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

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• 作者：Cristina Bolzati ; Elisa Benini ; Emiliano Cazzola ; Christian Jung ; Francesco Tisato ; Fiorenzo Refosco ; Hans-Jü ; rgen Pietzsch ; Hartmut Spies ; Licia Uccelli ; and Adriano Duatti
• 刊名：Bioconjugate Chemistry
• 出版年：2004
• 出版时间：May 2004
• 年：2004
• 卷：15
• 期：3
• 页码：628 - 637
• 全文大小：155K
• 年卷期：v.15,no.3(May 2004)
• ISSN：1520-4812

文摘

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)], whereLn 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 procedurestarting from generator-eluted pertechnetate through a prereduced mixture of [^99mTc(N)]-containingspecies, 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 investigatedin 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 remainingavailable for conjugation to target-specific molecules. Dithiolates incorporating pendant functionalgroup(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 respectto the terminal nitrido group, and no isomeric conversion was detected. ^99mTc species had been provento be identical with the ^99gTc complexes prepared at the macroscopic level by comparison of thecorresponding radiometric and UV/vis HPLC profiles. Challenge experiments with cysteine orglutathione indicated that these physiological agents had no effect on the stability of this class ofmixed-ligand ^99mTc-complexes. Biodistribution studies in rats of selected ^99mTc-complexes showed arapid clearance from the blood and tissues after 60 min pi.