BIOLOGICAL EVALUATION OF THROMBUS IMAGING AGENTS UTILIZING WATER-SOLUBLE PHOSPHINES AND TRICINE AS COLIGANDS WHEN USED TO LABEL A HYDRAZINONICOTINAMIDE-MODIFIED CYCLIC GLYCOPROTEIN IIB IIIA RECEPTOR ANTAGONISTWITH TC-99M/

A hydrazinonicotinamide-functianalized cyclic glycoprotein IIb/IIIa (G PIIb/IIIa) receptor antagonist p-Mamb(5-(6-(6-hydrazinonicotinamido)he xanamide))) (HYNICtide)] was labeled with Tc-99m using tricine and a w ater soluble phosphine [trisodium triphenylphosphine-3,3',3''-trisulfo nate (TPPTS); disodium triphenylphosphine-3,3'-disulfonate (TPPDS); or sodium triphenylphosphine-3-monosulfonate (TPPMS)] as coligands. Thre e complexes, [Tc-99m(HYNICtide)(L)(tricine)] (1, L = TPPTS; 2, L = TPP DS; 3, L = TPPMS), were evaluated in the canine arteriovenous shunt (A V shunt) model and canine deep vein thrombosis imaging (DVT) model. Al l three agents were adequately incorporated into the arterial and veno us portions of the growing thrombus (7.8-9.9 and 0.2-3.7% ID/g, respec tively) in the canine AV shunt model. In the canine DVT model all thre e complexes had thrombus uptake that far exceeded the negative control , [Tc-99m]albumin. The findings indicate similar incorporation into a venous thrombus (% ID/g = 2.86 +/- 0.4, 3.4 +/- 0.9, and 3.38 +/- 1.1 for complexes 1, 2, and 3, respectively) and similar blood clearance w ith a t(1/2) of approximately 90 min. Gamma camera scintigraphy allowe d visualization of deep vein thrombosis in as little as 15 min with th e thrombus/muscle ratios being 3.8 +/- 0.8, 2.8 +/- 0.4, and 3.0 +/- 0 .8 for complexes 1, 2, and 3, respectively. The visualization of the t hrombus improved over time, and the thrombus/muscle ratios were 9.7 +/ - 1.9, 13.8 +/- 3.6, and 9.4 +/- 2 for complexes 1, 2, and 3, respecti vely, at 120 min postinjection. The administration of complexes 1-3 di d not alter platelet function, hemodynamics, or the coagulation cascad e. Furthermore, complexes 1-3 did not significantly differ in their up take into the growing thrombus, blood clearance, and target to backgro und ratios. Therefore, all three complexes have the capability to dete ct rapidly growing venous and arterial thrombi.