Radiosynthesis of [C]LY2795050 for Preclinical and Clinical PET Imaging Using Cu(II)-Mediated Cyanation.

Copper-mediated C-cyanation reactions have enabled the synthesis of PET radiotracers from a range of readily available precursors and avoid the need to use more toxic Pd catalysts. In this work we adapt our recently developed C-cyanation of arylpinacolboronate (BPin) esters for the cGMP synthesis of [C]LY2795050, a selective antagonist radiotracer for the kappa opioid receptor (KOR). [C]LY2795050 was synthesized in 6 ± 1% noncorrected radiochemical yield (based on [C]HCN, = 3) using an automated synthesis module. Quality control testing confirmed the suitability of doses for preclinical and clinical PET imaging (radiochemical purity >99%; specific activity >900 mCi/μmol; residual Cu < 0.1 μg/mL). PET imaging was conducted in rodent and nonhuman primates, showing good brain uptake of [C]LY2795050 and the expected distribution of KOR. Analogous imaging with [C]carfentanil (a selective mu opioid receptor (MOR) radiotracer) revealed the anticipated regional differences in MOR and KOR distribution in the primate brain.