Synthesis, radiofluorination and pharmacological evaluation of a fluoromethyl spirocyclic PET tracer for central ¦Ò₁ receptors and comparison with fluoroalkyl homologs

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• 作者：Auré ; lie Maisonial^b ; ¹ ; Eva Groß ; e Maestrup^a ; ¹ ; Christian Wiese^a ; Achim Hiller^b ; Dirk Schepmann^a ; Steffen Fischer^b ; Winnie Deuther-Conrad^b ; Jö ; rg Steinbach^b ; Peter Brust^b ; Bernhard Wü ; nsch^a ; ^{wuensch@uni-muenster.de}
• 关键词：DMT ; N ; N-dimethyltryptamine ; MAM ; mitochondrion-associated ER membrane ; ER ; endoplasmatic reticulum ; BiP ; binding immunoglobulin protein ; IP3R ; inositol 1 ; 4 ; 5-triphosphate receptor ; PET ; positron emission tomography ; EMP ; emopamil-binding protein ; VAChT
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2012
• 出版时间：1 January, 2012
• 年：2012
• 卷：20
• 期：1
• 页码：257-269
• 全文大小：899 K

文摘

The spirocyclic ¦Ò₁ receptor ligand 1 (1?benzyl-3-(fluoromethyl)-3H-spiro[[2]benzofuran-1,4?piperidine]) was prepared in four steps starting from methoxy derivative 5. Due to its high ¦Ò₁ affinity (K_i = 0.74 nM) and selectivity against several other relevant targets, 1 was investigated as ¹⁸F-labeled PET tracer and its biological properties were compared with those of homologous fluoroalkyl derivatives 2-4. The fluoromethyl derivative 1 was faster metabolized in vitro than homologs 2-4. In contrast to the radiosynthesis of [¹⁸F]2-4, the nucleophilic substitution of the tosylate 15 using the K[¹⁸F]F-K₂₂₂-carbonate complex required heating to 150 ¡ãC in DMSO to achieve high labeling efficiencies. Whereas radiometabolites of [¹⁸F]2-4 were not detected in vivo in the brain of mice, two radiometabolites of [¹⁸F]1 were found. Analysis of ex vivo autoradiography images provided rather low target-to-nontarget ratio for [¹⁸F]1 compared with [¹⁸F]2-4. [¹⁸F]1 showed a fast uptake in the brain, which decreased continuously over time. The brain-to-plasma ratio of the radiotracer [¹⁸F]1 was only exceeded by the fluoroethyl tracer [¹⁸F]2.