Complexes of 4-(aminophenyl) benzothiazole derivatives with technetium and rhenium, and assessment of their properties as diagnostic and/or therapeutic radiopharmaceuticals

4-(Aminophenyl)benzothiazole derivatives have promising qualities for radiopharmaceutical chemistry, since they display both anticancer activity and affinity for amyloid plaques of Alzheimer's disease (AD). This chemical class is therefore an important candidate for the development of technetium (Tc) and rhenium (Re) radiopharmaceuticals for tumour imaging and/or radiotherapy, as well as, in vivo diagnosis of AD. In view of the interesting properties of the 4-(aminophenyl)benzothiazole derivatives and our long involvement in the chemistry of Tc and Re, we proceeded in the design and synthesis of new 4-(aminophenyl)benzothiazole ligands 1-5 properly modified for chelation with the M(I)+ and/or MO(V)3+ (M = Tc, Re) metal cores and the formation of stable complexes. Ligand 1 is designed for direct attachement to the MO3+ core through the heterocyclic nitrogens. In ligands 2?3 which are designed according to the conjugate approach, the 4-(aminophenyl)benzothiazole is joined through a 2-6 carbon atom chain to the [(Pyridin-2- ylmethyl)-amino]-acetic acid (PAMA), a chelate known to give stable complexes with the M(I)+ core. The purpose of the variable chain length is to test the effect of steric freedom in the interaction of the 4-(aminophenyl)benzothiazole moiety with its target. In addition, ligands 4-5 that carry the cysteine moiety in the place of PAMA are being synthesized. All ligands are being tested in vitro for their anticancer activity by cell uptake and inhibitory effect studies against the MCF-7 breast cancer cell line, as well as for their binding affinity to amyloid plaques in human AD brain sections. Complexes of ligands 1-5 are being prepared by ligand exchange reactions using either the Tc-gluconate and ReOCl03(PPh3)2 as precursors for the MO3+ core or the organometallic Tc and Re tricarbonyl precursor [M(OH2)3(CO)3]+ for the M(I)+ core (M = Tc, Re). Indicatively, the structure of complex 6, product of the reaction of ligand 2 with the Re(I)+ core, is shown. The complex is stable, neutral and was fully characterized with NMR spectroscopy and elemental analysis. Its radioactive 99mTc analogue was also synthesized proving that the complexation reaction is successfully transferred at Tc tracer level. Complex 6 has displayed satisfactory uptake in the MCF-7 cell line. The results of the synthesis of Tc and Re complexes with all ligands and their biological properties will be presented. (author)