with at least one
substituent that may be a biomolecule. In various embodiments, one
of R.sup.10, R.sup.11, and R.sup.12 may be
--P.sup.+R.sup.44R.sup.45R.sup.46 or --S.sup.+R.sup.47R.sup.48; and
at least one of R.sup.10, R.sup.11, R.sup.12, R.sup.44, R.sup.45,
R.sup.46, R.sup.47, and R.sup.48 may be a biomolecule, a linking
group optionally joined to a biomolecule, or a group that is
substituted with at least one substituent that may be a
biomolecule. In various embodiments, the C.sub.1-C.sub.15 alkyl
group may be a C.sub.1-C.sub.6 alkyl group. In various embodiments,
the C.sub.3-C.sub.18 cycloalkyl group may be a C.sub.4-C.sub.8
cycloalkyl group.
[0169] In various embodiments, each of R.sup.10, R.sup.11, and
R.sup.12 may independently be H, D, F, Cl, Br, I, CX.sub.3, a
biomolecule, a linking group optionally joined to a biomolecule, a
linear or branched C.sub.1-C.sub.15 alkyl group, or a
C.sub.3-C.sub.18 cycloalkyl group, wherein each of the
C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18 cycloalkyl
group is unsubstituted or substituted and is optionally intercepted
with at least one heteroatom selected from the group consisting of
O, S, N and P; each of the C.sub.1-C.sub.15 alkyl group and the
C.sub.3-C.sub.18 cycloalkyl group is joined to the carbon atom of
--R.sup.10C.dbd.CR.sup.11R.sup.12 through a carbon atom, and each X
is the same or different and is F, Cl, Br, or I; at least one of
R.sup.10, R.sup.11 and R.sup.12 may independently be F, Cl, Br, I,
or CX.sub.3; and at least one of R.sup.10, R.sup.11 and R.sup.12
may be a biomolecule, a linking group optionally joined to a
biomolecule, or a group that is substituted with at least one
substituent that may be a biomolecule. In various embodiments, two
of R.sup.10, R.sup.11 and R.sup.12 may independently be F, Cl, Br,
I, or CX.sub.3; and one of R.sup.10, R.sup.11, and R.sup.12 may be
a biomolecule, a linking group optionally joined to a biomolecule,
or a group that is substituted with at least one substituent that
may be a biomolecule. In various embodiments, the C.sub.1-C.sub.15
alkyl group may be a C.sub.1-C.sub.6 alkyl group. In various
embodiments, the C.sub.3-C.sub.18 cycloalkyl group may be a
C.sub.4-C.sub.8 cycloalkyl group.
[0170] In various embodiments, each of R.sup.10, R.sup.11, and
R.sup.12 may independently be H, D,
--N.sup.+R.sup.41R.sup.42R.sup.43, a biomolecule, a linking group
optionally joined to a biomolecule, a linear or branched
C.sub.1-C.sub.15 alkyl group, or a C.sub.3-C.sub.18 cycloalkyl
group, wherein each of the C.sub.1-C.sub.15 alkyl group and the
C.sub.3-C.sub.18 cycloalkyl group is unsubstituted or substituted
and is optionally intercepted with at least one heteroatom selected
from the group consisting of O, S, N and P; each of the
C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18 cycloalkyl
group is joined to the carbon atom of
--R.sup.10C.dbd.CR.sup.11R.sup.12 through a carbon atom; each of
R.sup.41, R.sup.42, and R.sup.43 may be as defined anywhere herein;
at least one of R.sup.10, R.sup.11 and R.sup.12 may independently
be --N.sup.+R.sup.41R.sup.42R.sup.43; and at least one of R.sup.10,
R.sup.11, R.sup.12, R.sup.41, R.sup.42, and R.sup.43 may be a
biomolecule, a linking group optionally joined to a biomolecule, or
a group that is substituted with at least one substituent that may
be a biomolecule, or forms a group that is substituted with at
least one substituent that is a biomolecule. In various
embodiments, one of R.sup.10, R.sup.11, and R.sup.12 may be
--N.sup.+R.sup.41R.sup.42R.sup.43; and at least one of R.sup.10,
R.sup.11, R.sup.12, R.sup.41, R.sup.42, and R.sup.43 may be a
biomolecule, a linking group optionally joined to a biomolecule, or
a group that is substituted with at least one substituent that may
be a biomolecule, or forms a group that is substituted with at
least one substituent that is a biomolecule. In an embodiment, the
positively charged 4 to 6-membered nitrogen containing heterocyclic
group may be a pyridinium group, an imidazolium group, a pyrazinium
group, a pyrimidinium group or a pyridazinium group, each of which
may be substituted or unsubstituted. In various embodiments, the
positively charged nitrogen containing heterocyclic group may be
unsubstituted. In various embodiments, the C.sub.1-C.sub.15 alkyl
group may be a C.sub.1-C.sub.6 alkyl group. In various embodiments,
the C.sub.3-C.sub.18 cycloalkyl group may be a C.sub.4-C.sub.8
cycloalkyl group.
[0171] In various embodiments, each of R.sup.10, R.sup.11, and
R.sup.12 may independently be H, D,
--P.sup.+R.sup.44R.sup.45R.sup.46, a biomolecule, a linking group
optionally joined to a biomolecule, a linear or branched
C.sub.1-C.sub.15 alkyl group, or a C.sub.3-C.sub.18 cycloalkyl
group, wherein each of the C.sub.1-C.sub.15 alkyl group and the
C.sub.3-C.sub.18 cycloalkyl group is unsubstituted or substituted
and is optionally intercepted with at least one heteroatom selected
from the group consisting of O, S, N and P; each of the
C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18 cycloalkyl
group is joined to the carbon atom of
--R.sup.10C.dbd.CR.sup.11R.sup.12 through a carbon atom; each of
R.sup.44, R.sup.45, and R.sup.46 may be as defined anywhere herein;
at least one of R.sup.10, R.sup.11, and R.sup.12 may independently
be --P.sup.+R.sup.44R.sup.45R.sup.46; and at least one of R.sup.10,
R.sup.11, R.sup.12, R.sup.44, R.sup.45, and R.sup.46 may be a
biomolecule, a linking group optionally joined to a biomolecule, or
a group that is substituted with at least one substituent that may
be a biomolecule. In various embodiments, one of R.sup.10,
R.sup.11, and R.sup.12 may be --P.sup.+R.sup.44R.sup.45R.sup.46;
and at least one of R.sup.10, R.sup.11, R.sup.12, R.sup.44,
R.sup.45, and R.sup.46 may be a biomolecule, a linking group
optionally joined to a biomolecule, or a group that is substituted
with at least one substituent that may be a biomolecule. In various
embodiments, the C.sub.1-C.sub.15 alkyl group may be a
C.sub.1-C.sub.6 alkyl group. In various embodiments, the
C.sub.3-C.sub.18 cycloalkyl group may be a C.sub.4-C.sub.8
cycloalkyl group.
[0172] In various embodiments, each of R.sup.10, R.sup.11, and
R.sup.12 may independently be H, D, --S.sup.+R.sup.47R.sup.48, a
biomolecule, a linking group optionally joined to a biomolecule, a
linear or branched C.sub.1-C.sub.15 alkyl group, or a
C.sub.3-C.sub.18 cycloalkyl group, wherein each of the
C.sub.1-C.sub.15 alkyl group and the C.sub.3-C.sub.18 cycloalkyl
group is unsubstituted or substituted and is optionally intercepted
with at least one heteroatom selected from the group consisting of
O, S, N and P; each of the C.sub.1-C.sub.15 alkyl group and the
C.sub.3-C.sub.18 cycloalkyl group is joined to the carbon atom of
--R.sup.10C.dbd.CR.sup.11R.sup.12 through a carbon atom; each of
R.sup.47 and R.sup.48 may be as defined anywhere herein; at least
one of R.sup.10, R.sup.11, and R.sup.12 may independently be
--S.sup.+R.sup.47R.sup.48; and at least one of R.sup.10, R.sup.11,
R.sup.12, R.sup.47, and R.sup.48 may be a biomolecule, a linking
group optionally joined to a biomolecule, or a group that is
substituted with at least one substituent that may be a
biomolecule. In various embodiments, one of R.sup.10, R.sup.11, and
R.sup.12 may be --S.sup.+R.sup.47R.sup.48; and at least one of
R.sup.10, R.sup.11, R.sup.12, R.sup.47, and R.sup.48 may be a
biomolecule, a linking group optionally joined to a biomolecule, or
a group that is substituted with at least one substituent that may
be a biomolecule. In various embodiments, the C.sub.1-C.sub.15
alkyl group may be a C.sub.1-C.sub.6 alkyl group. In various
embodiments, the C.sub.3-C.sub.18 cycloalkyl group may be a
C.sub.4-C.sub.8 cycloalkyl group.
