Synthesis and biological evaluation of technetium(III) mixed-ligand complexes with high affinity for the cerebral 5-HT1A receptor and the alpha1-adrenergic receptor

Tc(III) and Re(III) complexes [M(NS3)(CNR)] (M = Re, Tc-99m, NS3 = 2,2',2"-nitrilotris(ethanethiol), CNR = functionalized isocyanide bearing a derivative of WAY 100635) have been synthesized and characterized. Re was used as Tc surrogate for chemical characterization and in vitro receptor-binding studies. For two representatives subnanomolar affinities for the 5-HT1A as well as for the alpha1-adrenergic receptor were reached. Biodistribution studies in rats of the Tc-99m complexes showed brain uptakes between 0.3 and 0.5% ID/organ (5 min p.i.). In vitro autoradiography of one Tc-99m representative in sections of post mortem human brain indicate its accumulation in 5-HT1A receptor-rich brain regions. However, addition of the specific 5-HT1A receptor agonist 8-OH-DPAT as well as the alpha1-adrenoceptor antagonist prazosin could not substantially block this tracer accumulation. A preliminary SPET study in a monkey showed negligible brain uptake. (C) 2002 Elsevier Science Inc. All rights reserved.