Synthesis and biological evaluation of new [Tc(N)(PS)]-based mixed-ligand compounds useful in the design of target-specific radiopharmaceuticals: the 2-methoxyphenylpiperazine dithiocarbamate derivatives as an example |
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Authors: | Cristina Bolzati Nicola Salvarese Davide Carta Fiorenzo Refosco Alessandro Dolmella Hans Jürgen Pietzsch Ralf Bergmann Giuliano Bandoli |
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Institution: | (1) ICIS-CNR, Corso Stati Uniti, 4, Padua, Italy;(2) Department of Pharmaceutical Sciences, University of Padua, Via Marzolo, 5, Padua, Italy;(3) Forschungszentrum Dresden-Rossendorf, Institute of Radiopharmacy, PF 510 119, 01314 Dresden, Germany |
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Abstract: | This study presents the first application of a general procedure based on the use of the Tc(N)Cl(PS)(PPh3)] species (PS is an alkyl phosphinothiolate ligand) for the preparation of Tc(N) target-specific compounds. Tc(N)Cl(PS)(PPh3)] selectively reacts with an appropriate dithiocarbamate ligand (S∧Y) to give Tc(N)(PS)(S∧Y)] compounds. 1-(2-Methoxyphenyl)piperazine, which displays a potent and specific affinity for 5HT1A receptors, was selected as a functional group and conjugated to the dithiocarbamate unit through different spacers (L
n
). 99mTc(N)(PS)(L
n
)] complexes were prepared in high yield (more than 90%). The chemical identity of 99mTc complexes was determined by high performance liquid chromatography comparison with the corresponding 99gTc complexes. All complexes were found to be inert toward transchelation with an excess of glutathione and cysteine. No notable
biotransformation of the native compound into different species by the in vitro action of the serum and liver enzymes was
shown. Nanomolar affinity for the 5HT1A receptor was obtained for 99mTc(N)(PSiso)L3] (IC50 = 1.5 nM); a reduction of the affinity was observed for the other complexes as a function of the shortening of the alkyl
chain interposed between the dithiocarbamate and the pharmacophore. Negligible brain uptake was found from in vivo distribution
data of 99mTc(N)(PSiso)L3]. The key finding of this study is that the complexes maintained good affinity and selectivity for 5HT1A receptors, and the IC50 value for 99gTc(N)(PSiso)L3] being comparable to the IC50 value found for WAY 100635. This result confirmed the possibility of preparing 99mTc(N)(PS)]-based target-specific compounds without affecting the affinity and selectivity of the bioactive molecules for the
corresponding receptors. |
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Keywords: | |
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