Development and Optimization of ¹¹C-Labeled Radiotracers: A Review of the Modern Quality Control Design Process

Introduction - Several ¹¹C-tracers have demonstrated high potential in early diagnostic PET imaging applications of neurodegenerative diseases including Alzheimer's and Parkinson's disease. These radiotracers often track critical biomarkers in disease pathogenesis such as tau fibrils ([¹¹C]PBB3) or β-amyloid plaques ([¹¹C]PiB) associated with such diseases. Purpose - The short review aims to serve as a guideline in the future development of radiotracers for students, postdocs and/or new radiochemists who will be synthesizing clinical grade or novel research ¹¹C-tracers, including knowledge of regulatory requirements. We aim to bridge the gap between novel and established ¹¹C-tracer quality control (QC) processes through exploring the design process and regulatory requirements for ¹¹C-pharmaceuticals. Methods - A literature survey was undertaken to identify articles with a detailed description of the QC methodology and characterization for each of the sections of the review. Overview - First a general summary of ¹¹C-tracer production was presented; this was used to establish possible places for contamination or assurances for a sterile final product. The key mandated QC analyses for clinical use were then discussed. Further, we assessed the QC methods used for established ¹¹C-tracers and then reviewed the routine QC tests for preclinical translational and validation studies. Therefore, both mandated QC methods for clinical and preclinical animal studies were reviewed. Last, some examples of optimization and automation were reviewed, and implications of the QC practices associated with such procedures were considered. Conclusion - All of the common QC parameters associated with ¹¹C-tracers under clinical and preclinical settings (along with a few exceptions) were discussed in detail. While it is important to establish standard, peer-reviewed QC testing protocols for a novel ¹¹C-tracer entering the clinical umbrella, equal importance is needed on preclinical applications to address credibility and repeatability for the study.