[0173] The term `biomolecule` as used herein refers to a
biomolecule, or analog or derivative of a biomolecule, or other
molecule that may be delivered into a human or animal in order to
track or image distribution of the biomolecule within a human or
animal body or tissue via positron emission tomography. Examples
are disclosed in WO 2005/077967. In some embodiments, a
`biomolecule` refers to any molecule of medical, physiological or
scientific significance, analog or derivative thereof that may be
compatible with a biological system or which possesses biological
activity. Biomolecules may be delivered into a human or animal and
include biomolecules that become localized at particular places in
the organism. Examples include sugars, amino acids, nucleic acids,
nucleotides, nucleosides, peptide hormones (steroid and
nonsteroid), antibodies, aptamers and oligonucleotides, proteins,
peptides, oligonucleotides, lipids, hormones, drugs (synthetic
drugs and natural products), polysaccharides, liposomes, micelles,
microsomes, magnetic particles, metal chelators,
oligoribonucleotides, oligonucleotides and related analogs bearing
modifications in the backbone, nucleobase, or phosphate linker
regions that enhance stability or modulate specificity,
peptidomimetics, dendrimers, drug delivery agents, nanotubes,
fullerenes, virus particles, and other targeting molecules (e.g.
cancer targeting molecules). Specific examples include, but are not
limited to, biotin, matrix mettaloprotease inhibitors such as
marimastat, insulin, somatostatin, somatotropin, somatomedin,
adrenocorticotropic hormone, parathormone, follicle stimulating
hormone, luteinizing hormone, epidermal growth factor, thyroid
stimulating hormone, thyroid stimulating hormone releasing hormone,
luteinizing hormone releasing hormone, vasopressin, bombesin,
endothelin, gonadotropins, gonadotropin releasing hormone,
antiflamin I&II, NLE-antiflamin II, brain natriureitic peptide,
calcitonin, corticotropin releasing peptide, oxytocin, calpain
inhibitor peptide, alpha-CGRP, corticotropin releasing factor,
galanin, growth hormone releasing factor, guanylin, alpha-helical
corticotropin releasing factor, laminin, alpha-melanocyte
stimulating hormone, platelet derived growth factor, neuromedin,
neurotensin, pancreatic polypeptide, pentagastrin, peptide-YY,
pituitary adenylate cyclase activating peptide, secretin,
thyrotropin releasing hormone, urocortin, vasoactive intestinal
peptide, vasopressin, vascular endothelial growth factor, apamin,
bungarotoxin, calciceptin, charybdotoxin, cobrotoxin, conotoxin,
dendrotoxin, melittin, neuropeptide-Y, imperatoxin, taycatoxin,
annexin, inhibin, insulin-like growth factor, prolactin, melanin
stimulating hormone, melanin concentrating hormone, substance-P,
tachykinin, angiotensin, antibodies of general structural classes
of IgG, IgM, IgE, IgA, as well as single-chain, monoclonal, and
recombinant forms used for current and anticipated imaging,
diagnostic, and therapeutic applications. Specific targets that can
be recognized by antibodies comprise without limitation: melanoma
cell, melanoma specific antigen, myelin basic protein, breast
cancer specific tumor markers such as Her2-Neu and Brc-Abl,
alpha-fetoprotein, human chorionic gonadotropin, prostate specific
antigen, prostate specific membrane antigen, epidermal growth
factor receptors, fibroblast growth factor receptor, insulin
receptor. Other examples are antibodies approved for use in therapy
such as Herceptin.TM. (Amgen), Erbitux.TM. (Imelone). Polymers
containing nucleobases and nucleotides including RNA, DNA, and PNAs
and various synthetic derivatives thereof that reflect modification
of the sugar, internucleoside linkage (backbone) and nucleobase
portions are also contemplated. Oligonucleotides that can be used
for imaging, for example: antisense oligonucleotides that target
mRNA of genes implicated in the disease state, siRNA or RNAi
molecules that target mRNA via RNA silencing, and aptamer
structures which represent a diverse class of folded nucleic acid
structures that target protein or glycoforms of proteins or both,
or folded RNA structures. Further examples are aptamers approved
for clinical use or those intended for clinical and diagnostic use
such as Macugen.TM. (Eyetech) and aptamers that are used in the
context of surface arrayed aptamers for diagnostic purposes,
oligosaccharides of both synthetic and natural origin that are
found on the surface of cellular receptors or can mimic the
glycoforms of cellular receptors and proteins. Other saccharide
components in synthetic glycoforms are sialic acid, mannose,
fucose, N-acetyl-glucosamine, N-acetyl-mannosamine, maltose,
galactose and N-acetyl-galactosamine, small to mid-size molecular
weight ligands for proteins comprise various classes of compounds,
for example: porphyrins, lectins, lipids, steroids, barbiturates,
taxanes, terpenes, terpenoids, canabinoids, opioids, nucleosides,
purines, pyrimidines, heteroaromatics, quinolines, biogenic amines,
amino acids, indole-alkaloids, topane alkaloids, statins, enzyme
inhibitors, nonsteroidal anti-inflammatory agents, monosaccharides,
folates, derivatives of folate, methotrexate, derivatives of
methotrexate, trexates, vitamins, growth hormone, VEGF, EGF, an
antibody, a breast cancer antigen specific antibody, a prostate
cancer antigen specific antibody, a melanoma antigen specific
antibody, a ligand, a RGD-motif ligand recognizing a matrix
metalloprotease, an aptamer, an aptamer recognizing a cell surface
protein, folic acid, a folic acid derivative and a methotrexate.
Tracer molecules used in this invention may be conjugated to a
ligand such as a biomolecule that preferentially interacts with a
tissue type or cell type of interest. In some embodiments, a
precursor substituted alkyl-boronic acid may be pre-conjugated to a
biomolecule of interest and subsequently fluoridated when needed in
a one-step aqueous fluoridation reaction. A typical reaction may
occur in a buffered solution of KHF.sub.2 where the .sup.18F may be
generated in carrier free form and supplemented with carrier
.sup.19F either at the time of fluoridation or during a chase
reaction, while in another typical reaction the .sup.18F will be
used in an isotope exchange reaction. In various embodiments, the
biomolecule may be a sugar, a peptide, a nucleic acid, a lipid, a
steroid, a biogenic amine or derivative or analog thereof. In
various embodiments, the biomolecule may be a hormone, a drug,
insulin, somatostatin, growth hormone, VEGF, EGF, bombesin, a
gonadotropin, gonadotropin releasing hormone, corticotropin
releasing peptide, oxytocin, corticotropin releasing factor, growth
hormone releasing factor, platelet derived growth factor,
neurotensin, urocortin, vasoactive intestinal peptide, inhibin,
insulin-like growth factor, an antisense oligonucleotide that
targets mRNA of a gene implicated in the disease state, a siRNA or
RNAi molecule that targets mRNA via RNA silencing, an antibody, a
breast cancer antigen specific antibody, a prostate cancer antigen
specific antibody, a melanoma antigen specific antibody, a ligand,
a RGD-motif ligand recognizing a matrix metalloprotease, an
aptamer, an aptamer recognizing a cell surface protein, folic acid,
a folic acid derivative and a methotrexate or a derivative or
analog thereof.
[0174] Linking groups may include aliphatic or aromatic moieties
designed to insulate the biomolecule from the boron atom by an
appropriate distance or to ensure that appropriate atoms are
adjacent the boron atom to facilitate the fluoridation process.
Groups which facilitate subsequent addition of a biomolecule are
well known in the art and may include moieties which readily form a
bond to a selected biomolecule, a variety of such groups being
known in the art. These include thiol and amine reactive groups and
other such groups which may be useful for joining a compound of
this invention to functionalities on biomolecules including
hydroxide, carboxylic acid, amine, sulfhydryl groups, etc. Further
contemplated herein may be the joining of a compound of this
invention to a biomolecule through other linkages involving what is
known as "click chemistry" with examples that include reactions of
tetrazines with either strained alkenes or alkynes, or alkynes with
azides either by metal-mediated catalysis or strain promotion.
Alternatively, bonds other than covalent bonds are contemplated.
Thus, groups, which provide for ionic, hydrophobic and other
non-covalent linkages to a biomolecule are contemplated. Exemplary
linker groups for facilitating conjugation to a biomolecule
include:
##STR00046##
[0175] In various embodiments, n may be 1 or 2; and each Y.sup.1
may independently be selected from the group consisting of R.sup.1,
.sup.18F, and .sup.19F. In various embodiments, n may be 1 or 2.
