New and versatile ternary ligand system for technetium radiopharmaceuticals: water soluble phosphines and tricine as coligands in labeling a hydrazinonicotinamide-modified cyclic glycoprotein IIb/IIIa receptor antagonist with 99mTc.

A hydrazinonicotinamide-functionalized cyclic platelet glycoprotein IIb/IIIa (GPIIb/IIIa) receptor antagonist [cyclo(D-Val-NMeArg-Gly-Asp-Mamb(5-(6-(6-hydrazinonicotin amido) hexanamide))) (HYNIC-tide)] was labeled with 99mTc using tricine and a water soluble phosphine (TPPTS, trisodium triphenylphosphine-3,3',3"-trisulfonate; TPPDS, disodium triphenylphosphine-3,3'-disulfonate; or TPPMS, sodium triphenylphosphine-3-monosulfonate] as coligands. The synthesis of technetium complexes, [99mTc(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 (> or = 20,000 Ci/mmol). For example, the reaction of the HYNICtide, [99mTc]pertechnetate, stannous chloride, and tricine at pH 4-5 and room temperature results in the complex [99mTc(HYNICtide)(tricine)2], which reacts with TPPTS (50 degrees C for 30 min) to give complex 1 in > or = 90% yield as determined by radio-HPLC. Complexes 1-3 are formed as equal mixtures of two isomeric forms and are stable for > or = 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 99mTc-labeled HYNICtide and possess biological activity. The composition of these complexes was determined to be 1:1:1:1 for Tc:HYNICtide:L:tricine through a series of mixed ligand experiments on the tracer (99mTc) level. Surprisingly, this composition is maintained over a wide range of relative ligand ratios. 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 lipophilicity of the [99m Tc]HYNICtide complexes can be systematically varied by the choice of the phosphine and aminocarboxylate coligands. Using the combination of tricine and a phosphine ligand, HYNIC-derivatized peptides or other small molecules can be labeled with 99mTc in high specific activity and with high stability for potential use as radiopharmaceuticals.