New '3+1' Tc(V) oxocomplexes containing a tridentate H2PNS ligand and different monodentate ligands for the 5HT1A receptor


New '3+1' Tc(V) oxocomplexes containing a tridentate H2PNS ligand and different monodentate ligands for the 5HT1A receptor

Fernandes, C.; Correia, J. D. G.; Santos, I.; Spies, H.; Seifert, S.

The stability of the complexes of '3+1' type depends not only on the nature of the tridentate ligand but also on the nature of monodentate co-ligand.[1,2] The recently introduced (tri)bidentate heterofunctionalized phosphines, (H2PNX; X=O,S), which are quite versatile in terms of charge and denticity towards the [M=O]3+ core, form '3+1' mixed-ligand complexes with different thiolated monodentate co-ligands.[3,4] These complexes show different in vitro stabilities, confirming the importance of the nature of the donor atoms on the stability. Using the H2PNS ligand and a thiolated arylpiperazine derivative we succeeded on the preparation of the stable '3+1' oxocomplex [M(O)(eta3- PNS)(SCH2CH2NHCH2CH2CH2(2-MeOPhpip))] (M = Re, 99mTc). In spite of its high stability, the complex showed low affinity for the 5HT1A receptor (120 nM ± ).[5]
These results prompted us to introduce some chemical modifications in the monodentate co-ligand, in order to increase the affinity and selectivity to the receptor. So, herein we report on the synthesis and characterization of the new thiolated arylpiperazine derivatives and on the preparation of the corresponding '3+1' oxocomplexes at the macroscopic and at the n.c.a. level (80-95% yield). The 99mTc-complexes obtained were identified by comparing their radioactive HPLC profiles with those of the analogous Re complexes. After purification by semi-preparative HPLC, the radiochemical purity of the complexes is higher than 95%.
The stability of the purified 99mTc-complexes was studied in saline, 0.01M PBS (pH 7.4) at 37ºC, and all of the complexes revealed stable. No significant exchange with glutathione (1mM and 10mM solutions, 37ºC) was observed.
In order to determine the effect of the chemical modifications introduced in the monodentate ligand, binding affinities and specificities for the 5HT1A receptor have still to be evaluated.

Acknowledgements: This work is being supported by the COST Action B12.

References
[1] Syhre, R.; Seifert, S.; Spies, H.; Gupta, A.; Johannsen, B.; Eur. J. Nucl. Med. 1998, 25:793.
[2] Seifert S. et al Radioch. Acta, in press.
[3] Correia, J. D. G.; Domingos, A.; Santos, I.; Eur. J. Inorg. Chem. 2000, 7:1523.
[4] Correia, J. D. G.; Domingos, A.; Paulo, A.; Santos, I.; J. Chem. Soc. , Dalton Trans. 2000, 14: 2477.
[5] Fernandes, C.; Correia, J. D. G.; Gano, L.; Santos, I.; Seifert, S.; Syhre, R.; Spies, H.; J. Labelled Cpd. Radiopharm. 2001, 44, Suppl. 1, S518.

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