IND-Enabling Preclinical Studies of [¹¹C]COU, a Trapped Metabolite PET Radiotracer for Monoamine Oxidase-B

[¹¹C]COU is a trapped metabolite radiotracer for in vivo analysis of Monoamine Oxidase B activity using positron emission tomography (PET) imaging. [¹¹C]COU has the potential to quantify astrocytosis in the early stages of Alzheimer's disease, providing an earlier marker of disease than currently available for staging disease progression. Prior preclinical studies have demonstrated the efficacy of this radiotracer in preclinical imaging studies, warranting the translation for clinical evaluation. In this paper, we describe results of the requisite preclinical studies required to obtain approval for translation of [¹¹C]COU into first-in-human studies. Development and validation of a production method that conforms to the quality requirements described in the US Pharmacopeia was accomplished, along with preclinical rodent studies to determine human radiation dose estimates and a single acute dose pharmacology and toxicology study to establish that an injected mass dose 100-fold higher than the proposed PET imaging dose was below the no-observed-adverse-effect level (NOAEL). The production method was validated in triplicate, yielding [¹¹C]COU in sufficient radiochemical yield (9.3±0.008%), radiochemical purity (99.2±0.002%) and molar activity (165±65 TBq/mmol) for routine clinical use, and providing a product that was sterile and met (or exceeded) all quality control requirements for human use. Dosimetric analysis determined that the effective human dose of [¹¹C]COU is 0.005mSv/MBq, also acceptable for clinical use. Lastly, no observable adverse effects were noted at 86 μg/kg in rodent toxicology studies (100x the proposed human dose). From these results we received approval to advance [¹¹C]COU into clinical studies.