Lipophilic metal complexes for necrosis and infarction imaging

Details Lipophilic metal complexes for necrosis and infarction imaging Lipophilic metal complexes for necrosis and infarction imaging

1998-09-24

2002-12-17

Jones, Dameron L. (Department: 1614)

Drug, bio-affecting and body treating compositions

In vivo diagnosis or in vivo testing

C534S007000, C534S010000, C534S014000, C424S001110, C424S001650

Reexamination Certificate

active

06495118

ABSTRACT:

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.
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.
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.
Infarctions occur not only in the myocardium but also in other tissues, especially in the brain.
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.
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.
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
2
or T
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.
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.
They have a T
1
-relaxivity of at least 2.0 [s
−1
mM
−1
], measured at 37° C. and 20 MHz in plasma (see, e.g., Chem. Rev. 1987, 87, 901). Their stability constant is at least 10
15
(logK=15).
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.,
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
WP 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
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.
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.
As suitable chelating agents, the following can be mentioned by way of example:
2-(4-Ethoxybenzyl)-3,6,9-tris(carboxymethyl)-3,6,9-triazaundecane-1,11-dicarboxylic acid (ligand of Eovist®, EP 405704
2-(4-benzyloxybenzyl)-3,6,9-tris(carboxymethyl)-3,6,9-triazaundecane-1,11-dicarboxylic acid, EP 405704
2-(4-butylbenzyl)-3,6,9-tris(carboxymethyl)-3,6,9-triazaundecane-1,11-dicarboxylic acid, WO 95/28179
2,5,8,11-tetrakis(carboxymethyl)-2,5,8,11-tetraazabicyclo[10,4,0]-hexadecane, U.S. Pat. No. 5,358,704
2,5,12,15-tetrakis(carboxymethyl)-2,5,12,15-tetraazatricyclo[10,4,0,0
6,11
]-icosane, U.S. Pat. No. 5,358,704
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, WO 97/26017
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
2-[1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)cyclododecan-1-yl]-3-benzyloxypropionic acid, WO 89/05802
2-benzyloxymethyl-3,6,9-tris(carboxymethyl)-3,6,9-triazaundecane-1,11-dicarboxylic acid, EP 230893
DTPA-Lys-Asp-Asp-4-pentylbicyclo[2,2,2]-octane-1-carboxylic acid, Mallinckrodt MP-2269, Vancouver SMRM, April 1997
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
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)
N-(4-Decylphenylcarbamoylmethyl)-diethylenetriamine-N,N′,N″,N″-tetracetic acid, EP 603403
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.]
3,6
.18,11.0
14,19
]heptacosa-3,5,8,10,12,14,16,18,20,22,24-undecane. U.S. Pat. No. 5,583,220.
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 th

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