Each Y.sup.1 may independently be selected from the group
consisting of R.sup.1, .sup.18F, and .sup.19F. In various
embodiments, n may be 2 and each Y.sup.1 may independently be
selected from the group consisting of R.sup.1, .sup.18F, and
.sup.19F. In various embodiments, n may be 2, and each Y.sup.1 may
independently be R.sup.1 or .sup.18F, each Y.sup.1 may
independently be R.sup.1 or .sup.19F, or each Y.sup.1 may
independently be .sup.18F or .sup.19F. In various embodiments, n
may be 2, and each Y.sup.1 may be R.sup.1, each Y.sup.1 may be
.sup.18F, or each Y.sup.1 may be .sup.19F. In various embodiments,
n may be 1, and Y.sup.1 may be R.sup.1, .sup.18F, or .sup.19F.
[0176] In various embodiments, R.sup.1 may be absent or present. In
an embodiment, when R.sup.1 is present, R.sup.1 may be any
non-interfering group with regard to fluoridation of B. In an
embodiment, R.sup.1 may be a linear or branched C.sub.1-C.sub.15
alkyl group or a non-aromatic C.sub.3-C.sub.18 cycloalkyl group,
wherein each of the C.sub.1-C.sub.15 alkyl group and the
non-aromatic C.sub.3-C.sub.18 cycloalkyl group is unsubstituted or
substituted and is optionally intercepted with at least one
heteroatom selected from the group consisting of O, S, N and P. In
an embodiment, the C.sub.1-C.sub.15 alkyl group or non-aromatic
C.sub.3-C.sub.18 cycloalkyl group may be intercepted with at least
one heteroatom at or near the attachment point to B. In particular
embodiments, R.sup.1 may be a linear or branched C.sub.1-C.sub.6
alkyl group or a non-aromatic C.sub.3-C.sub.8 cycloalkyl group. In
various embodiments, the C.sub.1-C.sub.15 alkyl group may be a
C.sub.1-C.sub.6 alkyl group. In various embodiments, the
non-aromatic C.sub.3-C.sub.18 cycloalkyl group may be a
C.sub.4-C.sub.8 cycloalkyl group.
[0177] In various embodiments, Y.sup.2 may independently be
selected from the group consisting of R.sup.2, .sup.18F, and
.sup.19F. In an embodiment, Y.sup.2 may independently be selected
from the group consisting of R.sup.2 and .sup.18F. In an
embodiment, Y.sup.2 may independently be selected from the group
consisting of R and .sup.19F. In an embodiment, Y.sup.2 may
independently be selected from the group consisting of .sup.18F and
.sup.19F. In various embodiments, Y.sup.2 may be R.sup.2. In
various embodiments, Y.sup.2 may be .sup.18F. In various
embodiments, Y.sup.2 may be .sup.19F.
[0178] In various embodiments, R.sup.2 may be absent or present. In
an embodiment, when R.sup.2 is present, R.sup.2 may be any
non-interfering group with regard to fluoridation of B. In an
embodiment, R.sup.2 may be a linear or branched C.sub.1-C.sub.15
alkyl group or a non-aromatic C.sub.3-C.sub.18 cycloalkyl group,
wherein each of the C.sub.1-C.sub.15 alkyl group and the
non-aromatic C.sub.3-C.sub.18 cycloalkyl group is unsubstituted or
substituted and is optionally intercepted with at least one
heteroatom selected from the group consisting of O, S, N and P. In
an embodiment, the C.sub.1-C.sub.15 alkyl group or non-aromatic
C.sub.3-C.sub.18 cycloalkyl group may be intercepted with at least
one heteroatom at or near the attachment point to B. In particular
embodiments, R.sup.2 may be a linear or branched C.sub.1-C.sub.6
alkyl group or a non-aromatic C.sub.3-C.sub.8 cycloalkyl group. In
various embodiments, the C.sub.1-C.sub.15 alkyl group may be a
C.sub.1-C.sub.6 alkyl group. In various embodiments, the
non-aromatic C.sub.3-C.sub.18 cycloalkyl group may be a
C.sub.4-C.sub.8 cycloalkyl group.
[0179] In various embodiments, each of R.sup.1 and R.sup.2 may
independently be a linear or branched C.sub.1-C.sub.15 alkyl group
or a non-aromatic C.sub.3-C.sub.18 cycloalkyl group, wherein each
of the C.sub.1-C.sub.15 alkyl group and the non-aromatic
C.sub.3-C.sub.18 cycloalkyl group is unsubstituted or substituted
and is optionally intercepted with at least one heteroatom selected
from the group consisting of O, S, N and P. In various embodiments,
the C.sub.1-C.sub.15 alkyl group may be a C.sub.1-C.sub.6 alkyl
group. In various embodiments, the non-aromatic C.sub.3-C.sub.18
cycloalkyl group may be a C.sub.4-C.sub.8 cycloalkyl group.
[0180] In various embodiments, n may be 2; each Y.sup.1 may
independently be .sup.18F or .sup.19F; Y.sup.2 may be .sup.18F or
.sup.19F; and at least one of (Y.sup.1).sub.n and Y.sup.2 may be
.sup.18F.
[0181] In various embodiments, the a linear or branched
C.sub.1-C.sub.15 alkyl group may be a linear or branched saturated
C.sub.1-C.sub.2 alkyl group, or a linear or branched saturated
C.sub.1-C.sub.3 alkyl group, or a linear or branched saturated
C.sub.1-C.sub.4 alkyl group, or a linear or branched saturated
C.sub.1-C.sub.5 alkyl group, or a linear or branched saturated
C.sub.1-C.sub.6 alkyl group, or a linear or branched saturated
C.sub.1-C.sub.7 alkyl group, or a linear or branched saturated
C.sub.1-C.sub.8 alkyl group, or a linear or branched saturated
C.sub.1-C.sub.9 alkyl group, or a linear or branched saturated
C.sub.1-C.sub.10 alkyl group, or a linear or branched saturated
C.sub.1-C.sub.11 alkyl group, or a linear or branched saturated
C.sub.1-C.sub.12 alkyl group, or a linear or branched saturated
C.sub.1-C.sub.13 alkyl group, or a linear or branched saturated
C.sub.1-C.sub.14 alkyl group, or a linear or branched saturated
C.sub.1-C.sub.15 alkyl group, or a linear or branched saturated
C.sub.1 alkyl group, or a linear or branched saturated C.sub.2
alkyl group, or a linear or branched saturated C.sub.3 alkyl group,
or a linear or branched saturated C.sub.4 alkyl group, or a linear
or branched saturated C.sub.5 alkyl group, or a linear or branched
saturated C.sub.6 alkyl group, or a linear or branched saturated
C.sub.7 alkyl group, or a linear or branched saturated C.sub.8
alkyl group, or a linear or branched saturated C.sub.9 alkyl group,
or a linear or branched saturated C.sub.10 alkyl group, or a linear
or branched saturated C.sub.11 alkyl group, or a linear or branched
saturated C.sub.12 alkyl group, or a linear or branched saturated
C.sub.13 alkyl group, or a linear or branched saturated C.sub.14
alkyl group, or a linear or branched saturated C.sub.15 alkyl
group.
[0182] In various embodiments, the linear or branched
C.sub.1-C.sub.15 alkyl group may be a linear or branched
C.sub.2-C.sub.3 alkenyl group, or a linear or branched
C.sub.2-C.sub.4 alkenyl group, or a linear or branched
C.sub.2-C.sub.5 alkenyl group, or a linear or branched
C.sub.2-C.sub.6 alkenyl group, or a linear or branched
C.sub.2-C.sub.7 alkenyl group, or a linear or branched
C.sub.2-C.sub.8 alkenyl group, or a linear or branched
C.sub.2-C.sub.9 alkenyl group, or a linear or branched
C.sub.2-C.sub.10 alkenyl group, or a linear or branched
C.sub.2-C.sub.11 alkenyl group, or a linear or branched
C.sub.2-C.sub.12 alkenyl group, or a linear or branched
C.sub.2-C.sub.13 alkenyl group, or a linear or branched
C.sub.2-C.sub.14 alkenyl group, or a linear or branched
C.sub.2-C.sub.15 alkenyl group, or a linear or branched C.sub.2
alkenyl group, or a linear or branched C.sub.3 alkenyl group, or a
linear or branched C.sub.4 alkenyl group, or a linear or branched
C.sub.5 alkenyl group, or a linear or branched C.sub.6 alkenyl
group, or a linear or branched C.sub.7 alkenyl group, or a linear
or branched C.sub.8 alkenyl group, or a linear or branched C.sub.9
alkenyl group, or a linear or branched C.sub.10 alkenyl group, or a
linear or branched C.sub.11 alkenyl group, or a linear or branched
C.sub.12 alkenyl group, or a linear or branched C.sub.13 alkenyl
group, or a linear or branched C.sub.14 alkenyl group, or a linear
or branched C.sub.15 alkenyl group.
