CA2189967A1 - The use of porphyrin-complex or expanded porphyrin-complex compounds as localization diagnosticum for infarction or necrosis - Google Patents

Abstract

The invention relates to the use of porphyrin-complex or expanded porphyrin-complex compounds for the manufacture of a diagnosticum for the localization of an infarction and of a necrosis, wherein the infarction or necrosis may comprise an infarction of heart, kidney, intestine, lung, and/or brain, and wherein the porphyrin-complex compound may be Gd-MP and/or Mn-TPP. Gd-MP: Bis-Gd-DTPA-(Mesoporphyrin-IX-13, 17-bis¢2-oxo-4,7,10,10-tetra-(carboxylatomethyl)-1,4, 7,10-tetraazadecyl!-13, 17-diamide}, bis sodium salt of formula (A); Mn-TPP: Manganese-(III)-(Tetrakis-¢3!-(carboxylatomethoxy-phenyl)-p orphyrin)-acetate, tetra sodium salt of formula (B).

Description

21 8q9~7 The use of porphyr~n-~omplex or expanded porphyr~n-complex compounds aslocal1satlon d1agnost~cum for lnfarct~on or necros~s .

The present invention relates to the use of porphyrin-complex and P~ ntlP~ porphyrin-complex compounds for use as a diagnosticum, in particular for use as a diagnosticum for the detection, locali2ation, and monitoring of an infarction, and 5 of a necrosis.
Suitable porphyrin-complex compounds are subject of DE-A-4,232,925, DE-A-4,305,523, EP-A-336,879, and EP-A-355,041. The subject matter of these applications are inrll~lPr. by cross reference.
These porphyrin-complex compounds are used as a pharmaceutical preparation for the diagnosis and therapy of tumours .
Other suitable porphyrin-complex compounds are ~;3n prophyrin - c omp 1 ex c omp ounds ( 17 ) .
The present invention is based on the inside that these porphyrin-complex compounds can be used for the detection, lor~li7~tio~, and monitoring of an infarction, and of a necrosis, such as ischemic, alcohol, and biliary obstruction, ~-~
induced necrosis, and further laser lnduced hepatic, renal 20 and muscular necrosis.
EIereafter the use as an infarction localization diagnosticum is primarily exemplified for a myocardial infarction and for a renal infarction, but it will be obvious for a skilled person that due to similar pathophysiological 25 situations the same experimental findings apply to other infarction such as those of the intestines, lung, brain and the like .
Myocardial infarction is not a stable pathophysiological situation, but instead progresses to its 30 definite form over several weeks to months. This process can be subdivided, although overlapping, in at least three ~
periods. The first 24 hours after the start of ischemia - --CONFIRMATION COPY
, WO 95131219 PCr/EP95/01762 (acute evolving myocardial infarction~ damage progresses as a wavefront phPnnTn~nnn from the subendocardium to include the myocardium transmurally. During the second phase (established myocardial infarction~ this area stabilizes and fibrosis is S formed as a healing process. The third phase (healed infarction~ starts after all the damaged tissue is repl~ced by a fibrotic scar. During this phase, considerable remodelling takes place. So far no accurate and reliable t~-hni ~10 exists that can determine the evolution phase of lO the myocaraial infarction antemortem.
The most important long-term prognostic factor after a myocardial in~arction is the amount of myocardial tissue lost during this process. So far, no accurate and reliable technique exists to demonstrate the end-point, the amount of 15 irreversibly damaged tissue antemortem.
In the three phases described above, it is of extreme importance to have an accurate status about the amount and lor~l;7zltinn o~ the affected myocardial tissue. During an evolving myocardial infarction, it is important to assess the 20 amount of tissue at risk, the amount already lost, and from th~se parameters the amount of tissue that can be salvaged by reperfusion by thrombolysis or emergency surgical revascularisation, according to the hemodynamic status of the patient. In a--patient with unstable angina, it is often 25 impossible to discriminate between reversibly injured (akinetic, stunned) myocardium and irreversibly damaged tissue. This would nevertheless have a profound impact on the therapeutic strategy. In the case o~ compli--~t;nnc in the phase of est~hl i ~hPd infarction, requiring surgical 30 intervention, it is known that mortality is highest when dead tissue is revascularized, causing hemorrhagic infarctions. An operative strategy of repair of the ventricular septum defect or mitral insuf f iciency with selective revascularisation of non-necrotic tissue could save lifes.
