Synthesis and biological evaluation of 99mTc(CO)3-OH-PP-CS2 for brain receptor imaging

Document Type: Original Article

Authors

1 Nuclear Science Research School, Nuclear Science and Technology Research Institute, Atomic Energy Organization of Iran, Tehran, Iran

2 Department of Nuclear Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

3 Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

Abstract

Introduction: 5-HT1A receptor is related with a variety of neuropsychiatric disorders. . In this study a phenolic analogue derived from DWAY [Desmethyl WAY-100635 (N-(2-(1-(4-(2-methoxyphenyl)piperazinyl)-ethyl))-N-(2-pyridinyl) cyclohexanecarboxamide)] is used to design the desired structure of 5-HT1A receptor imaging agents after labeling with [99mTc (CO) 3(H2O) 3] + core via dithiocarbamate moiety. Methods: 2-(piperazin-1-yl) phenol Dithiocarbamate was synthesized by the reaction of 2-(piperazin-1-yl) phenol with an equivalent amount of carbon disulfide in KOH solution then radiolabeled with [99mTc(CO)3(H2O)3]+ core. Radioligand chemical analysis involved high-performance liquid chromatography methods. Radioconjugate stability and lipophilicity were determined. Biodistribution of labeled compound was studied in rats. Results: The final complex was characterized by HPLC and its radiochemical purity was more than 90%. In vitro stability studies have shown the complex was stable at least 6-hrs after labeling at room temperature. The n-octanol/water partition coefficient experiment demonstrated Log P = 0.74 for 99mTc(CO)3-OH-PP-CS2. Biodistribution results showed that radio tracer had moderate brain uptake (0.32 ± 0.03 %ID/g at 30 min post injection), Conclusion: This complex may lead to a further development of a radiotracer with specific binding to 5-HT1A receptor.

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Main Subjects


Passchier J, van Waarde A. Visualisation of serotonin-1A (5-HT1A) receptors in the central nervous system. Eur J Nucl Med. 2001 Jan;28(1):113-29.

Halldin C, Gulyás B, Langer O, Farde L. Brain radioligands--state of the art and new trends. Q J Nucl Med. 2001 Jun;45(2):139-52.

Aznavour N, Zimmer L. [18F]MPPF as a tool for the in vivo imaging of 5-HT1A receptors in animal and human brain. Neuropharmacology. 2007 Mar;52(3):695-707.

Farde L, Ito H, Swahn CG, Pike VW, Halldin C. Quantitative analyses of carbonyl-carbon-11-WAY-100635 binding to central 5-hydroxytryptamine-1A receptors in man. J Nucl Med. 1998 Nov;39(11):1965-71.

Lang L, Jagoda E, Schmall B, Vuong BK, Adams HR, Nelson DL, Carson RE, Eckelman WC. Development of fluorine-18-labeled 5-HT1A antagonists. J Med Chem. 1999 May 6;42(9):1576-86.

Garcia R, Xavier C, Paulo A, Santos I, Kniess T, Bergmann R, Wüst F. Synthesis and Synthesis and biological evaluation of S-[11C]methylated mercaptoimidazole piperazinyl derivatives as potential radioligands for imaging 5-HT1A receptors by positron emission tomography (PET). J Label Compd Radiopharm. 2005;48(4):301-15.

Le Bars D, Lemaire C, Ginovart N, Plenevaux A, Aerts J, Brihaye C, Hassoun W, Leviel V, Mekhsian P, Weissmann D, Pujol JF, Luxen A, Comar D. High-yield radiosynthesis and preliminary in vivo evaluation of p-[18F]MPPF, a fluoro analog of WAY-100635. Nucl Med Biol. 1998 May;25(4):343-50.

Pike VW, Halldin C, Wikström H, Marchais S, McCarron JA, Sandell J, Nowicki B, Swahn CG, Osman S, Hume SP, Constantinou M, Andrée B, Farde L. Radioligands for the study of brain 5-HT(1A) receptors in vivo--development of some new analogues of way. Nucl Med Biol. 2000 Jul;27(5):449-55.

Sanabria-Bohórquez SM, Biver F, Damhaut P, Wikler D, Veraart C, Goldman S. Quantification of 5-HT(1A) receptors in human brain using p-MPPF kinetic modelling and PET. Eur J Nucl Med Mol Imaging. 2002 Jan;29(1):76-81.

Vandecapelle M, Dumont F, De Vos F, Strijckmans K, Leysen D, Audenaert K, Dierckx  RA, Slegers G. Synthesis and preliminary in vivo evaluation of 4-[18F]fluoro-N-{2-[4-(6-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethyl}benzamide, a potential PET radioligand for the 5-HT1A receptor. J Label Compd Radiopharm. 2004;47:531-42.

Parsey RV, Belanger MJ, Sullivan GM, Simpson NR, Stabin MG, Van Heertum R, Mann JJ. Biodistribution and radiation dosimetry of 11C-WAY100,635 in humans. J Nucl Med. 2005 Apr;46(4):614-9.