[0183] In various embodiments, the linear or branched
C.sub.1-C.sub.15 alkyl group may be a linear or branched
C.sub.2-C.sub.3 alkynyl group, or a linear or branched
C.sub.2-C.sub.4 alkynyl group, or a linear or branched
C.sub.2-C.sub.5 alkynyl group, or a linear or branched
C.sub.2-C.sub.6 alkynyl group, or a linear or branched
C.sub.2-C.sub.7 alkynyl group, or a linear or branched
C.sub.2-C.sub.8 alkynyl group, or a linear or branched
C.sub.2-C.sub.9 alkynyl group, or a linear or branched
C.sub.2-C.sub.10 alkynyl group, or a linear or branched
C.sub.2-C.sub.11 alkynyl group, or a linear or branched
C.sub.2-C.sub.12 alkynyl group, or a linear or branched
C.sub.2-C.sub.13 alkynyl group, or a linear or branched
C.sub.2-C.sub.14 alkynyl group, or a linear or branched
C.sub.2-C.sub.15 alkynyl group, or a linear or branched C.sub.2
alkynyl group, or a linear or branched C.sub.3 alkynyl group, or a
linear or branched C.sub.4 alkynyl group, or a linear or branched
C.sub.5 alkynyl group, or a linear or branched C.sub.6 alkynyl
group, or a linear or branched C.sub.7 alkynyl group, or a linear
or branched C.sub.8 alkynyl group, or a linear or branched C.sub.9
alkynyl group, or a linear or branched C.sub.10 alkynyl group, or a
linear or branched C.sub.11 alkynyl group, or a linear or branched
C.sub.12 alkynyl group, or a linear or branched C.sub.13 alkynyl
group, or a linear or branched C.sub.14 alkynyl group, or a linear
or branched C.sub.15 alkynyl group.
[0184] In various embodiments, the C.sub.3-C.sub.18 cycloalkyl
group may be a C.sub.3-C.sub.4 cycloalkyl group, or a
C.sub.3-C.sub.5 cycloalkyl group, or a C.sub.3-C.sub.6 cycloalkyl
group, or a C.sub.3-C.sub.7 cycloalkyl group, or a C.sub.3-C.sub.8
cycloalkyl group, or a C.sub.3-C.sub.9 cycloalkyl group, or a
C.sub.3-C.sub.10 cycloalkyl group, or a C.sub.3-C.sub.11 cycloalkyl
group, or a C.sub.3-C.sub.12 cycloalkyl group, or a
C.sub.3-C.sub.13 cycloalkyl group, or a C.sub.3-C.sub.14 cycloalkyl
group, or a C.sub.3-C.sub.18 cycloalkyl group, or a
C.sub.3-C.sub.16 cycloalkyl group, or a C.sub.3-C.sub.17 cycloalkyl
group, or a C.sub.3-C.sub.18 cycloalkyl group, or a C.sub.4-C.sub.5
cycloalkyl group, or a C.sub.4-C.sub.6 cycloalkyl group, or a
C.sub.4-C.sub.7 cycloalkyl group, or a C.sub.4-C.sub.8 cycloalkyl
group, or a C.sub.4-C.sub.9 cycloalkyl group, or a C.sub.4-C.sub.10
cycloalkyl group, or a C.sub.4-C.sub.11 cycloalkyl group, or a
C.sub.4-C.sub.12 cycloalkyl group, or a C.sub.4-C.sub.13 cycloalkyl
group, or a C.sub.4-C.sub.14 cycloalkyl group, or a
C.sub.4-C.sub.18 cycloalkyl group, or a C.sub.4-C.sub.16 cycloalkyl
group, or a C.sub.4-C.sub.17 cycloalkyl group, or a
C.sub.4-C.sub.18 cycloalkyl group, or a C.sub.3 cycloalkyl group,
or a C.sub.4 cycloalkyl group, or a C.sub.5 cycloalkyl group, or a
C.sub.6 cycloalkyl group, or a C.sub.7 cycloalkyl group, or a
C.sub.8 cycloalkyl group, or a C.sub.9 cycloalkyl group, or a
C.sub.10 cycloalkyl group, or a C.sub.11 cycloalkyl group, or a
C.sub.12 cycloalkyl group, or a C.sub.13 cycloalkyl group, or a
C.sub.14 cycloalkyl group, or a C.sub.18 cycloalkyl group, or a
C.sub.16 cycloalkyl group, or a C.sub.17 cycloalkyl group, or a
C.sub.18 cycloalkyl group.
[0185] In various embodiments, the C.sub.3-C.sub.18 cycloalkyl
group may be a C.sub.3-C.sub.4 cycloalkenyl group, or a
C.sub.3-C.sub.5 cycloalkenyl group, or a C.sub.3-C.sub.6
cycloalkenyl group, or a C.sub.3-C.sub.7 cycloalkenyl group, or a
C.sub.3-C.sub.8 cycloalkenyl group, or a C.sub.3-C.sub.9
cycloalkenyl group, or a C.sub.3-C.sub.10 cycloalkenyl group, or a
C.sub.3-C.sub.11 cycloalkenyl group, or a C.sub.3-C.sub.12
cycloalkenyl group, or a C.sub.3-C.sub.13 cycloalkenyl group, or a
C.sub.3-C.sub.14 cycloalkenyl group, or a C.sub.3-C.sub.15
cycloalkenyl group, or a C.sub.3-C.sub.16 cycloalkenyl group, or a
C.sub.3-C.sub.17 cycloalkenyl group, or a C.sub.3-C.sub.15
cycloalkenyl group, or a C.sub.4-C.sub.5 cycloalkenyl group, or a
C.sub.4-C.sub.6 cycloalkenyl group, or a C.sub.4-C.sub.7
cycloalkenyl group, or a C.sub.4-C.sub.8 cycloalkenyl group, or a
C.sub.4-C.sub.9 cycloalkenyl group, or a C.sub.4-C.sub.10
cycloalkenyl group, or a C.sub.4-C.sub.11 cycloalkenyl group, or a
C.sub.4-C.sub.12 cycloalkenyl group, or a C.sub.4-C.sub.13
cycloalkenyl group, or a C.sub.4-C.sub.14 cycloalkenyl group, or a
C.sub.4-C.sub.15 cycloalkenyl group, or a C.sub.4-C.sub.16
cycloalkenyl group, or a C.sub.4-C.sub.17 cycloalkenyl group, or a
C.sub.4-C.sub.15 cycloalkenyl group, or a C.sub.3 cycloalkenyl
group, or a C.sub.4 cycloalkenyl group, or a C.sub.5 cycloalkenyl
group, or a C.sub.6 cycloalkenyl group, or a C.sub.7 cycloalkenyl
group, or a C.sub.8 cycloalkenyl group, or a C.sub.9 cycloalkenyl
group, or a C.sub.10 cycloalkenyl group, or a C.sub.11 cycloalkenyl
group, or a C.sub.12 cycloalkenyl group, or a C.sub.13 cycloalkenyl
group, or a C.sub.14 cycloalkenyl group, or a C.sub.15 cycloalkenyl
group, or a C.sub.16 cycloalkenyl group, or a C.sub.17 cycloalkenyl
group, or a C.sub.18 cycloalkenyl group.
[0186] In various embodiments, the C.sub.3-C.sub.18 cycloalkyl
group may be a C.sub.3-C.sub.4 cycloalkynyl group, or a
C.sub.3-C.sub.5 cycloalkynyl group, or a C.sub.3-C.sub.6
cycloalkynyl group, or a C.sub.3-C.sub.7 cycloalkynyl group, or a
C.sub.3-C.sub.8 cycloalkynyl group, or a C.sub.3-C.sub.9
cycloalkynyl group, or a C.sub.3-C.sub.10 cycloalkynyl group, or a
C.sub.3-C.sub.11 cycloalkynyl group, or a C.sub.3-C.sub.12
cycloalkynyl group, or a C.sub.3-C.sub.13 cycloalkynyl group, or a
C.sub.3-C.sub.14 cycloalkynyl group, or a C.sub.3-C.sub.15
cycloalkynyl group, or a C.sub.3-C.sub.16 cycloalkynyl group, or a
C.sub.3-C.sub.17 cycloalkynyl group, or a C.sub.3-C.sub.15
cycloalkynyl group, or a C.sub.4-C.sub.5 cycloalkynyl group, or a
C.sub.4-C.sub.6 cycloalkynyl group, or a C.sub.4-C.sub.7
cycloalkynyl group, or a C.sub.4-C.sub.8 cycloalkynyl group, or a
C.sub.4-C.sub.9 cycloalkynyl group, or a C.sub.4-C.sub.10
cycloalkynyl group, or a C.sub.4-C.sub.11 cycloalkynyl group, or a
C.sub.4-C.sub.12 cycloalkynyl group, or a C.sub.4-C.sub.13
cycloalkynyl group, or a C.sub.4-C.sub.14 cycloalkynyl group, or a
C.sub.4-C.sub.15 cycloalkynyl group, or a C.sub.4-C.sub.16
cycloalkynyl group, or a C.sub.4-C.sub.17 cycloalkynyl group, or a
C.sub.4-C.sub.15 cycloalkynyl group, or a C.sub.3 cycloalkynyl
group, or a C.sub.4 cycloalkynyl group, or a C.sub.5 cycloalkynyl
group, or a C.sub.6 cycloalkynyl group, or a C.sub.7 cycloalkynyl
group, or a C.sub.8 cycloalkynyl group, or a C.sub.9 cycloalkynyl
group, or a C.sub.10 cycloalkynyl group, or a C.sub.11 cycloalkynyl
group, or a C.sub.12 cycloalkynyl group, or a C.sub.13 cycloalkynyl
group, or a C.sub.14 cycloalkynyl group, or a C.sub.15 cycloalkynyl
group, or a C.sub.16 cycloalkynyl group, or a C.sub.17 cycloalkynyl
group, or a C.sub.18 cycloalkynyl group.