Up to now, a satisfactory in vivo method for localizing and defining an infarction and the size of an infarction has not yet been available, which impedes the progress of both the basic rese rch and clinical practice (l~ . For instance, current imaging techniques such as echocardiography ( 2 ~, _ _ _ . _ _ _ _ _ _ ~ 89~67 Wo 9~31219 3 pCr/EP95/01762 nuclear scintigraphy with perfusion and infarct avid tracers (3-5) and magnetic resonance imaging ~MRI) without and with different contrast media (6-9) are still far from optimal in terr3s of sensitivity, specificity, spatial resolution, 5 contrast and rPl;~hility (l).
Slmilar cnntomr~A~ions apply for infarctions of the kidney intestines, lung and brain Necrosis is a status of local tissue death, and results from the effects of ~iiCP;~RP¢ rP,q~ in~ in an adverse and lO detrimental effect on body tissue. Necrosis may be caused by radiation, injury, chemicals, local oxygen deficiency, infections, cancer, and the like. Monitoring, localization and detection of necrosis allowes the follow up and ef~ectiveness determination of all kinds of diagnostic and 15 therapeutic therapies and tro~tmpnt The present invention relates to the use of these :~
porphyrin-complex compounds or metalloporphyrins, for the lnc~li7a~ion, visualization of an infarction and of a necrosis. This invention is based on expprimpnr~l results 20 with myocardial and renal infarctions, and with hepatic, renal and muscle necrosis demonstrating an extraordinary effect with one-to-one correlation between ~.agnetic resonance images (MRI) and histochemical preparations. This preclinical ~
result open new horizons for especially the cardiac and F
25 necrotic imaging.
The porphyrin-complex compounds comprise a ligand having the general formula I
CH
, 1 3 H~C ~
~NH Nl -~N HN~ -H C ~ CH~
.2 3 R (I) WO 95131219 PCr/LP95/01762 and at least one metal ion suitable ~or e corporal determination. Suitable metal ions have an atomic number of 21-32, 37-39, :~L2-51 and 57=33 . ..
In this general ~ormula:
R1 represents a hydrogen atom, a stralght or branched C1-C6 alkyl group, a C-C~2 aralkyl group Qr a OR' group wherein R ' is a hydrogen atom or a C1 - C1 alkyl group, R' and R3 represent a group CO~- ~ or a group (NH) O- ~A) q-NH~D, wherein Z is a group OL with L is an l0 inorganic Qr organic cation or a C1-C~ alkyl group, A is a phenylenoxy group, a C,-C1, alkylene group possibly interrupted by one or more oxygen atoms, or a C,-C13 aralkylene group, o and o~ independently represent an integer 0 or l, and D
represents an hydrogen atom or a group CO-A (COOL)o= (H) = with 15 m e~uals 0 or l under the provisio that the sum of m and o e~uals l;
R' represents a group (C=M) (NR~)o~ (A) - (NRs) -K, wherein M
represents an oxygen atom or two hydrogen atoms;
R~ represents a group (A)q-H; and K represents a complex former having the general formula IIa or :IIb, and Rs when K is formula Ira has the same meaning as ~ and when K has the formula IIb has the same meaning as D, under the proviso that a direct oxygen-nitroyen bond is not 25 allowedr wherein L1 has the meaning of a C1-C~ alkyl group or an inorganic or oryanic cation and wherein L~ ~ L3 and Li independently have the same meaniny as L1 or are an hydrogen atom, under the proviso that the co~nplex former 3 0 comprises at least two f ree carbon acid groups, and optionally ~or charge mutuali ation of the metalloporphyrin other anions, and pharmaceutically acceptable addition salts and carrierE and diIuants.

