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See detailAutomated radiosynthesis of [18F]MPPF derivatives for imaging 5-HT1A receptors
Goblet, David ULg; Thonon, David ULg; Plenevaux, Alain ULg et al

Poster (2010, May 30)

TOPIC: Molecular Neuroimaging: from Bench to Bedside Automated radiosynthesis of [18F]MPPF derivatives for imaging 5-HT1A receptors Introduction: Dysfunction of the cerebral serotoninergic system is ... [more ▼]

TOPIC: Molecular Neuroimaging: from Bench to Bedside Automated radiosynthesis of [18F]MPPF derivatives for imaging 5-HT1A receptors Introduction: Dysfunction of the cerebral serotoninergic system is implicated in numerous neurodegenerative disorders such as Alzheimer disease’s, dementia, depression, anxiety, schizophrenia, and Parkinson disease’s. The 5-HT1A serotonin receptors are involved in several physiological functions including sleep, mood, neurogenesis and learning [1]. Consequently, there have been huge efforts in finding ligands for this receptor. [11C]WAY-100635 is a high affinity radioligand used for quantifying serotonin 5-HT1A receptors with positron emission tomography. An 18F-labeled radioligand is advantageous because of higher specific activity and physical/nuclear properties (t1/2= 109 min, 97% of positron decay and positron energy of 635 keV maximum). [18F]MPPF, a selective 5-HT1A antagonist derived from WAY-100635, is currently one of the most successful PET ligand used for 5-HT1A receptor imaging [2]. However the affinity is lower then WAY-100635 and the amount of [18F]MPPF reaching the brain is relatively low since MPPF is a substrate for p-glycoprotein [3]. Methods: In order to improve the brain uptake of the radiotracer, a desmethylated analog has been developed in our lab and preliminary in vitro studies show positive results [4]. Nevertheless, the radiosynthesis take place in two steps as a protecting group removal is needed. A one step procedure with a MPPF derivative could be of very great interest. We have synthesized many MPPF derivatives in our lab (modification on the phenylpiperazine moiety) and developed an automated radiosynthesis procedure for the production of these radiotracers. [18F]MPPF was chosen as the model compound. We used a GE Healthcare FASTlabTM module and made modifications to the [18F]FDG synthesis sequence and cassette. [18F]MPPF was synthesized by coupling of [18F]FBA with the corresponding amine. After coupling, the crude solution was diluted with water and passed through a tC18 cartridge for prepurification. After elution, the [18F]MPPF was purified by semi-preparative HPLC. Results: Total synthesis time, including purification was approximately 100 min. [18F]FBA and [18F]MPPF were obtained at a corrected yield of 55% (n=20) and 25% (n=5) respectively. The radiochemical purity, checked by radio-TLC and UPLC, was >95%. Conclusions: We have developed an automated method for [18F]MPPF and derivatives production using a commercial synthesizer (FASTlabTM from GE Healthcare) and a conventional HPLC system resulting in good yields and high (radio)chemical purity. By simply switching the vial containing the modified amine, an 18F-labeled MPPF derivative could be obtained. Radiosynthesis is still under optimization and the radiotracers synthesized need to be tested as suitable 5-HT1A radioligands. Acknowledgement: This work was supported by the Fondation Rahier. References: [1] Filip M., Bader M. et Al, Pharmacol Rep. 2009 Sep-Oct; 61(5):761-77 [2] Aznavour N, Zimmer L. Et Al, Neuropharmacology. 2007 Mar; 52(3):695-707 [3] Laćan G., Plenevaux A. et Al, Eur J Nucl Med Mol Imaging. 2008 Dec;35(12):2256-66 [4] Defraiteur C., Plenevaux A. et Al., Br J Pharmacol. 2007 Nov; 152(6):952-8 [less ▲]

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See detailCyclosporine, a P-glycoprotein modulator, increases [18F]MPPF uptake in rat brain and peripheral tissues: microPET and ex vivo studies.
Lacan, Goran; Plenevaux, Alain ULg; Rubins, Daniel J. et al

in European Journal of Nuclear Medicine and Molecular Imaging (2008), 35(12), 2256-66

PURPOSE: Pretreatment with cyclosporine, a P-glycoprotein (P-gp) modulator increases brain uptake of 4-(2'-methoxyphenyl)-1-[2'-(N-2"-pyridinyl)-p-[(18)F]fluorobenzamido]ethylpiperaz ine ([(18)F]MPPF) for ... [more ▼]

