CX3C chemokine receptor 1 (CX3CR1), also known as fractalkine receptor or G-protein coupled receptor 13 (GPR13), is a protein in humans. CX3CR1 binds the chemokine CX3CL1, also called fractalkine ligand or neurotactin. CX3CR1 is expressed in the brain, spleen, and in subpopulations of leukocytes, cells of monocytic lineage, but also in lymphocytes, and associated with various neurological, cancer and cardiovascular diseases. CX3CR1 has become a novel molecular target for treatment and PET (positron emission tomography) imaging of CX3CR1 associated diseases such as Alzheimer’s disease. We are interested in the development of PET CX3CR1 radioligands. We have previously synthesized [11C]methyl (2-amino-5-(benzylthio)thiazolo[4,5-d]pyrimidin-7-yl)-D-leucinate as a candidate PET CX3CR1 radioligand, but the preliminary biological evaluation of the radiotracer via radioligand depletion experiment indicated high non-specific binding to CX3CR1 (Gao M et al. Bioorg Med Chem Lett. 2017;27:2727-30). Despite the therapeutic potential of CX3CR1 antagonists, only a very limited number of inhibitors are known so far. However, potent and selective CX3CR1 antagonists are required as research tools for investigating the physiological functions of CX3CR1. JMS-17-2 (5-(3-(4-(4-chlorophenyl)piperidin-1-yl)propyl)pyrrolo[1,2-a]quinoxalin-4(5H)-one) is a recently reported potent and selective CX3CR1 antagonist with IC50 0.32 nM (Shen F, et al. Mol Cancer Res. 2016;14:518-27). Here we present the design and synthesis of a series of JMS-17-2 analogs as new potential CX3CR1 antagonists (ligands). JMS-17-2 and its analogs 5-(3-(4-(4-fluorophenyl)piperidin-1-yl)propyl)pyrrolo[1,2-a]quinoxalin-4(5H)-one (F-JMS-17-2) and 5-(3-(4-(4-methoxyphenyl)piperidin-1-yl)propyl)pyrrolo[1,2-a]quinoxalin-4(5H)-one (MeO-JMS-17-2) were synthesized from commercially available 2-(1H-pyrrol-1-yl)aniline with 4-(4-substitutedphenyl)piperidine in 3 steps with 41-47% overall chemical yield. Synthesis and biological evaluation of carbon-11 and fluorine-18 labeled JMS-17-2 analogs ([11C]MeO-JMS-17-2 and [18F]F-JMS-17-2) as new PET CX3CR1 radioligands are currently underway.

Synthesis of JMS-17-2 and its analogs as new potential CX3CR1 antagonists

255th National Meeting (2018)

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