U.S. patent application number 10/265369 was filed with the patent office on 2003-04-03 for lipophilic metal complexes for necrosis and infarction imaging.
This patent application is currently assigned to Schering AG. Invention is credited to Ebert, Wolfgang, Niedballa, Ulrich, Platzek, Johannes, Raduchel, Bernd, Speck, Ulrich, Weinmann, Hanns.
Application Number | 20030064026 10/265369 |
Document ID | / |
Family ID | 27217801 |
Filed Date | 2003-04-03 |
United States Patent
Application |
20030064026 |
Kind Code |
A1 |
Platzek, Johannes ; et
al. |
April 3, 2003 |
Lipophilic metal complexes for necrosis and infarction imaging
Abstract
This invention describes the use of metal complexes that have a
plasma protein bond of at least 10% as imaging diagnostic agents
for locating an infarction or a necrosis using lasting positive
visualization.
Inventors: |
Platzek, Johannes; (Berlin,
DE) ; Speck, Ulrich; (Berlin, DE) ; Niedballa,
Ulrich; (Berlin, DE) ; Raduchel, Bernd;
(Berlin, DE) ; Weinmann, Hanns; (Berlin, DE)
; Ebert, Wolfgang; (Mahlow, DE) |
Correspondence
Address: |
MILLEN, WHITE, ZELANO & BRANIGAN, P.C.
2200 CLARENDON BLVD.
SUITE 1400
ARLINGTON
VA
22201
US
|
Assignee: |
Schering AG
Berlin
DE
|
Family ID: |
27217801 |
Appl. No.: |
10/265369 |
Filed: |
October 7, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10265369 |
Oct 7, 2002 |
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09159657 |
Sep 24, 1998 |
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6495118 |
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60060977 |
Oct 6, 1997 |
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Current U.S.
Class: |
424/9.36 |
Current CPC
Class: |
A61K 49/06 20130101 |
Class at
Publication: |
424/9.36 |
International
Class: |
A61K 049/00 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 26, 1997 |
DE |
197 44 004.5 |
Claims
1. Use of metal complexes that have a plasma protein bond of at
least 10% as imaging diagnostic agents for locating an infarction
or a necrosis using lasting positive visualization.
2. Use of metal complexes according to claim 1, characterized in
that the latter have a protein bond of at least 50%.
3. Use of metal complexes according to claim 1, wherein the latter
have a protein bond of at least 80%.
4. Use of metal complexes according to claim 1, wherein the latter
have a molecular weight that is greater than 350 Da.
5. Use of metal complexes according to claim 1, wherein the latter
have a relaxivity that is greater than 2.0 [s.sup.-1mM.sup.-1] at
20 MHz and 37.degree. C. in plasma.
6. Use of metal complexes according to claim 1, wherein the latter
have a stability constant of at least 10.sup.15 (log
K.apprxeq.15).
7. Use of metal complexes according to claim 1, wherein the latter
contain paramagnetic metals for NMR diagnosis.
8. Use of metal complexes according to claim 1, wherein the latter
contain radioactive metals for radiodiagnosis.
9. Use of metal complexes according to claim 1, wherein the latter
contain, as a paramagnetic metal, iron, manganese, gadolinium, or
dysprosium.
10. Use of metal complexes according to claim 1, wherein the latter
contain, as a radioactive metal isotope, Tc-99m, In, Rh, Ga, Sc,
Bi, Y, Fe, Sm, Ho, Co, Cu, Gd, or Eu.
