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Background: [18F]THK5351 is a tau positron emission tomography tracer that has shown promise in quantifying tau distribution in tauopathies such as Alzheimer's disease (AD) and progressive supranuclear palsy (PSP). However, the interpretation of [18F]THK5351 uptake has been shown to be confounded by high monoamine oxidase B (MAO-B) availability across the brain in AD. Objectives: To test the hypothesis that the MAO-B inhibitor, rasagiline reduces [18F]THK5351 uptake in PSP. Methods: Six individuals (4: PSP; 2: cognitively unimpaired, CU) underwent [18F]THK5351 and [18F]AZD4694 to quantify baseline tau and amyloid deposition, respectively. Following a 10-day course of 1 mg rasagiline, all participants received a post-challenge [18F]THK5351 scan. The baseline and post-rasagiline challenge standardized uptake value (SUV) were generated normalized for patient weight and injected radioactivity. Results: The post-rasagiline regional SUV was reduced on average by 69–89% in PSP, and 53–81% in CU. The distributions of post-rasagiline [18F]THK5351 SUV among PSP individuals were not consistent with the typical pattern of tau aggregates in PSP. Conclusions: Similar to AD, the interpretation of [18F]THK5351 uptake in PSP is likely confounded by off-target binding to MAO-B binding sites. [18F]THK5351 is not sufficient in quantifying tau aggregates in PSP using the proposed rasagiline dosing regimen. Keywords: [18F]THK5351 tau tracer, Monoamine oxidase-B, Rasagiline, Progressive Supranuclear Palsy, Positron emission tomography