Optimization, automation and validation of NOP receptor PET radiopharmaceutical, [¹¹C]NOP-1A for human use

In vivo human studies of the nociceptin/orphanin FQ peptide (NOP) receptor have been limited by the availability and reliable production of suitable PET radioligands. [¹¹C]NOP-1A is a high-affinity PET radioligand for imaging NOP receptors; however, reproducible production suitable for routine clinical use has been challenging. The aim of this study was to optimize, automate, and validate the radiosynthesis of [¹¹C]NOP-1A for cGMP-compliant human PET imaging.

We developed a fully automated loop radiomethylation method for the production of [¹¹C]NOP-1A using the commercially available GE TRACERlab™ FXC Pro synthesis module and validated the process according to United States Food and Drug Administration (FDA) and United States Pharmacopeia (USP) requirements. Multiple radiolabeling conditions were evaluated using different bases and solvents. Optimal production was achieved using [¹¹C]CH₃I in the presence of sodium hydride (NaH) and dimethylformamide (DMF), resulting in reliable and reproducible synthesis with radiochemical conversion of up to 60%. Validation studies demonstrated successful production of [¹¹C]NOP-1A with radiochemical purity ranging from 97.5 to 99.6%, molar activity of 79.4-162.9 GBq/μmol at end of synthesis, and a corrected radiochemical yield of 13 ± 2.5% relative to starting [¹¹C]CO₂. All quality control parameters met predefined acceptance criteria for human administration.

A robust, fully automated, and cGMP-compliant production method for [¹¹C]NOP-1A was successfully developed and validated for human use. This approach provides reliable routine production of [¹¹C]NOP-1A and facilitates broader clinical and translational investigation of the NOP receptor system in neuropsychiatric and neurological disorders.