[0187] In various embodiments, the linear or branched
C.sub.1-C.sub.15 alkyl group or the C.sub.3-C.sub.18 cycloalkyl
group may be intercepted with at least one heteroatom that may
independently be O, S, N or P; or S, N or P; or O, N or P; or O, S,
or P; or O, S, or N; or N or P; or S or P; or S or N; or O or P; or
O or N; or O or S; or P; or N; or S; or O.
[0188] In various embodiment, the C.sub.1-C.sub.15 alkyl group or
the C.sub.3-C.sub.18 cycloalkyl group may be substituted with one
or more substituents selected from the group consisting of F, Cl,
Br, I, --N.sup.+(C.sub.1-15alkyl).sub.3,
--N.sup.+(C.sub.2-15alkenyl).sub.3,
--N.sup.+(C.sub.2-15alkynyl).sub.3,
--N.sup.+H(C.sub.1-15alkyl).sub.2,
--N.sup.+H(C.sub.2-15alkenyl).sub.2,
--N.sup.+H(C.sub.2-15alkynyl).sub.2,
P.sup.+(C.sub.1-15alkyl).sub.3, P.sup.+(C.sub.2-15alkenyl).sub.3,
P.sup.+(C.sub.2-15alkynyl).sub.3, S.sup.+(C.sub.1-15alkyl).sub.2,
S.sup.+(C.sub.2-15alkenyl).sub.2, S.sup.+(C.sub.2-15alkynyl).sub.2,
oxo (i.e., .dbd.O), --OC.sub.1-15alkyl, unsubstituted or
substituted aromatic C.sub.3-C.sub.18 cycloalkyl, unsubstituted or
substituted non-aromatic C.sub.3-C.sub.15 heterocyclic group,
unsubstituted or substituted aromatic C.sub.3-C.sub.18 heterocyclic
group, .dbd.NH, --C.sub.1-C.sub.15alkyl, non-aromatic
C.sub.3-C.sub.18 cycloalkyl, --N(C.sub.1-15alkyl).sub.2,
--N(C.sub.2-15alkenyl).sub.2, --N(C.sub.2-15alkynyl).sub.2, --COOH,
--NH.sub.2, --SH, a biomolecule, and a linking group optionally
joined to a biomolecule. In various embodiments, the
C.sub.1-C.sub.15 alkyl group or the C.sub.3-C.sub.18 cycloalkyl
group may be substituted with one or more substituents selected
from the group consisting of F, Cl, Br, I,
--N.sup.+(C.sub.1-15alkyl).sub.3,
--N.sup.+(C.sub.2-15alkenyl).sub.3,
--N.sup.+(C.sub.2-15alkynyl).sub.3,
--N.sup.+H(C.sub.1-15alkyl).sub.2,
--N.sup.+H(C.sub.2-15alkenyl).sub.2,
--N.sup.+H(C.sub.2-15alkynyl).sub.2,
P.sup.+(C.sub.1-15alkyl).sub.3, P.sup.+(C.sub.2-15alkenyl).sub.3,
P.sup.+(C.sub.2-15alkynyl).sub.3, S.sup.+(C.sub.1-15alkyl).sub.2,
S.sup.+(C.sub.2-15alkenyl).sub.2, S.sup.+(C.sub.2-15alkynyl).sub.2,
oxo (i.e., .dbd.O), --OC.sub.1-15alkyl, unsubstituted or
substituted aromatic C.sub.3-C.sub.18 cycloalkyl, unsubstituted or
substituted non-aromatic C.sub.3-C.sub.15 heterocyclic group,
unsubstituted or substituted aromatic C.sub.3-C.sub.18 heterocyclic
group, --C.sub.1-C.sub.15alkyl, non-aromatic C.sub.3-C.sub.18
cycloalkyl, --N(C.sub.1-15alkyl).sub.2,
--N(C.sub.2-15alkenyl).sub.2, --N(C.sub.2-15alkynyl).sub.2,
--C.sub.00H, --NH.sub.2, --SH, a biomolecule, and a linking group
optionally joined to a biomolecule. In various embodiments, the
C.sub.1-C.sub.15 alkyl group or the C.sub.3-C.sub.18 cycloalkyl
group may be substituted with one or more substituents selected
from the group consisting of a biomolecule and a linking group
optionally joined to a biomolecule.
[0189] The compounds may also include base-free forms, prodrugs, or
pharmaceutically acceptable salts thereof. The compounds described
herein are meant to include all racemic mixtures and all individual
enantiomers or combinations thereof, whether or not they are
represented herein.
[0190] Various embodiments of the invention provide a method of
making a precursor compound which comprises converting a
corresponding alkylboronic acid variant of any of the
aforementioned compounds to an alkylboronic ester, wherein one, two
or three of Y.sup.1 and Y.sup.2 may be a leaving group displaceable
by fluoride. This invention also provides a method of making a
.sup.18F containing compound which comprises replacing at least one
of said leaving group or groups of the aforesaid alkylboronic ester
with .sup.18F. Methods of this invention make use of substituted
alkyl-boronic compounds, wherein Y.sup.1 or Y.sup.2 may be a moiety
that can be displaced by reaction with fluoride. These may be used
as precursor molecules to the above-described .sup.18F labeled
alkyfluoroborate compounds by reaction with a suitable source of
.sup.18F. In this aspect of the invention, Y.sup.1 or Y.sup.2 may
(for example) be an alkoxy, halide, amine (e.g. alkyl, aryl), or
thiol (alkyl, aryl) moiety. Other examples of leaving groups that
can be displaced by fluoride are known. Particular examples are
described in WO 2005/077967.
[0191] Alkylfluoroborate compounds according to a formula described
herein may be made by a variety of synthetic methods, ranging in
complexity from de novo synthesis to a `wash-in` of the fluorine on
a previously prepared boronate (see, for example, Molander et al.,
J. Org. Chem. 2010, 75, 4304-4306; Lennox et al. JACS, 2012, 134,
7431-7441; Dumas et al., Organic Letters, 2012, 14, 2138-2141; and
Molander et al., Organic Letters, 2006, 8, 2031-2034).
[0192] A `wash-in` preparative method may include preparation of a
solution of a substituted alkylboronic acid or ester in an
appropriate solvent, to which aqueous fluoride is added. The pH may
be at a suitable range (e.g. about 2.5 to about 3.5) or according
to what is suitable for the solvents and the substituted
alkylboronic acid or ester. The solvent may be DMF or another
solvent that is miscible with an aqueous fluoride solution, and
solubilizes the substituted alkylboronic acid or ester of interest.
Examples of such solvents may include aqueous mixtures comprising
DMSO, DMF, MeOH, THF, MeCN, DMA, and NMP. Selection of a particular
solvent may vary with the particular substituted alkylboronic acid
or ester and in particular with regards to preserving the
bioactivity of the biomolecule, and is within the skill of one
versed in the art. Aqueous fluoride may be at any suitable
concentration. For example, the substituted alkylboronic acid may
be present at a concentration of about 1-4 mM, and the
KH.sup.18/19F.sub.2 may be present in 3 or 4 equivalents i.e. 3-12
mM or 4-16 mM, where the minimal concentrations are selected to
increase the specific activity of the labeling, and the maximal
concentrations determined by the maximal solubility of the
bioconjugate.
[0193] Clinical preparations of a substituted alkylboronic acid or
ester may involve use of about 800 mCi .sup.18F in no carrier added
form, which, barring environmental contamination with .sup.19F,
represents about 0.46 nmol of .sup.18F, or 3.8% of the total
fluoride used in a 10 .mu.L reaction at 12 mM total fluoride.
Microreactor and microfluidic techniques, (which provide reaction
volumes of about 50 nL) can reduce the quantity of carrier .sup.19F
needed. For instance in a 50 nL reaction at 10 mM fluoride, one
needs only 500 pmol of total fluoride. Thus, a no carrier added
reaction is readily contemplated for labeling alkylboronic
acids.