11. Use of metal complexes according to claim 1, wherein their
ligands are selected from
2-(4-Ethoxybenzyl)-3,6,9-tris(carboxymethyl)-3,6,9-triazaun-
decane-1,11-dicarboxylic acid (ligand of Eovist.sup.(R)),
2-(4-benzyloxybenzyl)-3,6,9-tris(carboxymethyl)-3,6,9-triazaundecane-1,11-
-dicarboxylic acid,
2-(4-butylbenzyl)-3,6,9-tris(carboxymethyl)-3,6,9-tria-
zaundecane-1,11-dicarboxylic acid,
2,5,8,11-tetrakis(carboxymethyl)-2,5,8,-
11-tetraazabicyclo[10,4,0]-hexadecane,
2,5,12,15-tetrakis(carboxymethyl)-2-
,5,12,15-tetraazatricyclo[10,4,0,0.sup.6,11]-icosane,
10-[1-methyl-2-oxo-3-aza-5-oxo-5-{4-perfluorooctylsulfonyl-piperazin-1-yl-
}-pentyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane,
10-[2-hydroxy-4-aza-5-oxo-7-oxa-10,10,11,11,12,12,13,13,14,14,15,15,16,16-
,17,17,17,-heptadecafluoroheptadecyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-t-
etraazacyclododecane,
2-[1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)-cycl-
ododecan-1-yl]-3-benzyloxypropionic acid,
2-benzyloxymethyl-3,6,9-tris(car-
boxymethyl)-3,6,9-triazaundecane-1,11-dicarboxylic acid,
DTPA-Lys-Asp-Asp-4-pentylbicyclo[2,2,2]-octane-1-carboxylic acid,
4-[hydroxymethyl-(4,4-diphenyl)cyclohexyloxy-phosphoric acid
diester]-3,6,9-carboxymethyl-3,6,9-triazaundecane-1,11-dicarboxylic
acid (MS-325), 4-[hydroxymethyl-(10-phenyl)-decyloxy-phosphoric
acid
diester]-3,6,9-carboxymethyl-3,6,9-triazaundecane-1,11-dicarboxylic
acid (MS-323)
N-(4-Decylphenylcarbamoylmethyl)-diethylenetriamine-N,N',N",N"-t-
etra acetic acid,
4,5-Diethyl-10,23-dimethyl-9,24-bis(3-hydroxypropyl)-16,-
17-bis[2-[2-(2-methoxyethoxy]ethoxy]-13,20,25,26,27-pentaazapentacyclo[20.-
2.1.].sup.3,6.cndot.18,11.0.sup.14,19]heptacosa-3,5,8,10,12,14,16,18,20,22-
,24-undecane.
Description
[0001] The invention relates to the subject that is characterized
in the claims, i.e., the use of metal complexes that have a plasma
protein bond of at least 10% as imaging diagnostic agents for
locating an infarction or a necrosis based on the persistent
accumulation of substances in the infarction or necrosis area.
[0002] Detection, location, and monitoring of necroses or
infarctions is an important area in medicine. Myocardial infarction
does not immediately result in irretrievable, non-functioning
tissue; rather, it initiates a dynamic process that extends over a
prolonged period (weeks to months). The disease proceeds in about
three phases, which overlap rather than being distinctly separated
from one another. The first phase, the development of myocardial
infarction, comprises the 24 hours after the infarction, in which
the destruction progresses like a shock wave (wave front
phenomenon) from the subendocardium to the myocardium. The second
phase, the already existing infarction, comprises the stabilization
of the area in which the formation of fibers (fibrosis) takes place
as a healing process. The third phase, the healed infarction,
begins after all destroyed tissue is replaced by fibrous scar
tissue. During this period, extensive restructuring takes
place.
[0003] Up until now, no precise and reliable process has been known
that would make it possible to diagnose the current phase of a
myocardial infarction in a living patient. For evaluating a
myocardial infarction, it is of decisive importance to know the
extent of the portion of tissue that is definitively lost in the
infarction and at what point the loss took place since the type of
treatment depends on this information.
[0004] Infarctions occur not only in the myocardium but also in
other tissues, especially in the brain.
[0005] While infarction can be healed to a certain extent, in the
case of necrosis, locally limited tissue death, only the harmful
sequelae for the rest of the organism can be prevented or at least
mitigated. Necroses can develop in many ways: due to injuries,
chemicals, oxygen deficits, or radiation. As with infarction,
knowing the extent and nature of a necrosis is important for
further medical treatment.
[0006] It is known that infarction and necrosis can be represented
by antibodies that are directed against biomolecules that occur
intracellularly and by porphyrins, metalloporphyrins and their
derivatives. Antibodies and porphyrins can be produced only at
great expense, however, and are problematical in terms of handling
and compatibility in several respects.