~ Wo95/31219 2~ 8~7 P~ l7~l,62 O~ ~ ~ rCOOL
N N N

5 COOH COOH COOL (lla) .

~COOL
0 ~LA--N N--OH ~N~,>
COOL (llb) For MR localization the pc,L~1-yLin-complex compounds comprises at least one paramagnetic metal ion, preferably di-or trivalent ions of the metal elements having the atomic nU~mber 21-29, 42, 44 and 57-70. Suitable metal ions are for instance chromium (III), m~nJ~nr~ce (II), r~nrg~nP~e (III), iron (III), cobalt (II), cobalt (III), nickel (II), copper =~
( I I ), praseodymium ( I I ), neodymium ( I I I ), samarium ( I I I ) and ytterbium (III) . Pre~ered are ~J~ l ;nium (III), terbium (III), dysprosium (III), holmium (III), eroium (III) and iron (III) .
For radioscintigraphic determination radioisotopes of the elements having the atomic num.ber 27, 29-32, 37-39, 42-51, 62, 64, 70, 75, 77, 82 or 83 are preferred It is noted that when the complex rr~mrQ~ln~l~ comprises various metal ions these metal ions may originate f rom the group for MR visualization and radioscintigraphic Visll~l; 7 t i on .
Futhermore the metal ion may be crmrl ~rcl in the 35 porphyrin skeleton, in the so called P~r~nr~r~ porhyrin skeleton, and/or in the complex forme~.
Examples of the porphyrin-complex compounds are the disodium salt of the digadolinium complex of N,N'-Bis[9-SUBSTITUTE S~iEET (RULE 26) ., . , . .. , . _ _ _ _ . _ . .

W095~31219 ~ 8996~7 r ~ )62 ~
carboxylato - 2 r 5, 8 - tris ( carboxylatomethyl ) - 2, 5, 8 - triazanonyl -carbamoyl~ -mesoporphyrin-IX-13, 17-diamides (Gd-MP) .
The disodium salt of the di~ l ;n;um complex of manganese ~III) - N,N' -Bis [ll-carboxylato-2-oxo-4, 7-5 bis(carboxylatomethyl)-10-(ethoxycarbonylmethyl)-1,4,7,1Q-tetr~7~lln~1Pcyl] -3,a-bis~l-propyl) -porphyrin-IX-13,17-diamides -acetates, and the di~ l In;llm complex of manganese (III) - N,N' -Bis [ll-carboxylato-2-oxo-~, 7-bi s ( carboxyl atomethyl ) -10 - ( e thoxycarbonylmethyl ) -1, 4, 7, 10 -10 tetr~il7~lln~ecyl]-3,8-bis(l-propyl)-porphyrin-IX-13,17-diamides -acetates (Mn-TPP) .
The diagnosticum has the form of a pharmaceutical formulation suitable for intra-veneous or intra-arterial injection in the form of a solution or suspension. The 15 diagnosticum m--ay comprise suitable additives, such as a buffer (tromet~amine), complex formers such as diethylenetriaminpenta-acetic acid, electrolyte such as sodium chloride, antioxydantia such as ascorbinic acid.
FurthP ~ additives, tencides and the like may be 2 0 added ~ :. .

WO 95/31219 2 ~ g 9 9 b 7 PCT/EP95/01762 Gd-MP
Bis-Gd-DTPA-{Mesoporphyrin-lX-l 3, 1 7-bis[2-oxo-4, 7,1 0,1 0-tetra-(carboxyla-tomethyl)-1, 4, 7, 10-tetraazadecyl]-13, 17-diamide}, bis sodium salt ~' r~ = NH-NHJ~ ~ Gd3~ ~COO
CO-R CO-R l`coo Mn-TPP:
Manganese-(lll)-{Tetrakis-[3]-(carboxylatomethoxy-phenyl)-porphyrin}-acetate, tetra sodium salt ¢~o~CO2'Na-Na~O~C~
~ MnOA,~
~ O~CO2-Na' Na~02C~O
Cl II~CTITI ITI: CL~CT 1^~

