Rhenium and technetium tricarbonyl complexes anchored by 5-HT1A receptor-binding ligands containing P,O/N donor atom sets

The (2-methoxyphenyl)piperazine pharmacophore, a part of the WAY 100635 structure, has been functionalized with phosphinoarylbenzylamide or phosphinoarylbenzylamine chelator groups using propylene or hexylene alkyl chains as linkers (L2-L4). These heterofunctionalized phosphines bearing an arylpiperazine moiety have been used to stabilize rhenium tricarbonyl complexes of the type [Re(CO)(3)Br(kappa(2)-L)] (4, L = L2; 5, L = L3; 6, L = L4), which have been fully characterized, including by X-ray crystallographic analysis in the case of compounds 4 and 5. These monomeric complexes are six-coordinate, displaying a distorted octahedral coordination geometry with a facial arrangement of the carbonyl groups. The other three remaining positions are occupied by a bromide and by the bidentate heterofunctionalized phosphine, which coordinates through the phosphorus and the oxygen atom or through the phosphorus and the nitrogen atom in 4 and 5, respectively. The Tc-99m complexes (3a-6a!
) were also prepared and their characterization established by comparative HPLC, using the Re complexes as surrogates. The in vitro binding affinity for the 5HT(1A) receptor subtype and the selectivity against the 5HT(2A) receptors for the rheniurn complexes were determined. Compound 3 is the only one which presents a reasonable affinity and selectively towards 5HT(1A) (IC50 = 20 nM) and 5HT(2A) (IC50 = 4680 nM) receptors, respectively. When the spacer length between the chelate unit and receptor binding domain increased and/or the amide group in the chelator was replaced by a secondary amine unacceptable affinity values for 5HT(1A) receptors (IC50 = 200-1100 nM) and lost of selectivity were observed. (C) 2004 Elsevier B.V. All rights reserved.