[Objective] We reported RXR partial agonist CBt-PMN (1a, Emax = 75%, EC50 = 143 nM) exerts potent glucose-lowering effect without the serious adverse effects caused by RXR full agonist bexarotene (targretin®), which has applications for treatment of cutaneous T cell lymphoma (CTCL) in US and Japan. Since bexarotene is reported to show curative effect for central nervous system disease (CNS disease) such as Alzheimer’s or Parkinson’s diseases, 1a is also expected to show similar therapeutic effect. In this study, we determined brain uptake and biodistribution of carbon-11 labeled CBt-PMN (1b) by performing PET imaging study. [Results] It is thought that induction of carbon-11 to carboxylic moiety is more easily than to a methyl group at a benzyl position because of the steric hindrance by the triazole ring. 11C-labeled carboxylation is performed by using [11C]CO or [11C]CO2. [11C]CO2 fixation can be performed directly by using organolithium or Grignard precursors or by the reaction with boronic ester precursors in the presence of copper(I)-catalysts. Thus, [11C]CO2 fixation was selected and applied to 1b. Lithiation of bromo derivative 2 was failed because of the low tolerance of the triazole ring. Though using turbo-Grignard, which is applicable to highly functionalized precursors, enabled to produce target molecule from 2, the low yield and the existence of byproduct hardly separated were problems. Cu-mediated [11C]CO2 fixation applied to [11C]bexarotene faced production of Cu-triazole complex. Finally, tin–lithium exchange reported by Staubitz et al, was applied and succeeded in synthesis of 1b from 3 with &gt;99% radiochemical purity within 30 min. Positron emission tomography−computed tomography(PET-CT) using 1b revealed brain uptake and enterohepatic circulation in mice. [Conclusion] This work is the first [11C]carboxylic acid radiotracer synthesized from [11C]CO2 using tin–lithium exchange, and this methodology may be useful in PET tracer syntheses with compounds chelating to Cu ion. And the results show 1a has potential to be a curative candidate for CNS disease such as Alzheimer’s disease, and Parkinson’s disease.

Synthesis of 11C labeled RXR partial agonist CBt-PMN by [11C] carbon dioxide fixation via organolithiation of trialkyltin precursor and PET imaging thereof

254th National Meeting (2017)

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