Timothy R. Carroll

Novel technetium-99m-labeled platelet GPIIb/IIIa receptor antagonists as potential imaging agents for venous and arterial thrombosis.

Objectives Either venous or arterial thrombosis is a potentially life‐threatening event and existing diagnostic modalities are inadequate to diagnose and to determine the morphology of the evolving thrombus. Thus development of a noninvasive imaging agent that can detect clot location remains a critical and unmet need in nuclear diagnostic medicine. The present study was undertaken to determine the potential of platelet GPIIb/IIIa receptors compared with direct thrombin inhibitors, in the detection of venous and arterial clots. Methods Initially, the validity of exploiting the degree and extent of specific uptake and retention of a potent GPIIb/IIIa receptor antagonist in venous and in arterial thrombus was confirmed in vitro in artificially created arterial‐ or venous‐type clots, using the radiolabeled antagonist, 3H‐DMP728. This was followed by comparing the in‐vivo clot/blood distribution of various technetium‐99m (99mTc)‐labeled, DMP728‐derived, GPIIb/IIIa receptor antagonists and of thrombin inhibitors, over time, in mixed arterial/venous or venous clots in arteriovenous shunt and in venous clot models in dogs. In addition, we performed noninvasive single‐photon emission tomographic imaging of the venous clot in a deep vein thrombosis model in dogs. Results Our data confirmed that potency for the platelet GPIIb/IIIa receptors was maintained after radiolabeling of the parent active GPIIb/IIIa receptor antagonists. DMP728 demonstrated a relatively greater affinity for activated than for unactivated human platelets, which might be essential for attaining an optimal thrombus/blood (target/background) distribution ratio and the optimal detection of small clots (i.e. greater sensitivity). Conclusions These data suggest a potential utility of 99mTc‐GPIIb/IIIa receptor antagonists, but not of direct thrombin inhibitors, in the diagnosis of venous clots in deep vein thrombosis, pulmonary embolism and arterial thromboembolic disorders including stroke and coronary and peripheral artery thrombotic disorders.

Synthesis, evaluation and Tc-99m complexation of a hydrazinonicotinyl conjugate of a GP IIb/IIIa antagonist cyclic peptide for the detection of deep vein thrombosis

Abstract A cyclic peptide GP IIb/IIIa receptor antagonist containing the N-Me-Arg-Gly-Asp motif has been derivatized with the technetium chelating hydrazinonicotinyl group (Hynic). The Hynic derivative, and the Tc-99 diazenido complex, retain the high receptor affinity of the parent peptide. The Tc-99m complex shows high thrombus uptake, and rapid clearance of background, producing excellent images in under 1 h.

Tc-99m-labeled fibrinogen receptor antagonists: design and synthesis of cyclic RGD peptides for the detection of thrombi

Abstract Tc-99m labeled derivatives of N-Me-Arg-Gly-Asp containing cyclic peptide GP IIb/IIIa receptor antagonists are potential radiopharmaceuticals for the diagnosis of thrombosis. The design and synthesis of these peptides are described. These compounds are incorporated in rapidly growing thrombi under both arterial and venous conditions in canine models. Thrombi are clearly visible in images acquired at 50 min.

SYNTHESIS AND TECHNETIUM-99M LABELING OF CYCLIC GP IIB/IIIA RECEPTOR ANTAGONISTS CONJUGATED TO 4,5-BIS(MERCAPTOACETAMIDO)-PENTANOIC ACID (MAPT)

Abstract The synthesis of cyclic Arg-Gly-Asp GP IIb/IIIa receptor antagonists conjugated to 4,5-bis(S-1-ethoxyethyl-mercaptoacetamido)pentanoic acid is reported. The corresponding Tc-99m-labeled complexes were prepared by exchange labeling with Tc-99m-glucoheptonate. This indirect labeling approach is an alternative to the preformed chelate approach using mapt.

Novel technetium-99m-labeled platelet GPIIb/IIIa receptor antagonists as potential imaging agents for venous and arterial thrombosis

ObjectivesEither venous or arterial thrombosis is a potentially life-threatening event and existing diagnostic modalities are inadequate to diagnose and to determine the morphology of the evolving thrombus. Thus development of a noninvasive imaging agent that can detect clot location remains a critical and unmet need in nuclear diagnostic medicine. The present study was undertaken to determine the potential of platelet GPIIb/IIIa receptors compared with direct thrombin inhibitors, in the detection of venous and arterial clots. MethodsInitially, the validity of exploiting the degree and extent of specific uptake and retention of a potent GPIIb/IIIa receptor antagonist in venous and in arterial thrombus was confirmed in vitro in artificially created arterial- or venous-type clots, using the radiolabeled antagonist, 3H-DMP728. This was followed by comparing the in-vivo clot/blood distribution of various technetium-99m (99mTc)-labeled, DMP728-derived, GPIIb/IIIa receptor antagonists and of thrombin inhibitors, over time, in mixed arterial/venous or venous clots in arteriovenous shunt and in venous clot models in dogs. In addition, we performed noninvasive single-photon emission tomographic imaging of the venous clot in a deep vein thrombosis model in dogs. ResultsOur data confirmed that potency for the platelet GPIIb/IIIa receptors was maintained after radiolabeling of the parent active GPIIb/IIIa receptor antagonists. DMP728 demonstrated a relatively greater affinity for activated than for unactivated human platelets, which might be essential for attaining an optimal thrombus/blood (target/background) distribution ratio and the optimal detection of small clots (i.e. greater sensitivity). ConclusionsThese data suggest a potential utility of 99mTc-GPIIb/IIIa receptor antagonists, but not of direct thrombin inhibitors, in the diagnosis of venous clots in deep vein thrombosis, pulmonary embolism and arterial thromboembolic disorders including stroke and coronary and peripheral artery thrombotic disorders. Coronary Artery Dis 9:131-141 ©1988 Lippincott-Raven Publishers.