[0194] Reaction temperature may be increased above room
temperature, but below a temperature that may destabilize or
denature the selected biomolecule. For example, some nucleic acids
or oligonucleotides may be suitable for use in labeling reactions
at temperatures of about 60.degree. C., while some proteins may
require lower temperatures. Peptides are known to withstand
temperatures as high as about 110.degree. C. Antibodies are known
in the art to have limited thermostability compared to most other
proteins however thermostable antibodies and enzymes may also be
suitable for use in labeling reactions at temperatures above room
temperature. Alternatively, some biomolecules may be preferentially
suitable for labeling reactions at reduced temperatures, i.e. below
room temperature.
[0195] General approaches and methods for direct chemical
modification of biomolecules for addition and/or substitution of
modifying groups are known. As an example, chemical modification of
proteins is described by Means and Feeney Bioconjugate Chemistry
1990 1: 2-12). Chemical modification of nucleic acids such as DNA
and RNA is described in, for example, Boutourine et al.
Bioconjugate Chemistry 1990 1:350-56. Chemical modification of
sugars and oligosaccharides is described in, for example Wood et
al. Bioconjugate Chemistry 1992 3: 391-6 and more recently in click
reactions
[0196] In various embodiments, there is provided a method for
selections or screening substituted organotrifluoroborate
compounds, for their ability to resist defluoridation as an
indicator of their longevity as a radio imaging agent for PET.
Various methods may be employed such as described below.
[0197] Chromatographic methods for separation of a fluoridated
compound from the free .sup.18F are useful for qualitative or
semi-quantitative assessment of the resistance to defluoridation of
the fluoridated compound. Such methods generally involve a
stationary phase, which may be a column matrix having qualities
such as hydrophobicity, porosity or size-exclusion capabilities,
charge, hydrophilicity or the like. Alternately, the stationary
phase may provide structural support only, and be largely inert to
interactions with a mobile phase or the solutes in the mobile
phase. The stationary phase may be further supported in, for
example, a column, or for thin-layer chromatography, on a glass
plate. Paper used in paper chromatography may provide both the
stationary phase and physical support of the stationary phase.
Alternatively a diol column can be used to remove unlabeled boronic
acid that may be present as unreacted starting material or
following competing solvolysis of the organotrifluoroborate during
labeling. The mobile phase is frequently a solvent, which may be
hydrophobic or hydrophilic, aqueous or non-aqueous, and may be
formulated to provide a fixed pH or a selected pH range, or a
particular salt or other solute concentration. In various
embodiments, the molecules or compounds of interest, such as the
fluoridated compounds above are soluble in the mobile phase, as is
the free fluorine that is to be separated from the fluoridated
compound. Choice of a particular chromatographic method may be
influenced by the molecule to be separated. For example, separation
of a labeled biomolecule, such as an antibody, gel-permeation or
affinity chromatography may be suitable. In another example,
separation of a labeled oligonucleotide or peptide, anion exchange
chromatography may be suitable. In another example, separation of
labeled biotin complexed with an avidin-conjugate may involve
gel-permeation chromatography. In another example, separation of
labeled free biotin, folate or methotrexate or other small
molecules, such as peptides may involve chromatographic separation
through a silica column or plug, or HPLC/FPLC.
[0198] General principles, methods and background relating to
chromatography are known, and may be found in, for example,
Jonsson, J. A. Chromatographic Theory and Basic Principles. 1987.
Marcel Dekker, or Ahuja S. Chromatography and Separation Science.
2003. Elsevier Press; Cox, G. B. Preparative Enantioselective
Chromatography. 2005. Blackwell Publishing; Wall, P. E. Thin-layer
chromatography: a modern practical approach 205. Royal Society of
Chemistry; Sherma, J. and Fried, B. Handbook of Thin-layer
chromatography. 2003. Marcel Dekker.
[0199] .sup.19F-NMR may be also used to monitor defluoridation
(e.g. see Ting et. al. (2008) J. Org. Chem. 73:4662-70; Hartwig et.
al. (2008) Tetrahedron Letters 49:3152-56; and, Ting et. al. (2008)
Journal of Fluorine Chemistry 129:349-58).
[0200] Isotopic wash-out or pulse-chase methods may also be used
for screening labeled trifluoroborates in order to identify
compositions that are suitably stable for use as imaging
agents.
[0201] It is recognized that stable organotrifluoroborates (no
.sup.18F incorporated) may be useful as radiochemically stable
precursors that will find use in labeling whereby they are treated
under acidic conditions to promote the exchange of an atom of
.sup.19F for an atom of .sup.18F. Following labeling, at least one
of F may be .sup.18F. It may be recognized that in the preparation
of compounds of this invention, that there may be a fraction of
molecules that will not be complexed with any .sup.18F when carrier
.sup.19F may be used. It may be recognized that the addition of
carrier .sup.19F may be advantageous in certain cases. A
final/overall specific activity suitable for imaging purposes can
be achieved even if a particular trifluoroborate molecule in a
mixture contains no .sup.18F, provided that at least some of the
trifluoroborates prepared contain at least one .sup.18F.
[0202] Other aspects and features of the present invention will
become apparent to those ordinarily skilled in the art upon review
of the following description of specific embodiments of the
invention in conjunction with the accompanying figures.
EXAMPLES
[0203] Aryltrifluoroborates undergo solvolysis (i. e., B--F bond
scission) at a nearly pH-independent rate above pH 3. The
electronic nature of the ring substituents is the main factor
affecting the rate of solvolysis. Groups on aryl rings impart their
effects on rates by both inductive and resonance effects whereby
the electron density in the pi-bonds is increased or diminished.
Increased pi electron density can delocalize from the ring into the
sp2 orbital on boron to promote loss of one fluoride ion whereupon
the other two are lost rapidly. Increasing the electron density
results in an enhancement of the rate of B--F bond scission,
whereas decreasing the electron density reduces the rate. The
inductive effects are difficult to separate from those related to
resonance, and both effects are further nuanced by whether the
substituents are in the meta vs ortho/para positions. Moreover, it
is critical to understand the magnitude of these effects in order
to understand how to create aryltrifluoroborates with sufficient
stability.
[0204] The magnitude of these effects may be given by the p value
in a quantitative linear free energy relationship. The effects of
substitution by several (at least two) electron withdrawing group
may be estimated by summing their known .sigma. values. The rate at
which such a composition reacts can be related to the rate of an
unsubstituted aryl-BF.sub.3 by the following equation
(log(k/k0)=.sigma..rho. where k is the solvolysis rate constant for
a certain aryl-BF.sub.3 under consideration and k0 is the
solvolysis rate constant for an unsubstituted aryl-BF.sub.3 Thus,
for aryl-BF.sub.3 solvolysis, the relationship between the rate of
B--F bond scission and the number and position of various electron
withdrawing groups may be understood in terms of known a values and
a value of .rho. .about.-1. Furthermore, owing to the change in the
hybridization of boron from sp3 to sp2 upon loss of a first
fluoride ion, which places the remaining two fluorine atoms
co-planar with the aryl ring, it has been recognized that bulky
ortho substituents may exert steric effects to retard
solvolysis.
[0205] While aryl-trifluoroborate solvolysis can be understood in
terms of delocalization of electron density from the arene
pi-system into the empty p-orbital on boron with concomitant
expulsion of a fluoride atom whose rate is correlated by the
Hammett relationship of (log(k/k0)=.sigma..rho. where
.rho..about.-1, this understanding based on a combination of
inductive effects and pi-delocalization effects, as expressed in
the pKa of (aryl) benzoic acids, and cannot be extended to
substituted nonaromatic organotrifluoroborates. Electron
withdrawing groups can greatly affect the rate of a reaction in
some cases, but not in others, and thus the application of linear
free energy relationships that hold well for aryl systems do not
necessarily apply to nonaromatic compositions. It was unclear to
what extent such relationships could be extended to the rate of
B--F bond scission in systems where the carbon atom to which the
boron is attached is not in an aromatic state, and of what
magnitude these effects would be.
Example 1: Fluoridation of a Organoboronic Acid or Ester
[0206] 22.4 mg (0.10 mmol) of
N,N,-dimethyl-N-propargylammoniomethylborate pinacol ester was
dissolved with 80 .mu.L of DMF, then 2.4 equiv. 120 .mu.L of 3 M
KHF.sub.2 (aqueous solution) and 80 .mu.L of 4 M HCl (aqueous
solution) were added as the fluoridation reagents. This reaction
was incubated at 37.degree. C. for two hours, then it was
concentrated with a vacuum concentrator (Speedvac). A yellowish
white powder was achieved and was ready for further
purification.
Example 2: Evaluation of Rates of Solvolytic Defluoridation of
Fluoridated Organotrifluoroborates by .sup.19F-Nuclear Magnetic
Resonance (.sup.19F-NMR) Spectroscopy
[0207] The following is are representative examples of testing of
solvolytic defluoridation of fluoridated organoborates as shown in
FIG. 1A to FIG. 1FF and Table 1. Solutions of the fluoridated
organotrifluoroborates were made by dissolving 30 mg of the
fluoridated organotrifluoroborate into 1 mL of 20%
ethanol/acetonitrile.
