NEW AND VERSATILE TERNARY LIGAND SYSTEM FOR TECHNETIUM RADIOPHARMACEUTICALS - WATER-SOLUBLE PHOSPHINES AND TRICINE AS COLIGANDS IN LABELINGA HYDRAZINONICOTINAMIDE-MODIFIED CYCLIC GLYCOPROTEIN IIB IIIA RECEPTOR ANTAGONIST WITH TC-99M/

A hydrazinonicotinamide-functionalized cyclic platelet glycoprotein II b/IIIa (GPIIb/IIIa) receptor antagonist p-Mamb(5-(6-(6-hydrazinonicoti namido)hexanamide))) (HYNICtide)] was labeled with Tc-99m using tricin e and a water soluble phosphine (TPPTS, trisodium triphenylphosphine-3 ,3',3''-trisulfonate; TPPDS, disodium triphenylphosphine-3,3'-disulfon ate; or TPPMS, sodium triphenylphosphine-3-monosulfonate] as coligands . The synthesis of technetium complexes, [Tc-99m(HYNICtide)(L)(tricine )] (1, L = TPPTS; 2, L = TPPDS; 3, L = TPPMS), can be performed in one or two steps in high yield and with high specific activity (greater t han or equal to 20 000 Ci/mmol). For example, the reaction of the HYNI Ctide, [Tc-99m]pertechnetate, stannous chloride, and tricine at pH 4-5 and room temperature results in the complex [Tc-99m(HYNICtide)(tricin e)(2)], which reacts with TPPTS (50 degrees C for 30 min) to give comp lex 1 in greater than or equal to 90% yield as determined by radio-HPL C. Complexes 1-3 are formed as equal mixtures of two isomeric forms an d are stable for greater than or equal to 6 h in the reaction mixture and in dilute solution. Both isomeric forms of complex 1 were found by a platelet-binding assay to contain the Tc-99m-labeled HYNICtide and possess biological activity. The composition of these complexes was de termined to be 1:1:1:1 for Tc:HYNICtide:L:tricine through a series of mixed ligand experiments on the tracer (Tc-99m) level. Surprisingly, t his composition is maintained over a wide range of relative ligand rat ios. The relative bonding capability of the three phosphine coligands to the Tc was determined by spiking various amounts of TPPDS or TPPMS into TPPTS and falls in the order TPPMS > TPPDS > TPPTS. The lipophili city of the [Tc-99m]HYNICtide complexes can be systematically varied b y the choice of the phosphine and aminocarboxylate coligands. Using th e combination of tricine and a phosphine ligand, HYNIC-derivatized pep tides or other small molecules can be labeled with Tc-99m in high spec ific activity and with high stability for potential use as radiopharma ceuticals.