Gina Kaup, Tanpreet Kaur, Bradford D Henderson, Wade P Winton, James R Hill, David M Raffel, Jenelle Stauff, Ka Kit Wong, Allen F Brooks, Xia Shao, Gary D Hammer, Benjamin L Viglianti, Peter J H Scott
These 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.
BACKGROUND: Sterol 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.
METHODS: Three 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.
CONCLUSIONS: These 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.