[0208] As the fluoridated organotrifluoroborate salts were often
contaminated with a significant amount of free fluoride, a silica
column was used to remove the free fluoride from the
organotrifluoroborate solution. After loading the crude reaction
onto the silica column, the fractions containing the desired
organotrifluoroborate were eluted and combined to form a combined
solution. In view of the strong stability of the fluoridated
organotrifluoroborate in organic solvent, 20% of the combined
solution was stored in an NMR tube and this sample served as the
"zero" minute time point. A purified organotrifluoroborate salt was
isolated from the remaining portion of the combined solution
(remaining 80% of the combined solution) by removing the organic
solvent from the combined solution by vacuum. Removal of the
organic solvent from the combined solution gave the purified
fluoridated alkylbornate salt in the form of a white solid. The dry
and purified fluoridated organotrifluoroborate salt was
re-dissolved into 3 mL of 200 mM phosphate buffer. Solvolytic
defluoridation started immediately upon dissolution of the
fluoridated organotrifluoroborate salt into phosphate buffer, and
accordingly, the time was recorded at the moment of dissolution.
The progress of solvolytic defluoridation of the fluoridated
organotrifluoroborate salt was monitored using .sup.19F NMR
spectroscopy. General principles, methods and background relating
to the use of .sup.19F NMR spectroscopy for monitoring
defluoridation are known, and may be found in, for example, Ting et
al. (2008, J. Org. Chem. 73; 4662-70; Harwig et al. (2008)
Tetrahedron Letters 49:3152-56; and Ting et al. (2008) Journal of
Fluorine Chemistry 129:349-58. For each time point, solvolytic
defluoridation data was collected using a 300 MHz .sup.19F NMR
spectrometer (Bruker). .sup.19F NMR spectroscopic tracers for the
fluoridated organotrifluoroborate salt at different times are shown
in FIG. 1A. Use of .sup.19F-NMR to measure solvolytic
defluoridation provides a useful model for measuring solvolytic
18F-defluoridation because if one F is lost, all are lost.
Moreover, it is understood that the kinetic isotope effect in terms
of B--F bond solvolysis is negligible. Hence whereas for PET
scanning purposes solvolytic 18F-defluoridation is of
consideration, .sup.19F-NMR provides a reliable measure of the rate
of 18F-defluoridation since both .sup.18F and .sup.19F rates are
the same in practice because there should be no measureable
isotopic difference. The degree of solvolytic defluoridation of the
fluoridated organotrifluoroborate salt was plotted as a function of
time, for example, as shown in FIG. 1B for Compound 6 of Table 1.
.sup.19F NMR spectroscopic tracers for the fluoridated
organotrifluoroborate salts of compounds listed in Table 1 at
different times are shown in FIGS. 1A, 1C, 1E, 1G, 1I, 1K, 1M, 1O,
1Q, 1S, 1U, 1W, 1Y, 1AA, 1CC, and 1EE, and the degree of solvolytic
defluoridation of the compounds as a function of time is shown in
FIGS. 1B, 1D, 1F, 1H, 1J, 1L, 1N, 1P, 1R, 1T, 1V, 1X, 1Z, 1BB, 1DD,
and 1FF. As can be seen from FIGS. 1B, 1D, 1F, 1H, 1J, 1L, 1N, 1P,
1R, 1T, 1V, 1X, 1Z, 1BB, 1DD, and 1FF, solvolytic defluoridation of
the fluoridated organoborate salts shows pseudo first-order
reaction kinetics.
Example 3: Rate Constant for Solvolytic Defluoridation
[0209] The time curves shown in FIGS. 1B and 1D were fitted and a
rate constant, k.sub.solvolysis, for each time curve was
calculated. As a measure of the stability of the fluoridated
organoborate to solvolytic defluoridation, pk.sub.B--F values were
calculated using the equation pk.sub.B--F=-log(k.sub.solvolysis).
In addition to pk.sub.B--F values, observed solvolytic
defluoridation half-life, t.sub.1/2, values and rate constants,
k.sub.solvolysis, for a number of different fluoridated
organoborates are listed in Table 1. As can be seen from Table 1,
the larger the pk.sub.B--F value, the more stable the fluoridated
organoborate was observed to be to solvolytic defluoridation.
TABLE-US-00001 TABLE 1 Rate Constant Data for Solvolytic
Defluoridation of Fluoridated Organoborate pk (solvoly- sis) =
half- pKa of -log k (solvoly- life, Compound Corresponding k
(solvoly- sis) in units of t1/2 No. Structure COOH.dagger. sis)
min-1 (min.) 1 ##STR00047## 4.81 0.52 0.3 2.3-3 2 ##STR00048## 4.25
1.01 0.099 7 3 ##STR00049## 3.53 2.32 0.00476 145 4 ##STR00050##
2.86 2.98 0.000768 658 5 ##STR00051## 2.5 3.5249 0.000298 2311 6
##STR00052## 2.34 3.7554 0.000175 3929 7 ##STR00053## 2.45 3.7409
0.000181 3800 8 ##STR00054## 2.35 4.0700 8.52 .times. 10.sup.-5
8100 9 ##STR00055## 2.15 4.1823 6.57 .times. 10-5 10500 10
##STR00056## 1.83 4.5036 3.14 .times. 10.sup.-5 22000 11
##STR00057## 1.29 5.3372 4.6 .times. 10.sup.-6 150000 12
##STR00058## 0.93* 5.82 1.5 .times. 10.sup.-6 460000 13
##STR00059## 2.34 3.77 0.000170 4053 14 ##STR00060## 2.14 4.19 6.45
.times. 10.sup.-5 10700 15 ##STR00061## 3.2* 2.59 0.00259 266 16
##STR00062## 2.1* 4.17 0.0000673 10300 17 ##STR00063## 3.15* 2.70
0.0020 346 18 ##STR00064## 2.5* 3.61 0.0002460 2818 .dagger.For
example, pKa of the corresponding COOH to Compound 1 would be the
pKa of the corresponding carboxylic acid ##STR00065## *= predicted
by calculation
[0210] It has been reported that aryltrifluoroborates can be
considerably stabilized by an electron-poor environment (see, for
example, Ting et al. (2008, J. Org. Chem. 73; 4662-70). It has also
been reported that EWGs (electron withdrawing group) on the benzene
ring can significantly slow down hydrolysis, resulting in longer
solvolytic half-lives. A similar correlation with such substituent
effects is seen with regards to the nitration of benzene or the
solvolysis of substituted benzyl tosylates. Without being bound by
theory, a possible mechanistic reason for this effect was that
pi-electrons in the aryl ring could delocalize into the empty
p-orbital on boron thus promoting B--F bond dissociation. As such,
a group that weakened this effect could result in greater B--F bond
stability. However, in contrast to aryltrifluoroborates, for
organotrifluoroborates, there may or may not be pi-overlap by an
electron withdrawing group and hence there is no reason a priori to
have thought that electron withdrawing groups would have any
effects on the B--F bond stability or to what extent they might
have retarded solvolysis.
[0211] The existence of any relationship between pk.sub.B--F
observed for a particular alkyl moiety of the fluoridated
organotrifluoroborate compound and the pKa of a carboxylic acid
conjugated to the same alkyl moiety was also investigated. The pKa
values for the carboxylic acids conjugated to the same alkyl
moieties of the fluoridated organotrifluoroborates tabulated in
Table 1 are also included in the same table. For example, for
comparison purposes with pk.sub.B--F for Compound 1 of Table 1, the
pKa of the carboxylic acid
##STR00066##
is also listed in Table 1. pk.sub.B--F values for a number of
fluoridated organotrifluoroborates were plotted as a function of
the pKa values for the corresponding carboxylic acids as shown in
FIG. 2. Unexpectedly, a simple yet previously unknown relationship
was observed between pKa and pk.sub.B--F as seen in FIG. 2, i.e.
that the log of the pseudo-first order solvolytic rate constant,
log k.sub.solv.(B--F), of RBF.sub.3 is correlated to the pKa of the
corresponding carboxylic acid RCOOH (R=0.99) with a slope of
.about.-1.4. Without being bound by theory, one possible
explanation for this relationship could involve consideration of
the impact of various substituents on the electronic environment
experienced by the carboxylic acid and in turn, the impact of the
various substituent groups on the dissociability of the carboxylic
acid proton. The observation of a relationship between the pKa and
pk.sub.B--F values also provides, in turn, an unexpected
relationship between the pKa values and the stability or half-life
of the fluoridated organotrifluoroborate compounds in terms of
solvolytic defluoridation. A pKa of 2.85 or lower for the
corresponding COOH may inform the design of organotrifluoroborate
compositions with solvolytic half-lives of about 1000 min or
longer. The box provides an approximate range that is indicative,
although not determinative, of preferred utility.