WO 95131219 2 1 8 q ~ ~ 7 PCT/EP9~/0176~ --The diagnosticum may comprise the porphyrin or expanded porphyrin complex compound in an amount of 0 . 0001 - 10 . 0 mmol/kg body weight . Preferred is an amount of 0 . 005 - 2 mmol/kg body weight, more preferred 0.01 - 1.0 mmol/kg body 5 weight. The actual dose is also dependent on the infarction to be localized, on the patient and on the localization technique to be~ used.
Hereafter the use of a diagnosticum comprising these specific metalloporphyrins, for the localization of an 10 infarction and of necrosis, according to the invention will be shown for the visualization of an acute myocardial infarction and renal infarction, and of necrosis. The result obtained so far did not Pncollntpr neither false positive nor false negative findings. Striking is the almost perfect 15 matching of the ex corporal localization and the histochemical confirmation.
In the experlments two paramagnetic metalloporphyrins have been used which were originally developped as potential tumour specific MRI contrast agents (10-14) . GA~lnl inium 20 mesoporphyrin (Gd-MP) and m~ln~nPCe tetraphenylporphyrin (Mn-TPP) have been used.
Rl~mrl e 1 The model of myocardial infarction was produced in rats 25 by ligation of=the left coronary artery according to an est~hl i chP~ technique (15) . Two groups of rats (12 in each~
with myocardial infarction aging 2 to 24 hours received intravenously either Gd-MP (IDF Gm.bH, Berlin) or Mn-TPP
(IDF ~m.~bH, Berlin) at dosefi of 0.1, 0.05 and 0.01 m.mol/kg 30 (4 rats each) . After an interval of 3 to 24 hours postinj ection, axial and coronal Tl weighted spin echo MR
images were obt=ained i ~i~tely before and after sacrificing the animals The excised heart was incubated with triphenyl tetrazolium chloride (TTC), which is a reliable histochemical 35 staining to distinguish the infarcted from the non-infarcted myocardium (16). In addition, two groups of rats (6 in each) were used as controls and underwent the same imaging and histochemical procedures, i . e . one group with infarction but without contrast agent injection, the other group with 2 ~ 89961 Wo 95/31219 PCT/EP95~01762 injection (3 with Gd-MP, 3 with Mn-TPP) but without inf arction . The dif f erence between the inf arcted and non-infarcted myocardium seen on MR images was quantified by measuring the signal intensities (SI) with a monitor defined =~
5 region of interest and expresse_ as contrast ration (CR) :CR = SI infarct / SI noninfarct (mean i SD) . The metal content of the tissue was measured by ICP-AES. Finally the MR
images were carefully compared with the corresponding macro-and microscopic tissue preparations and correlated with the lO results of local metal content measurement.
The infarct of the 6 control rats could not be discerned by MRI without contrast media. E~owever, 3 to 24 hours after injection of either Gd-MP or Mn-TPP, all 24 rats with myocardial infarction exhibited on MR imag~s a clear 15 flPl in~Ation of the infarcted areas of the heart, which precisely matched the areas of negative staining on the histochemical samples (Fig. l) . The CRs between the infarcted and nnninfArcted regions were 3 40 i 0.26 at 3 hours and 1.92 i 0.17 at 24 hours after contrast agent injection. Even the 20 small dose of O.Ol mmol/kg worked well (CR = 1.84 ~ 0.13 at lO hours postinjection). Neither false positive findings (i.e. contrast ~nhAnn~mPnt in noninfarcted area) nor false negative findings (i.e. infarcted myocardium not ~nhAnnPfl with the agents) were obtained. The Gd content was as much as 25 9 fold higher in the infarcted myocardium (Table l), suggesting that the MRI signal ~nhAn~ t is mainly due to a preferential accumulation of metalloporphyrins in infarcted -~
tissue .

3 0 Exam~l e 2 ` -Using the same model of myocardial infarction, in two rats minor necrotic lesions were found at the ligation sides.
The MRI was per_ormed lO hours after Mn-TPP (0.05 mmol/kg body weight) intervenous injection. The technique is 35 so sensitive that even lesions between l to ' mm in size were easily detectable (Fig.2) .

