Dramatic effect of the tridentate ligand on the stability of 99mTC "3 + 1" oxo complexes bearing arylpiperazine derivatives.
Mixed-ligand model complexes of general formula [(99m)Tc(O)(kappa(3)-PNX)(kappa(1)-SPh))] [X = O (1a), S (2a)] were prepared in a one-step procedure from [(99m)TcO(4)(-)] 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)(kappa(3)-PNS)(kappa(1)-SL))] (M = (99m)Tc, 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 (99m)Tc complexes have been characterized by comparison of their retention times in the HPLC chromatogram (gamma-detection) with the retention times of the analogous Re complexes (UV detection at 254 nm). The (99m)Tc 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 degrees C), and glutathione (10 mM solutions, 2h, 37 degrees C). Binding affinity and selectivity for 5-HT(1A) receptors (relative to the 5-HT(2A) receptor) were determined, complex 5 demonstrating the best values (IC(50) for the 5-HT(1A) 2.35 +/- 0.02 nM; competitor 5-HT(2A) 372 +/- 11 nM). Biodistribution and stability studies in mice indicated a preferred hepatobiliary excretion, a high in vivo stability, but a poor brain uptake.
Fernandes
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Departamento de Química, ITN, Estrada Nacional 10, 2686-953 Sacavém Codex, Portugal.
Correia
J D G
JD
Gano
L
L
Santos
I
I
Seifert
S
S
Syhre
R
R
Bergmann
R
R
Spies
H
H
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D020128:Inhibitory Concentration 50; D008024:Ligands; D013058:Mass Spectrometry; D051379:Mice; D015394:Molecular Structure; D010100:Oxygen / Q000737:chemistry*; D010879:Piperazines / Q000737:chemistry*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000737:chemistry*; D051381:Rats; D013667:Technetium / Q000737:chemistry*
D008024:Ligands; D010879:Piperazines; D019275:Radiopharmaceuticals; D013667:Technetium; D010100:Oxygen