Automated synthesis, preclinical toxicity, and radiation dosimetry of [F-18]MC225 for clinical use: a tracer for measuring P-glycoprotein function at the blood-brain barrierToyohara, J., Sakata, M., Tago, T., Colabufo, N. A. & Luurtsema, G., 22-Jul-2020, In : EJNMMI Research. 10, 1, 11 p., 84.
Research output: Contribution to journal › Article › Academic › peer-review
Introduction: [18F]MC225 is a selective substrate for P-glycoprotein (P-gp) that has good metabolic stability and shows higher baseline uptake compared with other P-gp substrates such as (R)-[11C]Verapamil. Prior to clinical translation, it is necessary to perform process validation of the radiosynthesis, assessment of preclinical toxicity, and radiation dosimetry. Methods: The production of [18F]MC225 was automated on a CFN-MPS200 multipurpose synthesizer. The acute toxicity of MC225 was evaluated at a dose of 2.5 mg/kg bodyweight, which is more than 10,000-fold the postulated maximum clinical dose of [18F]MC225. The acute toxicity of [18F]MC225 injection at a 200-fold dose, to administer a postulated dose of 185 MBq of [18F]MC225, was also evaluated after the decay-out of 18F. The mutagenicity of MC225 was studied by a reverse mutation test using Salmonella typhimurium and Escherichia coli (Ames test). In vivo biodistribution and dosimetry studies of [18F]MC225 were carried out in normal mice. Human dosimetry was estimated using OLINDA software. Results: The mean decay-corrected yields of [18F]MC225 at end of synthesis were 13%, with > 99% radiochemical purity, > 1000 GBq/μmol molar activity, and ≤ 1.5 μg/185 MBq of total chemical contents. All process validation batches complied with the product specifications and the process was confirmed to be appropriate for the production of [18F]MC225. No acute toxicity of MC225 or [18F]MC225 injection was found. No mutagenic activity was observed for MC225. The biodistribution study demonstrated both hepatobiliary and renal excretion of radioactivity. The most critical organ was the pancreas, with (63.8 μGy/MBq) or without urination (63.9 μGy/MBq) at 360 min after injection. The estimated effective dose (μSv/MBq) with and without urination at 360 min after injection was calculated as 15.7 and 16.9, respectively. Conclusion: [18F]MC225 shows acceptable pharmacological safety at the dose required for adequate PET imaging. The potential risk associated with [18F]MC225 PET imaging is well within acceptable dose limits.
|Number of pages||11|
|Publication status||Published - 22-Jul-2020|
- Positron emission tomography, P-glycoprotein, MC225, Fluorine-18, Dosimetry, Toxicology, INTERNAL DOSE ASSESSMENT, ABC TRANSPORTERS, DRUG-RESISTANCE, PET TRACERS, EXPRESSION, EPILEPSY, EFFLUX, RADIOPHARMACEUTICALS, SAFETY, MODEL