21 ~9~7 Wo 95131219 PCTIEP95/01762 ExamQle 3 A rat with partial renal infarction of the rlght kidney was injected with Gd-MP (O.l mmol/kg body weiyht by intervenous inj ection) .
24 Bours after Gd-MP injection, the Gd-content (measured with ICP-AES technir,~ue) of the infarcted and non infarcted kidney were similar but the signal intensities was at least two fQld higher for the infarcted kidney (Table 2).
Presumably the mprhAn; ~m for metalloporphyrin induced lO specific Pnh~nrPmPnt seems not only related to an ~rr~lm~ tion of the porphyrin-complex compound in the infarcted tissue. An increased relaxivity of the metalloporphyrins induced by a change in local molecular environment plays also a role in the observed increased 15 signal intens~ty (Fig . 3 ) .
ExamQle 4 In order to evaluate the potential of these agents for the detection and monitoring of other types of necrosis 20 following experiments were performed.
.Srnnt~ner,l-~ liver necrosis was induced by ligation of the common bile duct in rats. 72 ~ours after surgery both types of metalloporphyrins (Gd-MP and Mn-TPP) were intravenously injected at a dose of 0 05 mmol/kg. Already lO
25 minutes after injection areas of strong PnhAnrPmPnt could be observed in the liver. This ~nh~nrPm.~nt lasted for about one week. Macroscopic Plr~m1n~tlrr~ confirmed that the Pnh~nrinq areas corresponded to cholestatically related liver necrosis.
A second exper~ment consisted in the induction of local 30 necrosis ln liver, kidney and muscle in rats by local inj ection of absolute alcohol . Imaging 8 to 24 hours af ter alcoholisation of both metalloporphyrins caused a concentric Pnhilnr~ t of the induced lesions. Those remained enhanced for several days. Macroscopy and microscopy after sacrifice 35 confirmed the necrotic nature of the lesions (Fig. 4A, 4B, 4C) Wo 95/31219 2 1 ~ 9 q 6 7 PcrlEP95/01762 mnl e 5 Infarcted myocàrdium induced the model of example l and laser induced necrosis using standard laser model techniques were studied in rats.
Before injection of the contrast agents, the induced necrosis were not visible on MR images. However, positive Pnh;~nr~ t appeared in these lesions after contrast agent injection and persisted for more than 24 hours.
The contrast agents used were Mn-~PPS4 ~Mn-meso-tetra-~4-sulfonato-phenyl)-porphyrine (available from Porphyrin Products Inc., Logan, Utah, USA), in an amount of 0.05 mmol/kg, and Gd-Mn-porphyrin (Mn(III) -{N-Bis- [ll-carboxylato-2-oxo-4, 7, lO-tris- (carboxylatomethyl) -l, 4, 7, lO-tetr~7~-ln~1Pcyl~-methylpyrroporphyrin-XXI-amide}-acetate, Gd-15 complex, sodium salt can be prepared according to example l/14 in W084/07894).
Methylpyrroporphyrinethylester (Aldrich Chemicals) jis reacted with hydrazine in pyridine and subsequently with ~-nr~nPce acetate in acetic acid. The obtained intPrmP~i ~te 20 i5 reacted with DTPA-monoanhydride-monoethyleSter in absolute N,N-dimethylf~ ~1P and addition of triethylamine. After hydrolysis and neutralisation complexation is carried out with the use of ra~ 1 inivm acetate in an amount of 0 . 05 mmol/kg .
The experimental results are summarized in tables 3 and 4.
The fact that necrosis of different origine, vascular and biliary infarction and alcoholisation, all show similar degreEs of enhancement opens new prospectives f or the 30 monitoring of therapies that ultimately cause tissue necrosis, such as radiot_erapy, chemotherapy, thermotherapy, laser therapy, ultrasound and radiofrequency ablation, alrnhnl i ~tion, etc. ...
~***~

WO 95l312lg 2 ~ ~ 9 q 6 7 PCT/EP9~/01762 Table Gd content and MRI signal intensity in rats with myocardial infarction measured 24 hours after Gd-MP (0.05 mmol/kg) Myocardium Gd (llmol/g) Signal Intensity ICP -AES ( ROI ) infarcted ~ 0 . 065 i O 006 422 :~ 31 non infarcted 0.007 i 0.002 193 i 17 ratio7 9 . 29 2 .19 Note: iinfarcted/non infarcted .

Ta~l~ 2 Gd content and signal intensity in a rat ~ith partial renal infarction measured 24 hours after Gd-MP (0.1 mmol/kg).

Tissue . Gd (~mol/g) Signal intensity ICP-AES (24 h) inf~rcted kidney 0 . 75 1340 40 non-infarcted kidney 0.79 63 WO 9~/31219 l3 PCT/EP95101762 Table 3 MRI Findings af ter myocardial in~arction*
Signal Intensity CR
Normal Infarcted Myocardium Myocardium Infarct/Normal Mn-TPPS4 343 583 1.7 Gd-Mn-porphyrin 320 669 2 . l * The agents were inj ected 12 hours be~ore MR imaging in rats with myocardial infarction (MI) aging 24 hours.

