Technetium(V) and rhenium(V) complexes for 5-HT2A serotonin receptor binding: Structure-affinity considerations

Starting from the lead structure of ketanserin, a prototypic serotonin (5-HT) antagonist, new oxotechnetium(V) and oxorhenium(V) complexes were synthesized that are able to compete with [H-3]ketanserin in receptor binding assays. To imitate organic 5-HT2 receptor ligands, fragments of ketanserin were combined with chelate moieties. Neutral compounds of the general formula [MOL(1)L(2)] (M = Tc, Re; L(1) = HS-CH2CH2-S-CH2CH2-SH,N-(2-mercaptophenyl)salicylideneimine,N-(2-mercaptoethyl)-salicylideneimine,3-(2{[N,N-bis(2-mercapto-S-ethyl)]-amino}ethyl)-2,4-(1H,3H)-quinazolinedione and L(2) = HS-R with R = subst. alkyl) were prepared by common action of a Tc(V) or Re(V) precursor with a mixture of equimolar amounts of a tridentate ligand L(1) and a monodentate thiolate L(2) bearing fragments of the lead structure. Lipophilic complexes consisting of a small S-4 thiolate/thioether chelate unit, protonable nitrogen-containing spacer, and simple benzyl moiety significantly inhibited the specific binding of [H-3]ketanserin with IC50 values between 10 and 50 nM.