Development of Rhenium-188 Complexes Based on Novel Chelators Derived from Dimercaptosuccinic Acid (DMSA) Suitable for easy Linking of Biomolecules

This work is part of our efforts to develop chelating agents for stable binding and easy conjugation of rhenium-188 to biologically interesting structures. Keeping in mind the high in vivo stability of [¹⁸⁸ReO(DMSA)₂]^- (1) we want to exploit this coordination system for the design of ¹⁸⁸ReO(V) chelates which are stable towards re-oxidation to perrhenate and towards ligand exchange under all conditions of radiopharmaceutical procedures and applications.
The new type of tetradentate ligand has been synthesized by bridging two molecules of dimercaptosuccinic acid (DMSA) with an alkylene triamine chain. The resulting stereo-isomeric tetrathiolato S₄ ligand 1 forms five-coordinate oxorhenium(V) complexes 2 (exo-cis) and 3 (exo-trans) by ligand exchange reaction of NBu₄[ReOCl₄] in methanol. Without addition of base the compounds will be isolated as “betain”, [ReO(S₄)], with the protonated nitrogen of the bridge as internal “counter ion”. X-ray crystal structure determination of both stereoisomeric forms reveals the square-pyramidal coordination geometry of the ReOS₄ core. The orientation of the metal-oxo core is exo in relation to the carbamido groups in both isomers.
The activated BFCA 4 enables easy linking of biomolecules containing a terminal amino group. Prototypic model conjugates with tripeptides have been identified in non-radioactive form by electrospray mass spectrometry.
The Re-188 labelling procedure runs fast, in good yields and under mild conditions, making the new complexes interesting as a further access to stable rhenium-188 radiotherapeutics.