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 (Ln). [99mTc(N)(PS)(Ln)] 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.
Similar content being viewed by others
References
Duatti A, Marchi A, Pasqualini R (1990) J Chem Soc Dalton 3729–3733
Bolzati C, Malago E, Boschi A, Cagnolini A, Porchia M, Bandoli G (1999) N J Chem 23:807–809
Bolzati C, Benini E, Cavazza-Ceccato M, Cazzola E, Malago E, Agostini S, Tisato F, Refosco F, Bandoli G (2006) Bioconjug Chem 17:419–428
Bolzati C, Cavazza-Ceccato M, Agostini S, Tisato F, Bandoli G (2008) Inorg Chem 47:11972–11983
Kung HF, Kung MP, Choi SR (2003) Semin Nucl Med 33:2–13
Nutt DJ, Stein DJ (2006) CNS Spectr 11:13–20
Pike VW, Halldin C, McCarron JA, Lundkvist C, Hirani E, Olsson H, Hume SP, Karlsson P, Osman S, Swahn CG, Hall H, Wikström H, Mensonidas M, Poole KG, Farde L (1998) Eur J Nucl Med 25:338–346
Mensonides-Harsema MM, Liao Y, Böttcher H, Bartoszyk GD, Greiner HE, Harting J, de Boer P, Wikström HV (2000) J Med Chem 43:432–439
Pike VW, Halldin C, Wikström H, Marchais S, Mc-Carron JA, Sandell J, Nowicki B, Swahn CG, Osman S, Hume SP, Constantinous M, Andrée B, Farde L (2000) Nucl Med Biol 27:449–455
Lang L, Jagoda E, Schmall B, Sassaman M, Ma Y, Eckelman WC (2000) Nucl Med Biol 27:457–462
Kung HF, Bradshaw JE, Chumpradit S, Zhuang MP, Kung M-P, Mu M (1995) In: Nicolini M, Bandoli G, Mazzi U (eds) Technetium and rhenium in chemistry and nuclear medicine, vol 4. SGEditoriali, Padua, pp 293–298
Mahmood A, Kronauge JF, Barbarics E, Freiberg E, Madras BK, Li J, Davison A, Jones AG (1999) In: Nicolini M, Mazzi U (eds) Technetium, rhenium and other metals in chemistry and nuclear medicine, vol 5. SGEditoriali, Padua, pp 393–399
Johannsen B, Berger R, Brust P, Pietzsch HJ, Scheunemann M, Seifert S, Spies H, Syher R (1997) Eur J Nucl Med 24:316–319
Heimbold I, Drews A, Syhre R, Kretzschmar M, Pietzch HJ, Johannsen B (2002) Eur J Nucl Med 29:82–87
León A, Rey A, Mallo L, Pirmettis I, Papadopoulos M, León E, Pagano M, Manta E, Incerti M, Raptopoulou C, Terzis A, Chiotellis E (2002) Nucl Med Biol 29:217–226
Heimbold I, Drews A, Kretzschmar M, Varnäs K, Hall H, Halldin C, Syhre R, Kraus W, Pietzsch HJ, Seifert S, Brust P, Johannsen B (2002) Nucl Med Biol 29:375–387
Drews A, Pietzsch HJ, Syhre R, Seifert S, Varnäs K, Hall H, Halldin C, Kraus W, Karlsson P, Johnsson C, Spies H, Johannsen B (2002) Nucl Med Biol 29:389–398
Fernandes C, Correia JDG, Gano L, Santos I, Seifert S, Syhre R, Bergmann R, Spies H (2005) Bioconjug Chem 16:660–668
Papagiannopoulou D, Pirmettis I, Maina T, Palecanou M, Nikolopoulou A, Chiotellis E, Raptopoulou CP, Valahos A, Papadopoulos ATM, Chiotellis E (2001) J Biol Inorg Chem 6:256–265
Alberto R, Schibli R, Schubiger AP, Abram U, Pietzsch HP, Johannsen B (1999) J Am Chem Soc 121:6076–6077
Garcia R, Gano L, Maria L, Paulo A, Santos I, Spies H (2006) J Biol Inorg Chem 11:769–782
Bolzati C, Mahmood A, Malago E, Uccelli L, Boschi A, Jones AG, Refosco F, Duatti A, Tisato F (2003) Bioconjug Chem 14:1231–1242
Bolzati C, Boschi A, Uecelli L, Malago E, Bandoli G, Tisato F, Refosco F, Pasqualini R, Duatti A (1999) Inorg Chem 38:4473–4479
Pietrogrande MC, Bighi C, Borea PA, Barbaro AM, Guerra MC, Biagi GL (1985) J Liq Chromatogr 8:1711–1729
Boschi A, Bolzati C, Benini E, Malago E, Uccelli L, Duatti A, Piffanelli A, Refosco F, Tisato F (2001) Bioconjug Chem 12:1035–1042
Elsinga PH, Hendrikse NH, Bart J, van Waarde A, Vaalburg W (2005) Mol Imaging Biol 7:37–44
Doze P, Van Waarde A, Elsinga PH, Hendrkese NH, Vaalburg W (2000) Synapse 36:66–74
Liow JS, Lu S, McCarrron JA, Hong J, Musachio JL, Pike VW, Innis RB, Zoghbi SS (2007) Synapse 61:96–105
Colabufo NA, Berardi F, Perrone R, Rapposelli S, Digiacomo M, Vanni M, Balsamo A (2008) J Med Chem 51:7602–7613
Acknowledgments
The authors wish to thank Anna Rosa Moresco for her work on the elemental analysis, Daniele Dalzoppo for his support in mass-spectrometric analysis, and Francesco Tisato for his assistance in NMR analysis.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Bolzati, C., Salvarese, N., Carta, D. et al. 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. J Biol Inorg Chem 16, 137–155 (2011). https://doi.org/10.1007/s00775-010-0712-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00775-010-0712-4