[0212] This discovery now permits the stability of such
organotrifluoroborate structures to be predicted, such that
candidates for organoorganotrifluoroborates that will be useful in
imaging may be selected and tested. A person skilled in the art of
synthesis may consider the pKa of any carboxylic acid (with
whatever modifications) by measurement or which is known (e.g.
Jencks, Bordwell, CRC Handbook) or predicted by computer
simulation, and use this knowledge to contemplate and design
alkyltrifluoroborate structures that would have sufficiently long
half-lives for use in the production of radiotracers.
[0213] Accordingly, a person skilled in the art may exploit this
newly discovered relationship to identify candidate
organotrifluoroborate compounds that are most likely to be useful
as imaging agents. However, the invention is in no way limited to
compounds that follow this relationship. Even though certain useful
nonaromatic substituted oragnotrifluoroborate structures may
deviate from this relationship when considered based solely on the
pKa of a corresponding carboxylic acid, a person skilled in the art
will understand that certain second order effects may dampen or
accentuate the impact of various substituents on the electronic
environment. Such deviations may easily be understood in terms of
second-order effects related to steric interactions, to the
presence of a second ionizable or charged group, or to other
constraints that become clear in light of this relationship.
Moreover, this relationship may guide the person skilled in the art
when considering compounds that have no corresponding carboxylic
acid.
[0214] This relationship also allows an electron withdrawing group
to be placed as close to the boron as the carbon to which the boron
is attached, whereas the geometry of an aryl ring requires that any
electron withdrawing group be placed at least two carbon atoms away
from the boron.
Example 4A: Evaluation of Stability of .sup.18F-radiolabeled
Fluoridated Organotrifluoroboratesby Thin Layer Chromatography
(TLC)
[0215] The following is a representative example of testing of
solvolytic defluoridation of a fluoridated organotrifluoroborateas
shown in FIG. 3. 2 nmol Rhodamine-BF.sub.3 was added into 100 NL
plasma, and then incubated at 37.degree. C. After 2 hours, 200
.mu.L acetonitrile (ACN) was added to precipitate the protein from
the solution. The crude was filtered with 40 .mu.m filter paper,
and then a reddish purple solution was achieved. 1 .mu.L of this
solution was loaded on the TLC plate. The TLC plate was developed
by 15% methanol/DCM. The TLC chromatograms for an
aryltrifluoroborate (Rhodamine-ArBF.sub.3), Rhodamine-PyrBF.sub.3,
and a quaternary ammoniomethyltrifluoroborate (Rhodamine-Compound
10 of Table 1) are shown as FIG. 3.
##STR00067##
[0216] In the TLC chromatograms, Rhodamine B was conjugated with
the trifluoroborate to trace the decomposition. The hydrolyzed
product lost the negative charge, and therefore migrated much more
rapidly than the precursor. Based on the TLC chromatograms the
ArBF.sub.3 showed decomposition after incubation in plasma for two
hours. PyrBF.sub.3 exhibited greater stability than ArBF.sub.3
because less decomposition was detected on the TLC chromatogram.
Moreover, for Compound 10 of Table 1, almost no hydrolyzed product
was detected based on the fluorescence analysis. The lack of
detection of hydrolyzed product for Compound 10 of Table 1 suggests
that Compound 10 has extraordinary stability in plasma and may also
show excellent stability in animal models.
Example 4B. Evaluation of Stability of .sup.18F-radiolabeled
Fluoridated Organotrifluoroborates by High-performance Liquid
Chromatography (HPLC)
[0217] 1.1 mCi of .sup.18F-Compound 10
(.sup.18F-ammoniomethyltrifluoroborate) was mixed with 100 .mu.L of
plasma to form a .sup.18F-Compound 10-plasma mixture, and then
incubated at 37.degree. C. for two hours. 200 uL of acetonitrile
(ACN) was then added to the .sup.18F-Compound 10-plasma mixture to
precipitate the protein from the mixture. The precipated protein
portion was separated from the mixture by filtration with 40 .mu.m
filter paper, and the clear filtrate was injected into an HPLC for
stability analysis. Chromatograms for independent HPLC tests of
Rhodamine-Compound 10 of Table 1 at 0 minutes (A), 80 minutes (B),
150 minutes (C), 0 minutes (D), 150 minutes (E), and 150 minutes
(F) are shown in FIG. 4A through FIG. 4F. Based on the in vitro
test (n=3), almost no decomposition was observed in 150 mins, which
proved that Compound 10 has excellent stability in plasma. The
observed excellent stability of Compound 10 in plasma suggest that
it should present good stability under in vivo conditions.
Example 5. Radiolabeling and Animal Study with
Rhodamine(B)-AMBF.sub.3
[0218] The following compound, wherein Rhodamine(B) is conjugated
to Compound 10, was synthesized and injected into mice.
##STR00068##
[0219] Compound 18 was synthesized according to the method outlined
below:
##STR00069##
(i. NaOH, EtOAc/water, R.T., 90%; ii. 2.0 equiv. trimethyl
aluminum, 4.0 equiv. piperazine, DCM, R.T., work up, 45%; iii. 2.0
equiv. 5-Hexynoic acid NHS ester, DMF/DCM, R.T., 65%; IV. One-pot
two steps copper-catalyzed click reaction, purified by HPLC,
80%).
[0220] FIG. 5A shows HPLC traces of radioactivity in the plasma of
a rat injected with Compound 18 at 0, 80 and 150 min post
injection. FIG. 5B shows PET/CT images of the mouse at 10, 30, and
60 min post injection.
Example 7. Radiolabeling and Animal Study with
Bissulfo-Rhodamine(B)-AMBF.sub.3
[0221] The following compound, wherein sulforhodamine(B) is
conjugated to Compound 13, was synthesized and injected into
mice.
##STR00070##
[0222] FIG. 6A show the uptake value of different organs for
Rhodamine-Compound 10 at 60 min post injection into a mouse. FIG.
6B is a PET/CT image of a mouse injected with Rhodamine-Compound 10
at 60 min post injection.
Example 7. Folate-ammoniomethylamino-BF.sub.3
[0223] The following compound, Compound 10 conjugated to folic
acid, has been synthesized.
##STR00071##
[0224] Compound 20 was synthesized according to the method outlined
below:
##STR00072##
Example 8. BisRGD-rho-AMBF.sub.3
[0225] Various embodiments of the invention provide peptides or
neurotracers conjugated to the positron-emitting organofluoroborate
compounds described herein. A person skilled in the art will
understand that the positron-emitting organofluoroborate compounds
described herein can be conjugated to a ligand (e.g. a peptide or a
neurotracer) with affinity and specificity for a biomolecule of
interest, provided that a suitable linker is chosen such that the
affinity of the ligand for the biomolecule of interest is not
reduced by not more than a factor of 100. Such compounds may serve
as useful tracers.
[0226] For example, BisRGD-rho-AMBF.sub.3 (Compound 21) has been
synthesized according to the methods described in Zhibo Liu et al.
MedChemComm 2014 5: 171-179 and Liu et al. Nucl. Med and Biology
2013 40: 841-849. Methods for conjugation may include use of an
alkyne- or azide-linked tri-substituted ammonium methyl-BF.sub.3 or
disubstituted protonated ammonium-methyl-BF3 that is linked to the
peptide by copper-catalyzed or strain promoted cycloaddition
reactions. A person skilled in the art will understand that
rhodamine is used for the purposes of screening various RBF3 on TLC
and for easily measuring the specific activity of a tracer, and has
also been used specifically to direct tracers for cardiac imaging.
However, those skilled in the art will further understand that the
rhodamine can be replaced with a peptide or other ligand to be
imaged.
##STR00073##
[0227] FIG. 7 shows PET-CT images of mice injected with Compound
21.
[0228] Although various embodiments of the invention are disclosed
herein, many adaptations and modifications may be made within the
scope of the invention in accordance with the common general
knowledge of those skilled in this art. Such modifications include
the substitution of known equivalents for any aspect of the
invention in order to achieve the same result in substantially the
same way. Numeric ranges are inclusive of the numbers defining the
range. The word `comprising` may be used herein as an open-ended
term, substantially equivalent to the phrase `including, but not
limited to`, and the word `comprises` has a corresponding meaning.
As used herein, the singular forms `a`, `an` and `the` include
plural referents unless the context clearly dictates otherwise.
Thus, for example, reference to `a thing` includes more than one
such thing. Citation of references herein may be not an admission
that such references are prior art to the present invention.
Publications, including patents and patent applications, cited in
this specification are incorporated herein by reference as if each
individual publication were specifically and individually indicated
to be incorporated by reference herein and as though fully set
forth herein. The invention includes all embodiments and variations
substantially as hereinbefore described and with reference to the
examples and drawings.
* * * * *