Rhenium and Technetium Complexes with Pentadentate Thiocarbamoylbenzamidines: Steps toward Bioconjugation

Abstract

Thiocarbamoylbenzimidoyl chlorides, PhC(Cl)═N-(C═S)-NR(1)R(2), react with 2-(iminodiacetic acid)benzylamine under formation of the potentially pentadentate ligands H3L (R(1), R(2) = Et) and H3L-COOEt (R(1) = Me, R(2) = C6H4-4-COOEt) in high yields. Hydrolysis of H3L-COOEt in NaOH/MeOH gives quantitatively another benzamidine ligand H3L-COOH. The novel ligands readily react with (NBu4)[MOCl4] (M = Re, Tc) under formation of stable complexes with the general composition [MO(L)], in which they are triply deprotonated and fully occupy the remaining five coordination positions of the {MO}(3+) cores. In a "proof-of-principle" reaction for possible bioconjugations, the complex [ReO(L-COOH)] has been labeled with triglycine ethyl ester in high yields.

ReVO and ReVNPh complexes with pentadentate benzamidines – Synthesis, structural characterization and DFT evaluation of isomeric complexes

“…The disubstituted product is formed almost quantitatively within 10 h when an excess of 25% bromoacetic acid ethylester is used. It should be mentioned that a similar procedure with aromatic amines requires more drastic conditions [14].…”

“…Neutralization of the products of such reactions with citric acid gives the pentadendate ligands H 3 L in high yields. An alternative route, which contains the hydrolysis of the ester in the first step produces a number side products due to the low solubility of the dicarboxylic acid in non-alcoholic solvents such as THF or acetone, which are normally used for preparation of benzamidine ligands [14,19,20].…”

“…This may possibly be understood by the fact that the syntheses of pentadentate ligands are frequently related to multi-step procedures, which are too time-consuming for the preparation of only one single molecule with uncertain biodistribution features. In the light of another strategy, which focuses on the synthesis of a 'bioconjugation kit' [14], however, any effort in the synthesis of a robust 'multi-use ligand' seems to be justified. Following this approach, first 99m Tc or 186,188 Re complexes with a strong chelator (having an anchor group in its periphery) are produced.…”

“…Recently, we reported about such a pentadentate ligand system based on thiocarbamoylbenzamidines, which provides an anchor for the coupling of peptides, and its rhenium and technetium complexes (H 3 L * and [M(L*)] in Scheme 1) [14]. Such multidentate ligands can be prepared from benzimidoyl chlorides and functionalized primary amines [14][15][16][17].…”

“…Such multidentate ligands can be prepared from benzimidoyl chlorides and functionalized primary amines [14][15][16][17].…”