N-(4-[18F]-fluoropyridin-2-yl)-N-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}carboxamides as analogs of WAY100635. New PET tracers of serotonin 5-HT1A receptors

• Four [18F]-fluorinated PET tracers were prepared for imaging 5-HT1A receptors.
• Labeling was carried out efficiently by SNAr on a 4-nitro-pyridin-2-ylamine moiety.
• Cyclohexyl derivative is a selective and potent in vitro 5-HT1A receptor antagonist.
• It showed high uptake and slow clearance in brain and radiolabel stability in vivo.
• This tracer is a promising candidate for imaging of neuropsychiatric disorders.

N-(4-[18F]-Fluoropyridin-2-yl)-N-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}-carboxamides were prepared by labeling their 4-nitropyridin-2-yl precursors through nitro substitution by the 18F anion. In vitro and in vivo tests showed that the cyclohexanecarboxamide derivative is a reversible, selective and high affinity 5-HT1A receptor antagonist (IC50 = 0.29 nM, ki = 0.18 nM) with high brain uptake, slow brain clearance and stability to defluorination when compared with conventional standards. This PET radioligand is a promising candidate for an improved in vivo quantification of 5-HT1A receptors in neuropsychiatric disorders.

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