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 prepn. of Tc(N) target-specific compds. [Tc(N)Cl(PS)(PPh3)] selectively reacts with an appropriate dithiocarbamate ligand (S-Y) to give [Tc(N)(PS)(S-Y)] compds. 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 (Ln). [99mTc(N)(PS)(Ln)] complexes were prepd. in high yield (more than 90%). The chem. identity of 99mTc complexes was detd. by HPLC comparison with the corresponding 99gTc complexes. All complexes are inert toward trans-chelation with an excess of glutathione and cysteine. No notable biotransformation of the native compd. 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 redn. of the affinity was obsd. 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 prepg. [99mTc(N)(PS)]-based target-specific compds. without affecting the affinity and selectivity of the bioactive mols. for the corresponding receptors.

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

SALVARESE, NICOLA;CARTA, DAVIDE;DOLMELLA, ALESSANDRO;
2011

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 prepn. of Tc(N) target-specific compds. [Tc(N)Cl(PS)(PPh3)] selectively reacts with an appropriate dithiocarbamate ligand (S-Y) to give [Tc(N)(PS)(S-Y)] compds. 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 (Ln). [99mTc(N)(PS)(Ln)] complexes were prepd. in high yield (more than 90%). The chem. identity of 99mTc complexes was detd. by HPLC comparison with the corresponding 99gTc complexes. All complexes are inert toward trans-chelation with an excess of glutathione and cysteine. No notable biotransformation of the native compd. 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 redn. of the affinity was obsd. 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 prepg. [99mTc(N)(PS)]-based target-specific compds. without affecting the affinity and selectivity of the bioactive mols. for the corresponding receptors.
2011
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11577/2459202
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