Benzodiazepine derivatives for imaging thrombi

Details Benzodiazepine derivatives for imaging thrombi Benzodiazepine derivatives for imaging thrombi

1999-04-14

2001-01-09

Dudash, Diana (Department: 1619)

Drug, bio-affecting and body treating compositions

Radionuclide or intended radionuclide containing; adjuvant...

In an organic compound

C424S001110, C424S001650, C424S009100, C540S504000, C540S569000, C540S518000, C544S285000, C534S014000, C514S213010

Reexamination Certificate

active

06171578

ABSTRACT:

The present invention relates to the field of diagnostic imaging of thrombosis. More particularly, the invention relates to pharmaceutical compositions for imaging thrombi.
BACKGROUND OF THE INVENTION
Thrombi are blood clots which form within the cardiovascular system. Formation of thrombi, i.e., thrombosis, may cause local obstruction of blood vessels, for example in veins, arteries, or capillaries. Venous thrombi usually form in lower limbs and may produce acute symptoms by causing inflammation of the vessel wall or obstruction of the vein. Pieces of venous thrombi may also circulate through the cardiovascular system to form a plug, or embolus, at a distant site such as the lung. Arterial thrombi are commonly associated with vascular disease such as atherosclerosis and may produce tissue ischemia (local anemia) by obstructing blood flow or by embolizing into capillaries. Thrombi may also form in the heart, for example, on inflamed or damaged valves, on tissue adjacent to myocardial infarcts, within injured chambers, or on prosthetic valves.
While all thrombi contain the protein fibrin and blood cells, the proportions of particular blood cells present and of fibrin/blood cell may differ, for example, because of the blood flow at the site of thrombus formation and thrombus age. Arterial thrombi which form at sites of high blood flow contain platelet aggregates bound together by thin fibrin strands. Venous thrombi form in areas of stagnant blood flow and contain red blood cells with interspersed fibrin and fewer platelets. Thrombi which form under conditions of slow to moderate flow contain a mixture of red cells, platelets, and fibrin. Leukocytes, the white blood cells, migrate to and become incorporated into thrombi as they age. In addition, aggregated platelets in aging thrombi lyse and are replaced by fibrin.
Accurate detection of the various kinds of thrombi is necessary to choose, to optimize and to monitor treatment, which may differ by virtue of the location and nature of the thrombus. Recently, ACUTECT™, a kit for making the
99m
Tc-radiolabeled peptide, apcitide, was approved for sale in the U.S. as a radiopharmaceutical product for imaging acute deep vein thrombosis (DVT). The commercial availability of ACUTECT™ will significantly improve the accuracy of detection of acute DVT, and consequently, treatment of such thrombi. However, no radiopharmaceutical has thus far been approved for detection of other kinds of thrombi, and the most accurate methods available for detection of other venous thrombi such as pulmonary emboli and of arterial thrombi are invasive. Additional non-invasive agents capable of detecting the various kinds of thrombi are needed.
99m
Tc-radiolabeled apcitide binds to the GPIIb/IIIa receptor, the most abundant glycoprotein on the surface of platelets. The GPIIb/IIIa receptor is required for platelet aggregation and is a critical component of thrombus formation, functioning as the receptor for the adhesive proteins fibrinogen (the precursor of fibrin), fibronectin, von Willebrand factor, and vitronectin. The interaction between GPIIb/IIIa and its natural ligands is mediated by the tripeptide sequence arginine-glycine-aspartic acid (RGD). Apcitide contains the tripeptide—L-[S-(3-aminopropyl)cysteine]-glycine-aspartic acid—, which is believed to interact with GPIIb/IIIa.
U.S. Pat. No. 5,645,815 discloses that high quality thrombus imaging agents comprise GPIIb/IIIa receptor binding compounds which are capable of inhibiting platelet aggregation with an IC
50
less than about 0.3 &mgr;M. U.S. Pat. No. 5,830,856 discloses that such imaging agents may comprise GPIIb/IIIa receptor binding compounds which are capable of inhibiting platelet aggregation with an IC
50
less than about 1.0 &mgr;M.