PURPOSE: Pretreatment with cyclosporine, a P-glycoprotein (P-gp) modulator increases brain uptake of 4-(2'-methoxyphenyl)-1-[2'-(N-2"-pyridinyl)-p-[(18)F]fluorobenzamido]ethylpiperaz ine ([(18)F]MPPF) for binding to hydroxytryptamine(1A) (5-HT(1A)) receptors. Those increases were quantified in rat brain with in vivo microPET and ex vivo tissue studies. MATERIALS AND METHODS: Each Sprague-Dawley rat (n = 4) received a baseline [(18)F]MPPF microPET scan followed by second scan 2-3 weeks later that included cyclosporine pretreatment (50 mg/kg, i.p.). Maximum a posteriori reconstructed images and volumetric ROIs were used to generate dynamic radioactivity concentration measurements for hippocampus, striatum, and cerebellum, with simplified reference tissue method (SRTM) analysis. Western blots were used to semiquantify P-gp regional distribution in brain. RESULTS: MicroPET studies showed that hippocampus uptake of [(18)F]MPPF was increased after cyclosporine; ex vivo studies showed similar increases in hippocampus and frontal cortex at 30 min, and for heart and kidney at 2.5 and 5 min, without concomitant increases in [(18)F]MPPF plasma concentration. P-gp content in cerebellum was twofold higher than in hippocampus or frontal cortex. CONCLUSIONS: These studies confirm and extend prior ex vivo results (J. Passchier, et al., Eur J Pharmacol, 2000) that showed [(18)F]MPPF as a substrate for P-gp. Our microPET results showed that P-gp modulation of [(18)F]MPPF binding to 5-HT(1A) receptors can be imaged in rat hippocampus. The heterogeneous brain distribution of P-gp appeared to invalidate the use of cerebellum as a nonspecific reference region for SRTM modeling. Regional quantitation of P-gp may be necessary for accurate PET assessment of 5-HT(1A) receptor density when based on tracer uptake sensitive to P-gp modulation. [less ▲]

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See detailRadiochemical synthesis and tissue distribution of p-[F-18]DMPPF, a new 5-HT1A ligand for PET, in rats
Defraiteur, Caroline; Lemaire, Christian ULg; Luxen, André ULg et al

in Nuclear Medicine & Biology (2006), 33(5), 667-675

Several studies have demonstrated the potential of p-[F-18]MPPF as a radiophanilaceutical to study the 5-HT1A receptor family in animals and humans. A structural modification leading to a higher ... [more ▼]

Several studies have demonstrated the potential of p-[F-18]MPPF as a radiophanilaceutical to study the 5-HT1A receptor family in animals and humans. A structural modification leading to a higher radioactive signal at an equipotent dose would greatly enhance this potential. With this goal, the desmethylated 4-(2'-methoxyphenyl)-1-[2'-[N-(2"-pyridinyl)-p-fluorobenzamidolethyl]-piperazine (p-MPPF), identified as p-DMPPF, was synthesized, labeled with fluorine-18 and evaluated through ex vivo tissue distribution in rats. The new compounds p-DMPPF, p-DMPPNO2, MEM-p-MPPF and MEM-p-MPPNO2 were isolated and fully identified (H-1 and C-13 NMR, LC-MS). The final compound, p-[F-18]DMPPF, was obtained ready for injection, with an overall radiochemical yield of 10% (EOB corrected) within 90 min and a specific activity of 62 GBq/mu mol. Tissue distributions showed that the carbon-fluorine bond was stable in vivo and that this compound could cross the blood-brain barrier. For kidney, lung, heart, spleen, bone, testicle, liver and muscle, the percentage of injected dose per gram of tissue obtained with p-[F-18]DMPPF was of the same order of magnitude as that of p-[F-18]MPPF. The amount of radioactivity reaching the brain was much higher (approximately fivefold at 60 min) for p-[F-18]DMPPF compared with p-[F-18]MPPF, which was taken as reference. The distribution and specificity were in total agreement with the known localization of 5-HT1A receptors in rats. The radioactivity increase was more important for specific tissues (hippocampus and frontal cortex) than for cerebellum or striatum, leading to better contrast (hippocampus/cerebellum=5.8 at 60 min). The levels of metabolites found in plasma showed that p-[F-18]DMPPF appears to be less metabolized than p-[F-18]MPPF. p-[F-18]DMPPF deserves further evaluation as a radiopharmaceutical candidate. (c) 2006 Elsevier Inc. All rights reserved. [less ▲]

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See detailRadiochemical Synthesis of p-[18F]Desmethyl-MPPF (p-[18F]D-MPPF) for the Study of 5-HT1A Receptors
Defraiteur, Caroline; Plenevaux, Alain ULg; Lemaire, Christian ULg et al

in Journal of Labelled Compounds & Radiopharmaceuticals (2003, August), 46(S1), 157

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