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+m 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 three-step procedure starting from generator-eluted pertechnetate through a pre-reduced mixture of [^99mTc(N)] containing species, followed by contemporary or sequential addition of the relevant dithiolate and aminodiphosphine. The reaction of 2,3-dimercapto propionic acid (H₂L1) with [Tc(N)(PNP)]²⁺ was 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 mixed-ligand ^99mTc-complexes. Biodistribution studies in rats of selected ^99mTc-complexes showed a rapid clearance from the blood and tissues after 60 min. p.i..