Tal~le 4 MR Imaging in Laser Induced Necrosis~

Signal Intensity CR
Precontrast 24 h post-contrast Lesion/
Liver tissue Necrosis Normal Mn-TPPS4 518 ~ 21 625 + 34 1063 + 52 1. 7 Gd-Mn-porphyrin 501 t 30 593 + 27 1126 + 18 1.9 * The signal intensities of the liver and necrotic lesions were derived from pre- and 24 hours postcontrast MR images.

21 899b7 WO 95/31219 14 P~ /62 Legends for figures-Fig. 1 (A-C). MRI and macroscopic photographs of a rodent heart with myocardial infarction. The MRI was p~. [Ol ..led 24 hours after Gd-MP
(0.lmmol/kg) illL~r-.~-uu~ injection and imm~flia~r-~y after sacrificing the animal.
A, B: Coronal (A) and axial (B) T1 weighted spin echo images (TR/TE =
300/15 msec, slice thickness = 2 mm, FOV = 100 mm, matrix size = 256 x 256, NEX = 6) display a strongly signal ~nhanrm~n~ in almost all left ventrical wall including part of the ventricular septum (arrows) but not some papillary .ll~u..l-dial structures (arrowheads). The graduation near the frame on the right side represents I cm.
C: Axial section of the heart on a similar piane to the axial MR image (B), incubated with 1 % triphenyl t~L.~uliull. chloride (TTC) for 15 minutes and fixed overnight with 10 % formalin, shows the left Yentricai wall including part of the septum as unstained, (pale) infarcted area. Arrowheads indicate the intact myocardial papillae shown in B.
Fig. 2 (A-C). MF;I and macroscopic ~IluLù~ ,uhs of a rodent heart with lûcal injury caused by ligation. Such minute necrotic Icsions werc found at the ligation sites in two rats who failed to form real infarction and were exduded as successful models from the study. The MRI was performed 10 hours after Mn-TPP (0.05 mmol/kg) intravenous injection and immP~iia~ly after sacrificing the animal.
A, B: On both the coronai (A) and axial (B) MR images (the same p~
as in fig. 1), an }Iy~c:l;llL~ -~e lesion(arrow) of a~u~u;dl~aL~:ly I mm in size. can be clearly seen in the left ventricular wall, despite a parhal volume effect (i.e. the diameter of the lesion is smaller than the thickness of the MR slice;
otherwise the lesion would appear brighter). The graduation near the frame on the right side represents I cm.

2 ~ 9 b7 C.: TIC stained axiai section of the heart on a simiiar plane to the MR image (B) displays the ligature and adjacent minutc unstain~d n~crotic l~sion (arrow).
Fig. 3 ~A - D~. MRI and ~la~us~ulJic phulu~ s of a rat with parhal r~nal infarction in the right kidney.
A - C: ~xial T1 weighted spin echo images (Ti~/TE = 600/15 msec, the rest iJA~ rl ~ are the same as in Fig. I A and B.
A: On i~leLul~Lld~l plain scan in the right kidney, infarcted and nu...l~f.l.~Le.
parts cannot be discerned.
B: Ten minutes after Gd-MP 0.1 mmol/kg) intravenous injection, the nulul.rdl~led pdl~ yllla (lower part) is strongly enhanced in contrast with the lln~nh~nr~l infarcted ~dle~ a (upper part), which is gradually filled up with time by the agent (images not shown).
C: Forty-eight hours postcontrast, when the signal intensity of the nu.ul,rdl.~d kidney (lower part) has almost normalized, the infarcted upper part of the kidney is still strikingly enhanced.
D: Macroscopic view of the right kidney on a similar section as in C. Note how well the areas of the infarcted and noninfarcted parenchyma seen on the speomwr~ m~ch with the con~ it e h~nc~ MR im~e (C).