[0007] It has now been shown that, surprisingly enough, metal
complexes that have a plasm protein bond of at least 10% are
suitable as imaging diagnostic agents for locating necroses that
are produced by infarction or caused in some other way. In this
case, the basic advantage consists of a persistent positive
(bright) dyeing of necrotic areas with little to no signal
enhancement of the environs. Non-protein-bonded, otherwise
comparable complexes lead for only a short time to signal
enhancement of well-perfused tissue, whereby underperfused--even
vital--tissues remain unaffected. The blood supply to the tissues
can also be detected using T.sub.2 or T.sub.2-star (susceptibility)
effects, but differentiates non-vital from necrotic tissue. The
plasma protein bond is, as is familiar to one skilled in the art,
determined by equilibrium dialysis.
[0008] Preferably suitable are metal complexes that have a plasma
protein bond of at least 50%, especially preferably of at least
80%. The metal complexes according to the invention have a
molecular weight of at least 350 Da, and preferably at least 400
Da.
[0009] They have a T.sup.1-relaxivity of at least 2.0
[s.sup.-1mM.sup.-1], measured at 37.degree. C. and 20 MHz in plasma
(see, e.g., Chem. Rev. 1987, 87, 901). Their stability constant is
at least 10.sup.15 (log K=15).
[0010] The metal complexes according to the invention are metal
derivatives of, e.g., polyaminopolycarboxylic acids,
polyaminopolyphosphonic acids, porphyrins, texaphyrins, sapphyrins,
peptides and their derivatives, as they are described in, e.g.,
1 U.S. Pat No. 5,403,576 WO 94/27644 EP 452 392 EP 391 766 U.S. Pat
No. 5,512,294 U.S. Pat No. 5,536,491 WO 95/09848 U.S. Pat No.
5,462,725 WO 95/32741 EP 425571 U.S. Pat No. 5,562,894 WO 95/32004
U.S. Pat No. 5,407,657 U.S. Pat No. 5,370,860 U.S. Pat No.
5,463,030 WO 94/10182 JP 05186372 U.S. Pat No. 5,277,895 WO
93/16375 EP 413405 DE 43 02 287 EP 352218 DE 40 11 684 EP 405704 DE
38 34 704 EP 292689 WO 97/26017 EP 230893 WO 95/28179 U.S. Pat No.
5,318,771 WO 89/05802 U.S. Pat No. 5,422,096 U.S. Pat No. 4,899,755
U.S. Pat No. 5,527522 U.S. Pat No. 5,250,285 WO 93/03351 WO
91/03200 WO 96/23526 EP 0722739 WO 95/28392 EP 165716 EP 540075
U.S. Pat No. 5,480,990 WO 95/32192 WO 95/31219 U.S. Pat No.
5,358,704 U.S. Pat No. 5,466,438 WO 92/11232 WO 95/31444 WO
95/15319 WO 95/09161 U.S. Pat No. 5,453,264 JP 05186372 EP 661279
WO 94/03593 WO 97/30734 WO 97/30733 DE 44 05 140 GB 8903023 U.S.
Pat No. 4,880,008. U.S. Pat No. 5,583,220
[0011] If the metal complexes according to the invention are used
for NMR diagnosis, the metal must be paramagnetic. This can be an
element from the series of transition metals or lanthanides.
Suitable ions include those of the elements iron, manganese,
gadolinium, and dysprosium.
[0012] If the metal complexes according to the invention are used
for radiodiagnosis, the metal must be radioactive. This can be an
isotope from the series of elements Tc, In, Rh, Ga, Sc, Bi, Y, Fe,
Sm, Ho, Co, Cu, Gd, and Eu.
