Synthesis, Characterization, and Biological Evaluation of Neutral Nitrido Technetium(V) Mixed Ligand Complexes Containing Dithiolates and Aminodiphosphines. A Novel System for Linking Technetium to Biomolecules

A new biomolecule labeling method that utilizes the [99mTc(N)(PNP)]2+ metal fragment is presented. Thus, a series of nitrido mixed-ligand M(V) complexes (M = 99mTc, 99gTc, Re), [M(N)(Ln)(PNP)], where Ln is the dianionic form of a dithiolate or substituted-dithiolate ligand and PNP is an aminodiphosphine, is described. 99mTc complexes can be prepared using either a two-step or a threestep procedure starting from generator-eluted pertechnetate through a prereduced mixture of [99mTc(N)]-containing species, followed by sequential or contemporary addition of the relevant dithiolate and aminodiphosphine. The reactions of 2,3-dimercaptopropionic acid (H2L1) with [Tc(N)(PNP)]2+ were investigated in detail. It was found that this bidentate ligand coordinated the metal fragment through the [S-,S-] donor atom pair, to yield neutral mixed-ligand complexes [99mTc(N)(L1)(PNP)] in high specific activity. The additional carboxylic functional group was not involved in metal coordination, thus remaining available for conjugation to target-specific molecules. Dithiolates incorporating pendant functional group(s) gave rise to a 1:1 diastereoisomeric mixture of syn-[M(N)(Ln)(PNP)] and anti[M(N)(Ln)(PNP)] derivatives, depending on the relative orientation of the dithiolate substituent(s) with respect to the terminal nitrido group, and no isomeric conversion was detected. 99mTc species had been proven to be identical with the 99gTc complexes prepared at the macroscopic level by comparison of the corresponding radiometric and UV/vis HPLC profiles. Challenge experiments with cysteine or glutathione indicated that these physiological agents had no effect on the stability of this class of mixedligand 99mTc-complexes. Biodistribution studies in rats of selected 99mTc-complexes showed a rapid clearance from the blood and tissues after 60 min pi.