WO9S/31219 2 1 899 67 P~ . I/OZ

Legends for Fig. 4 A-D: Axial Tl W SE MR images and macroscopic pllulu~l~ s of rat liver with alcohol induced l-oA~ nn necrosis.
A. On ~ u~ aal image, the 10 hours old necrotic lesion (arrow) is isointerl3e and therefore can not be detected.
B. Ten minutes after illlla~_~.vuS injection of ~e ~ .._3u~lplly~
(Gd-MP, 0.05 mmol/kg), the lesion (arrow) appear3 ~y~uill~ Se with some central bright spots (blood vessels). The lesion .. ~i ;. Ally enhances with time whereas the liver intensity l~.ù~ Iy decreases (images not shown).
C 24 houls later when the liver intensity has largely decreased, the bright 'i Iesion appears bright (arrow~ with some central dark spots. This suggests a specific retention and a strong affinity of the mehlloporphyrin for the necrosis.
D. Macroscopic phu~u;~;~apl~ of the liver section in the plane similar to MR
images, The alcohol induced .u~bul~liull necrosis (arrow) has the same J..VI~' ' 6Y with some in~ mAI blood vessels, as shown on the contrast enhanced MR images.

WO g5/31219 17 . ~ t. . 1762 References 1. Roberts R, Kleiman N 5. Earlier diagnosis and treatment of acute myocardial infarction nPcpccifAtpc the need lor a n~w diagnostic mind-set'. Circulation 1994; 89: 872-881.
2. Stamm R, Gibson R, Bishop H, Carabello B, Beller G, Martin R, Echocardiographic detection of infarct-localized asynergy and remote asynergy during acute myocardial infarction: correlation with the extent Of .~ ,;r~ ~ coronary disease. Circulation 1983; 67: 233-234.
3. Wackers FJT, Busemann Sokole E, Samson G et al. Value and ljmitAtinnc of thallium-201 scintigraphy in the acute phase of myocardial infarction. N Engl J Med 1976; 295:1-5.
4. Lahiri A, RhAttArhArya A, Carrio I. Antimyosin antibody imaging of l~yu~ di~l necrosis. In: Zaret BL, Beller GA, eds. Nuclear cardiology:
shte of the art and future directions. Philadelphia: Mosby - Year Book, 1993; 331-338.

5. Zaret BL, Wackers FJ. Nuclear cardiology (review). N Engl l Med 1993;
329: 775-783.

6. De Roos A., Van Rossum A., Van der Wall E., Postema S., Doornbos J., ~thPijccPn N. Reperfused and n.a...~t,~.r.lsed myocardial infarction:
diagnostic potential of Gd-DTPA-enhanoed MR Imaging. Radiology 1989;
172: 717-720.

7. Saeed M., Wendland M., Takehara Y., Masui T., lliggins C. Reperfusion and irreversible myocardial injury: idPntifirAtic~ with a nonionic MR
imaging contrast medium. Radiology 1992;182. 675-683.

8. Weissleder R., Lee A., Khaw B., Shen T., Brady T. Antimyosin-labeled ... u.. o~.~Jl~lline iron oxide allows detection of myocardial infarct: MR
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9. Johnston D, Thompson R, Liu P. Magnetic resonance imaging during acute myocardial infarction. Am J Cardiol 1986; 58: 214-219.
.. ...

WO95/31219 ~1 89967 P~,J~ , I/62 10. Chen. C., Cohen J., Myers C., Sohn M. I'aramagnPtic me~alloporphyrins as potential contrast agents in NMR imaging. E~EBS lPtters 198~; 168: 70-74.

11. Nelson J., Schmiedl U., C;h~nlcl~nd E. Metailoporphyrins as tumor-seeking MR~ contrast media and as potential selective treatment c~ncifi7f~rc Invest Radiol 1990; 25: 571-73.

12. Nelson J., Schmiedl U. ru~ s as contrast media. Magn Res Med 1991; 22: 366-371.

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Claims (5)

19

1. The use of porphyrin- complex or expanded porphyrin-complex compounds for the manufacture of a diagnosticum for the localization of an infarction and of a necrosis.

2. Use of claim 1, wherein the infarction and/or the necrosis comprises an infarction or necrosis of hart, kidney, intestine, lung, and/or brain.

3. Use of claim 1 or 2, wherein the porphyrin-complex compounds comprise a radioactive and/or (super) paramagnetic label metal.

4. Use of claim 1-3, wherein the diagnosticum comprises the porphyrin-complex compound in an amount of 0.001 - 1.0 mmol/kg body weight.

5. Use of claim 1-4, wherein the porphyrin-complex compound is Gd-MP and/or Mn-TPP.