[0013] As suitable chelating agents, the following can be mentioned
by way of example:
[0014]
2-(4-Ethoxybenzyl)-3,6,9-tris(carboxymethyl)-3,6,9-triazaundecane-1-
,11-dicarboxylic acid (ligand of Eovist.sup.(R)), EP 405704
[0015]
2-(4-benzyloxybenzyl)-3,6,9-tris(carboxymethyl)-3,6,9-triazaundecan-
e-1,11-dicarboxylic acid, EP 405704
[0016]
2-(4-butylbenzyl)-3,6,9-tris(carboxymethyl)-3,6,9-triazaundecane-1,-
11-dicarboxylic acid, WO 95/28179
[0017]
2,5,8,11-tetrakis(carboxymethyl)-2,5,8,11-tetraazabicyclo[10,4,0]-h-
exadecane, U.S. Pat. No. 5,358,704
[0018]
2,5,12,15-tetrakis(carboxymethyl)-2,5,12,15-tetraazatricyclo[10,4,0-
,0.sup.6,11]-icosane, U.S. Pat. No. 5,358,704
[0019]
10-[1-methyl-2-oxo-3-aza-5-oxo-5-{4-perfluorooctylsulfonyl-piperazi-
n-1-yl}-pentyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane,
WO 97/26017
[0020]
10-[2-hydroxy-4-aza-5-oxo-7-oxa-10,10,11,11,12,12,13,13,14,14,15,15-
,16,16,17,17,17,-heptadecafluoroheptadecyl]-1,4,7-tris(carboxymethyl)-1,4,-
7,10-tetraazacyclododecane, WO 97/26017
[0021]
2-[1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)-cyclododecan-1-yl]--
3-benzyloxypropionic acid, WO 89/05802
[0022]
2-benzyloxymethyl-3,6,9-tris(carboxymethyl)-3,6,9-triazaundecane-1,-
11-dicarboxylic acid, EP 230893
[0023] DTPA-Lys-Asp-Asp-4-pentylbicyclo[2,2,2]-octane-1-carboxylic
acid, Mallinckrodt MP-2269, Vancouver SMRM, April 1997
[0024] 4-[hydroxymethyl-(4,4-diphenyl)cyclohexyloxy-phosphoric acid
diester]-3,6,9-carboxymethyl-3,6,9-triazaundecane-1,11-dicarboxylic
acid (MS-325), WO 96/23526
[0025] 4-[hydroxymethyl-(10-phenyl)-decyloxy-phosphoric acid
diester]-3,6,9-carboxymethyl-3,6,9-triazaundecane-1,11-dicarboxylic
acid (MS-323, WO 96/23526)
[0026]
N-(4-Decylphenylcarbamoylmethyl)-diethylenetriamine-N,N',N",N"-tetr-
acetic acid, EP 603403
[0027]
4,5-Diethyl-10,23-dimethyl-9,24-bis(3-hydroxypropyl)-16,17-bis[2-[2-
-(2-methoxyethoxy]ethoxy]-13,20,25,26,27-pentaazapentacyclo[20.2.1.].sup.3-
,6.cndot.18,11.0.sup.14,19]heptacosa-3,5,8,10,12,14,16,18,20,22,24-undecan-
e. U.S. Pat. No. 5,583,220.
[0028] The production of the pharmaceutical agents is carried out
in a way known in the art by the corresponding complex
compounds--optionally with the addition of the additives that are
commonly used in galenicals--being suspended or dissolved in an
aqueous medium and then the suspension or solution optionally being
sterilized. Suitable additives are, for example, physiologically
harmless buffers (such as, for example, tromethamine), additives of
complexing agents or weak complexes (such as, for example,
diethylenetriaminepentaacetic acid or the Ca complexes that
correspond to the metal complexes according to the invention)
or--if necessary--electrolytes such as, for example, sodium
chloride or--if necessary--antioxidants such as, for example,
ascorbic acid.
[0029] If suspensions or solutions of the agents according to the
invention in water or in a physiological salt solution are desired
for enteral or parenteral administration or for other purposes,
they are mixed with one or more adjuvant(s) that are commonly used
in galenicals [for example, methyl cellulose, lactose, mannitol]
and/or surfactant(s) [for example, lecithins, Tween.sup.(R),
Myrj.sup.(R)] and/or flavoring substances for taste correction [for
example, ethereal oils].
[0030] In principle, it is also possible to produce the
pharmaceutical agents without isolating the complexes. Special care
must always be taken to perform chelation in such a way that the
complexes according to the invention are virtually free of
uncomplexed metal ions that have a toxic action.
[0031] This can be ensured with the aid of, for example, color
indicators such as xylenol orange by control titration during the
production process. The invention therefore also relates to the
process for the production of complex compounds and their salts. As
a final precaution, there remains purification of the isolated
complex.
[0032] The pharmaceutical agents preferably contain 0.1 .mu.mol-1
mol/l of the complex and are generally dosed in amounts of 0.0001-5
mmol/kg. They are intended for enteral and parenteral
administration. The complex compounds are used
[0033] 1. for NMR diagnosis in the form of complexes of them with
the ions of elements with atomic numbers 21-29, 42, 44 and
58-70;
[0034] 2. for radiodiagnosis in the form of complexes of them with
the radioisotopes of elements with atomic numbers 27, 29, 31, 32,
37-39, 43, 49, 62, 64, 70, 75 and 77.
