Dramatic Effect of the Tridentate Ligand on the Stability of 99mTc "3 + 1" Oxo Complexes Bearing Arylpiperazine Derivatives

• Published in: Bioconjugate chemistry 2005-05, Vol.16 (3), p.660-668
• Main Authors: Fernandes, C, Correia, J. D. G, Gano, L, Santos, I, Seifert, S, Syhre, R, Bergmann, R, Spies, H
• Format: Article
• Language: English
• Subjects: Animals; Chemistry; Chromatography, High Pressure Liquid; Effects; Inhibitory Concentration 50; Ligands; Mass Spectrometry; Mice; Molecular Structure; Oxygen - chemistry; Piperazines - chemistry; Radiopharmaceuticals - chemical synthesis; Radiopharmaceuticals - chemistry; Rats; Technetium - chemistry
• ISSN: 1043-1802; 1520-4812
• DOI: 10.1021/bc049718k

Mixed − ligand model complexes of general formula [99mTc(O)(κ3-PNX)(κ1-SPh))] [X = O (1a), S (2a)] were prepared in a one-step procedure from [99mTcO4 -] using stannous chloride as reducing agent. Stability studies and challenge experiments with glutathione showed that complex 2a presented promising features for pursuing animal studies. The activity in the brain (% dose injected/organ) at 5 min (0.14% ± 0.03) and 120 min (0.11% ± 0.02) pi encouraged the synthesis of several mixed-ligand "3 + 1" oxo complexes of general formula [M(O)(κ3-PNS)(κ1-SL))] (M = 99mTc, 3a−6a, Re, 3−6), in which the tridentate ligand is the heterofunctionalized phosphine 2-(diphenylphosphanyl)-N-(2-thioethyl)benzamide (PNS) and the co-ligands are different arylpiperazine derivatives (HSL1−HSL4). The 99mTc complexes have been characterized by comparison of their retention times in the HPLC chromatogram (γ-detection) with the retention times of the analogous Re complexes (UV detection at 254 nm). The 99mTc complexes, obtained with radiochemical purity higher than 95%, after HPLC purification, are stable in saline, 0.01 M PBS (pH 7.4), rat plasma (4 h, 37 °C), and glutathione (10 mM solutions, 2h, 37 °C). Binding affinity and selectivity for 5-HT1A receptors (relative to the 5-HT2A receptor) were determined, complex 5 demonstrating the best values (IC50 for the 5-HT1A 2.35 ± 0.02 nM; competitor 5-HT2A 372 ± 11 nM). Biodistribution and stability studies in mice indicated a preferred hepatobiliary excretion, a high in vivo stability, but a poor brain uptake.