One class of GPIIb/IIIa binding platelet aggregation inhibitors, disclosed in U.S. Pat. Nos. 5,403,836; 5,493,020; 5,565,449; 5,663,166; 5,674,863; 5,674,865; 5,705,890; and 5,716,951, are substituted benzodiazepinediones. The benzodiazepinedione scaffold approximates the “cupped” configuration of the RGD tripeptide, which correlates with platelet aggregation inhibitory activity. U.S. Pat. Nos. 5,403,836; 5,493,020; 5,565,449; 5,663,166; 5,674,863; 5,674,865; 5,705,890; and 5,716,951 describe several large classes of benzodiazepinedione derivatives, including derivatives of the general formula:
where R
1
, R
2
, and R
4
are each independently H or a reactive group; R
3
and R
5
are each independently H, alkyl, substituted alkyl, aryl, substituted aryl, or a combination thereof; D is hydrogen, phenyl, or lower alkyl; L
1
is a linking moiety; and Q
1
, is a positively charged nitrogen-containing moiety. The substituted benzodiazepinediones of U.S. Pat. Nos. 5,403,836; 5,493,020; 5,565,449; 5,663,166; 5,674,863; 5,674,865; 5,705,890; and 5,716,951 are exclusively described as therapeutic agents.
Ku, et al. (1993)
J. Amn. Chem. Soc
. 115, 8861-8862 describes design and synthesis of benzodiazepine derivatives useful as inhibitors of glycoprotein IIb/IIIa receptor mediated platelet aggregation. The 1,4-benzodiazepine derivatives of Ku, et al. are exclusively described as potential antithrombotic agents.
U.S. Pat. No. 4,656,026 describes spin-labeled benzodiazepines for magnetic resonance imaging of brain tissue. U.S. Pat. No. 4,777,169 discloses radioiodinated benzodiazepines used in radioimmunoassays to determine benzodiazepine levels in body fluids. U.S. Pat. No. 4,885,152 describes radioiodinated and radiobrominated benzodiazepine derivatives for detection of benzodiazepine receptors in cerebral diseases. U.S. Pat. No. 4,997,771 discloses
3
H-benzodiazepines used to assay benzodiazepine receptor binding activity. U.S. Pat. No. 5,096,695 discloses radioiodinated benzodiazepine derivatives for use as brain imaging agents. WO 95/12610 discloses N-alkyl peptide chelators which may be covalently linked to a variety of ligands, including benzodiazepines, for use in complexing rhenium or technetium ions. JP 5-310711 discloses N-substituted benzodiazepin-2-one derivatives for electron spin resonance imaging of benzodiazepine receptors in brain nerves to diagnose epilepsy, parkinsonism, cerebral ischemia and cerebral edema.
SUMMARY OF THE INVENTION
The present inventors have found that benzodiazepine derivatives may be employed as effective thrombus imaging agents.
In one embodiment, the invention provides a compound comprising a glycoprotein IIb/IIIa receptor binding benzodiazepine derivative covalently linked to a metal ion chelator, wherein the compound retains substantial potency, as measured in a standard assay for inhibition of platelet aggregation.
In another embodiment, the invention provides a compound having a formula:
wherein M is a metal ion chelator.
In another embodiment, the invention provides a scintigraphic imaging agent comprising a &ggr;-emitting radionuclide and a compound of the invention.
In another embodiment, the invention provides a complex of a &ggr;-emitting radionuclide and a compound of the invention.
In yet another embodiment, the invention provides a
99m
Tc chelate of a compound comprising a glycoprotein IIb/IIIa receptor binding benzodiazepine covalently linked to a metal ion chelating moiety, wherein the compound retains substantial potency for inhibition of human platelet aggregation, as measured in a standard inhibition of platelet aggregation assay, when chelated to
99m
Tc, and wherein the chelate contains at least one sulfur ligand bound to
99m
Tc.
In another embodiment, the invention provides a method of detecting a thrombus in a mammalian body, comprising the steps of administering an effective diagnostic amount of the scintigraphic imaging agent or complex of the invention to the body and detecting radiation localized at the thrombus.
DETAILED DESCRIPTION OF THE INVENTION
The patent and scientific literature referenced herein establish the knowledge available to those with skill in the art. The issued U.S. patents and allowed applications are hereby incorporated by reference.
The compounds of the invention comprise a g

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