[0035] The agents meet the varied requirements for suitability as
contrast media for nuclear spin tomography. They are thus extremely
well suited for improving the image, obtained with the aid of the
nuclear spin tomograph, as regards its informational value after
oral or parenteral administration by increasing the signal
intensity. They also show the great effectiveness that is necessary
to burden the body with the smallest possible amounts of foreign
substances, and the good compatibility that is necessary to
preserve the noninvasive nature of the studies.
[0036] The good water solubility and low osmolality of the agents
make it possible to produce highly concentrated solutions, i.e., to
keep the volume load on the circulation within reasonable bounds
and to offset the dilution by bodily fluids. In addition, the
agents have not only high stability in vitro, but also surprisingly
high stability in vivo, so that release or exchange of the bonded
ions--which are inherently toxic--in the complexes occurs only
extremely slowly within the time during which the contrast media
are completely eliminated.
[0037] In general, the agents for use as NMR diagnostic agents are
dosed in amounts of 0.0001-5 mmol/kg, preferably 0.005-0.5 mmol/kg.
Owing to their advantageous radioactive properties and the good
stability of the complex compounds contained therein, the agents
are also suitable as radiodiagnostic agents. Details on such use
and dosage are described in, e.g., "Radiotracers for Medical
Applications," CRC Press, Boca Raton, Fla.
[0038] In in-vivo administration of the agents, the latter can be
administered together with a suitable vehicle such as, for example,
serum or a physiological common salt solution or together with a
protein such as, for example, human serum albumin. In this case,
the dosage depends on the type of cellular disruption, the metal
ion used, and the type of imaging method.
[0039] The agents are usually administered parenterally, preferably
i.v. They can also be administered--as already
discussed--intravascularly or interstitially/intracutaneously.
BRIEF DESCRIPTION OF THE DRAWINGS
[0040] FIGS. 1a-c are MRI images of a rat with induced renal
infarctions
[0041] FIGS. 2 a-c are MRI images of a rat with induced renal
infarctions
[0042] FIG. 3a is a graph of Contrast (infarction in Myocardium) vs
time (0-180 minutes after i.v. administration of contrast
medium)
[0043] FIG. 3b is a graph of Percentage Enhancement vs time (0-180
minutes after i.v. administration of contrast medium)
[0044] FIGS. 4a-d are four MRI images of a rat (Han. Wistar,
Schering SPF, male, .apprxeq.300 g) with myocardial infarction ( )
that is induced--by occulsion of the left coronary artery--before
and after administration of MS-325 (100 .mu.mol of Gd/kg of body
weight). (MR technology: SE_SAT, EKG-triggered, T.sub.R: about 400
ms, T.sub.E: 10 ms, nt=4, Ma: 128*256, FOV: 7*7 cm, SD.apprxeq.3
mm, 1 layer, axial)
[0045] FIG. 4a is precontrast
[0046] FIG. 4b is 6.5 minutes p.i.
[0047] FIG. 4c is 60 minutes p.i.
[0048] FIG. 4d is 19 hours p.i.
[0049] The examples below are used to give a more detailed
explanation of the subject of the invention:
[0050] MRI Experiments on Animals with Induced Renal
Infarctions
[0051] Enhancement in the MRI experiment was studied after one-time
intravenous administration of the substance Eovist.sup.(R) in
animals with experimentally induced renal necroses or infarctions.
Plasma protein bond: 10% (Europ. Workshop on Magn. Reson. in
Medicine, Santiago de Compostela, Spain, Sep. 28-30, 1994).
[0052] The induction of the renal infarctions was carried out on
anesthetized (Rompun.sup.(R)/Ketavet.sup.(R), i.p.) rats (Han.
Wistar, Schering SPF, about 200 g of body weight) by occlusion of a
(caudal) branch of the left renal artery. The contrast medium was
administered (dose: 300 or 500 .mu.mol of Gd/kg of body weight)
about 24 hours after the induction of infarction. The animals were
studied before and up to 24 hours after contrast medium
administration by MR-tomography (SISCO SIS 85, 2 tesla; SE
sequence, T.sub.R: 400 ms, T.sub.E: 15 ms, nt=4, ni=128, FOV: 12-7
cm, SD.apprxeq.3 mm, 1 layer each axial or coronary).
