NOVEL TC-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, Th us development of a noninvasive imaging agent that can detect clot loc ation remains a critical and unmet need in nuclear diagnostic medicine , The present study was undertaken to determine the potential of plate let GPIIb/IIIa receptors compared with direct thrombin inhibitors, in the detection of venous and arterial clots. Methods Initially, the val idity of exploiting the degree and extent of specific uptake and reten tion of a potent GPllb/llla receptor antagonist in venous and in arter ial thrombus was confirmed in vitro in artificially created arterial- or venous-type clots, using the radiolabeled antagonist, H-3-DMP728, T his was followed by comparing the in-vivo clot/blood distribution of v arious technetium-99m (Tc-99m)-labeled, DMP728-derived, GPllb/llla rec eptor antagonists and of thrombin inhibitors, over time, in mixed arte rial/venous or venous clots in arteriovenous shunt and in venous clot models in dogs, In addition, we performed noninvasive single-photon em ission tomographic imaging of the venous clot in a deep vein thrombosi s model in dogs. Results Our data confirmed that potency for the plate let GPllb/llla receptors was maintained after radiolabeling of the par ent active GPllb/llla receptor antagonists, DMP728 demonstrated a rela tively greater affinity for activated than for unactivated human plate lets, which might be essential for attaining an optimal thrombus/blood (target/background) distribution ratio and the optimal detection of s mall clots (i,e, greater sensitivity) Conclusions These data suggest a potential utility of Tc-99m-GPIIb/IIIa receptor antagonists, but not of direct thrombin inhibitors, in the diagnosis of venous clots in dee p vein thrombosis, pulmonary embolism and arterial thromboembolic diso rders including stroke and coronary and peripheral artery thrombotic d isorders. Coronary Artery Dis 9:131-141 (C) 1998 Lippincott-Raven Publ ishers.