Automated clinical production, dosimetry estimates and preclinical safety considerations for clinical translation of a SOAT1-targeted PET imaging agent.

Abstract

BackgroundSterol O-acyl transferase 1 (SOAT1) esterifies free cholesterol for storage in the adrenal glands and macrophages. The SOAT1 inhibitor, nevanimibe, has previously been investigated as a therapeutic in preclinical models of atherosclerosis and in clinical trials for adrenal diseases. Previously, our lab radiolabeled nevanimibe with carbon-11 to image hypercholesteremic mouse models via PET, and its biodistribution was characterized in rats. Here, we establish an automated production method for [¹¹C] nevanimibe using Class III solvents and report both preclinical dosimetry estimates and safety considerations in anticipation of clinical translation.MethodsThree process verification batches were completed in sequence using the same radiolabeling protocol. Using a GE TRACERlabC-Pro, the precursor was reacted with [¹¹C]CH₃OTf using a previously established loop methylation method. Each dose was subject to all quality control tests to ensure reproducibility and consistency. The results from the biodistribution studies were used with OLINDA/EXM 2.0 to identify a human effective dose, and a retrospective review of prior preclinical and clinical literature was conducted to establish a safe mass dose.Results[¹¹C]Nevanimibe was produced in an average activity yield of 1.41 ± 0.77 GBq with a 4.25 ± 2.3% non-decay corrected radiochemical yield in 37.3 ± 10 min from end of beam. Each dose had >90% radiochemical purity with an average molar activity of 630.04 ± 191.03 TBq/mmol. The human effective dose was found to be 3.23 × 10-3 mSv/MBq, and a mass dose of 6.3 μg per subject was established as safe for future human studies.ConclusionsThese findings support further investigation of [¹¹C]nevanimibe in the clinic as a novel PET tracer to replace invasive diagnostic tools for cholesterol indications such as catheter-based vascular imaging for atherosclerosis and adrenal vein sampling for endocrine disorders. Translation into first-in-human studies is underway and will be reported in due course.