Tipre DN, Zoghbi SS, Liow JS, Green MV, Seidel J, Ichise M, Innis RB, Pike VW. PET imaging of brain 5-HT1A receptors in rat in vivo with 18F-FCWAY and improvement by successful inhibition of radioligand defluorination with miconazole. J Nucl Med. 2006 Feb;47(2):345-53.

Papagiannopoulou D, Pirmettis I, Tsoukalas Ch, Nikoladou L, Drossopoulou G, Dalla C, Pelecanou M, Papadopoulou-Daifotis Z, Papadopoulos M, Chiotellis E. Oxotechnetium 99mTcO[SN(R)S][S] complexes as potential 5-HT1A receptor imaging agents. Nucl Med Biol. 2002 Nov;29(8):825-32.

Heimbold I, Drews A, Syhre R, Kretzschmar M, Pietzsch HJ, Johannsen B. A novel technetium-99m radioligand for the 5-HT(1A) receptor derived from desmethyl-WAY-100635 (DWAY). Eur J Nucl Med Mol Imaging. 2002 Jan;29(1):82-7.

Heimbold I, Drews A, Kretzschmar M, Varnäs K, Hall H, Halldin C, Syhre R, Kraus W, Pietzsch HJ, Seifert S, Brust P, Johannsen B. Synthesis, biological and autoradiographic evaluation of a novel Tc-99m radioligand derived from WAY 100635 with high affinity for the 5-HT(1A) receptor and the alpha1-adrenergic receptor. Nucl Med Biol. 2002 May;29(4):375-87.

León A, Rey A, Mallo L, Pirmettis I, Papadopoulos M, León E, Pagano M, Manta E, Incerti M, Raptopoulou C, Terzis A, Chiotellis E. Novel mixed ligand technetium complexes as 5-HT1A receptor imaging agents. Nucl Med Biol. 2002 Feb;29(2):217-26.

Bolzati C, Mahmood A, Malagò E, Uccelli L, Boschi A, Jones AG, Refosco F, Duatti A, Tisato F. The [(99m)Tc(N)(PNP)](2+) metal fragment: a technetium-nitrido synthon for use with biologically active molecules. The N-(2-methoxyphenyl)piperazyl-cysteine analogues as examples. Bioconjug Chem. 2003 Nov-Dec;14(6):1231-42.

Alberto R, Schibli R, Egli A, Schubiger AP, Abram U, Kaden TA. A novel organometallic aqua-complex of technetium for the labeling of biomolecules: synthesis of 99mTc(OH2)(CO)3]+ from [99mTcO4]- in aqueous solution and its reaction with bifunctional ligands. J Am Chem Soc. 1998;120:7987-88.

Alberto R, Schibli R, Schubiger AP, Abram U, Pietzsch HJ, Johannsen B. First application of fac[99mTc(OH2)3(CO)3]+ in bioorganometallic chemistry: Design, structure and in vitro affinity of 5HT1A receptor ligand labeled with 99mTc. J Am Chem Soc. 1999;121:6076-77.

Baldas J, Bonnyman J. Substitution reactions of 99mTcNCl-4--A route to a new class of 99mTc-radiopharmaceuticals. Int J Appl Radiat Isot. 1985 Feb;36(2):133-9.

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. [carbonyl-11C]Desmethyl-WAY-100635 (DWAY) is a potent and selective radioligand for central 5-HT1A receptors in vitro and in vivo. Eur J Nucl Med. 1998 Apr;25(4):338-46.

Andrée B, Halldin C, Pike VW, Gunn RN, Olsson H, Farde L. The PET radioligand [carbonyl-(11)C]desmethyl-WAY-100635 binds to 5-HT(1A) receptors and provides a higher radioactive signal than [carbonyl-(11)C]WAY-100635 in the human brain. J Nucl Med. 2002 Mar;43(3):292-303.

Defraiteur C, Lemaire C, Luxen A, Plenevaux A. Radiochemical synthesis and tissue distribution of p-[18F]DMPPF, a new 5-HT1A ligand for PET, in rats. Nucl Med Biol. 2006 Jul;33(5):667-75.

 Zhuang ZP, Kung MP, Kung HF. Synthesis and evaluation of 4-(2'-methoxyphenyl)-1-[2'-[N-(2"-pyridinyl)-p- iodobenzamido]ethyl]piperazine (p-MPPI): a new iodinated 5-HT1A ligand. J Med Chem. 1994 May 13;37(10):1406-7.

Cliffe IA. A retrospect on the discovery of WAY-100635 and the prospect for improved 5-HT(1A) receptor PET radioligands. Nucl Med Biol. 2000 Jul;27(5):441-7.

Kung HF, Kim HJ, Kung MP, Meegalla SK, Plössl K, Lee HK. Imaging of dopamine transporters in humans with technetium-99m TRODAT-1. Eur J Nucl Med. 1996 Nov;23(11):1527-30.

Kung HF. Development of Tc-99m labeled tropanes: TRODAT-1, as a dopamine transporter imaging agent. Nucl Med Biol. 2001 Jul;28(5):505-8.