Fully automated radiosynthesis of [11C]OMAR ([11C]JHU75528), a CB1 radioligand for clinical investigation of brain disorders

132 Objectives Cerebral cannabinoid receptor subtype 1 (CB1) is predominantly expressed in the central nervous system, and involved in a variety of brain functions and disorders such as schizophrenia and depression, obesity, drug addiction and alcoholism, and traumatic brain injury. [11C]OMAR ([11C]JHU75528) is a promising radioligand for PET imaging of CB1 receptors, originally developed and characterized at the John Hopkins University. Wishing to study this compound in our PET center, we decided to make our own material by following the literature methods, and we also investigated a fully automated radiosynthesis of [11C]OMAR. Methods OMAR and desmethyl-OMAR were synthesized from 2,4-dichloroaniline in 4 and 5 steps, respectively. [11C]OMAR was prepared by O-[11C]methylation of desmethyl-OMAR with [11C]CH3OTf in CH3CN at 80 oC under basic conditions, in a home-built automated 11C-radiosynthesis module, allowing measurement of specific activity during synthesis, and purified by HPLC combined with SPE method. Results The published method for the synthesis of OMAR and desmethyl-OMAR gave poor yields. Therefore, alternate approaches and modifications were investigated. We used Et3N/t-BuOH instead of EtONa/EtOH in cycloaddition reaction to improve the yield from 19% to 63%. We used oxalyl chloride/DMF/CH2Cl2 instead of SOCl2/toluene in coupling reaction to raise up the yield from 37% to 60%. Direct demethylation of OMAR to desmethyl-OMAR was failed and a multiple-step synthesis of desmethyl-OMAR was employed in the literature. We succeeded in one-step direct demethylation by using LiBr/DMF at reflux with 91% yield. The overall chemical yields for OMAR and desmethyl-OMAR were 33% and 30%, respectively. The decay corrected radiochemical yield for [11C]OMAR was 60-70%. The specific activity at EOB for [11C]OMAR was 370-740 GBq/μmol. Conclusions A high-yield synthetic route to OMAR and desmethyl-OMAR has been described, and an improved synthesis of [11C]OMAR has been developed, which were superior to previous works. Research Support Indiana Spinal Cord & Brain Injury Fund (ISDH EDS-A70-2-079612)