[0053] After the MRI experiments were completed, the anesthetized
animals were sacrificed by exsanguination (via the V. cava), and
both kidneys were prepared. To verify the infarction (size and
position), the left (infarcted) kidney was removed and sliced into
disks, and then NBT ("vital") coloring was carried out.
[0054] Before the contrast medium was administered, no
differentiation was possible between vital and avital (infarcted)
areas in the (left, treated) kidney (see FIGS. 1a, 2a).
[0055] Immediately after substance administration, the nonperfused
portion of the kidneys in each case was shown as a hypointense area
(see FIGS. 1b, 2b). Starting at about 15-30 minutes p.i., the
signal intensity increased somewhat in the non-perfused area or the
size of the delimited (low-signal) area decreased (.fwdarw.slow
diffusion in the necrosis). In the late phase (about 4-6 hours
p.i.), a considerable signal increase (enhancement) in the necrotic
area of the kidneys was noted in all of the animals studied (see
FIGS. 1c, 2c). The delineation of the necrotic area in the MRI
experiment correlated very well with the results of the
histological "vital" coloring.
[0056] MRI Experiments on Animals with Induced Myocardial
Infarctions
[0057] Necroselective enhancement was studied after one-time
intravenous administration of the substance MS-325 (WO 96/23526,
Example 10, Gd-DTPA derivative) in animals with experimentally
induced myocardial infarctions in the MRI experiment. The induction
of the myocardial infarctions was carried out on anesthetized
(Domitor.sup.(R)/Dormicum.sup.(R) i.m.) rats (Han. Wistar, Schering
SPF, male, about 300 g of body weight, N=10) by occlusion of the
left coronary artery. The contrast medium was administered (initial
solution diluted with blood, dose 100 .mu.mol/kg, i.v. bolus) 24
hours after the induction of infarction. The animals were studied
before and up to 3 hours (1, 5, 10, 15, 30, 45, 60, 75, 90, 105,
120, 135, 150 and 180 minutes) p.i. (see FIG. 3a) continuously and
24 hours after the contrast medium administration by MR tomography
(SE, SAT, EKG-triggered, T.sub.R: about 400 ms, T.sub.E: 10 ms,
nt=4, Ma: 128*256, FOV: 7*7 cm, SD.apprxeq.3 mm, 1 layer each
axial) (see FIGS. 4a-d).
[0058] After the 24 hours p.i., the animals--in the MRT--were
killed by a narcotic overdose, and an MRI experiment on
"freshly-killed" animals (no artifacts of movement) was performed.
To verify the infarction (size and position), the heart was
prepared, cut into disks and subjected to coloring with NBT (nitro
blue tetrazolinium chloride). Subjective evaluation of the
enhancement and correlation with the colored tissue were carried
out. The signal intensities were standardized to a GD-DTPA solution
(0.25 mmol/1) and the percentage enhancement S1 post-S1 pre)/S1 pre
100% and the contrast S1 inf/S1 myocard were calculated.
[0059] In the healthy myocardium (septum) and in the muscle,
maximum enhancement was shown immediately after the administration
of substance with 100% or 60%. The signal intensity then dropped
and reached a value of between 10 and 20% after 150 minutes (see
FIG. 3b).
[0060] In the infarcted area, however, the signal intensity
increased within 60-75 minutes to about 130% and then remained
almost unchanged (up to 180 minutes) (see FIG. 3b).
[0061] In contrast, it was possible to observe a negative contrast
(S1 inf/S1 myocard<1) within the first 10 to 15 minutes.
Starting approximately from the 30th minute, it was possible to
ascertain a positive contrast (S1 inf/S1 myocard>1) (see FIG.
3b).
[0062] After one day p.i., approximately the starting intensity
(.apprxeq.5-15%) was again reached in all tissues, and a
contrasting of the myocardial infarction (S1 inf/S1
myocard.apprxeq.0.98) could no longer be detected.
[0063] MS-325 shows suitability as an infarction contrast
medium.
* * * * *