First in Human Assessment of the Novel M1 Muscarinic Acetylcholine Receptor PET Radiotracer 11C-LSN3172176.

Objectives: This is a first-in-human study of the PET radiotracer 11C-LSN3172176 for the muscarinic acetylcholine receptor subtype 1 (M1). The objectives of this study were to determine the appropriate kinetic model to quantify the tracer's binding to M1 receptors, and the reliability of the chosen quantification method. Methods: Six healthy subjects completed the test-retest protocol and five healthy subjects completed the baseline-scopolamine blocking protocol. Multiple modeling methods were applied to calculate volume of distribution (VT) and binding potentials (BPND) in various brain regions. The reference region was selected from the blocking study. The occupancy plot was applied to compute receptor occupancy by scopolamine and non-displaceable distribution volume (VND). Results: Tracer uptake was highest in the striatum, followed by neocortical regions and white matter, and lowest in the cerebellum. Regional time-activity curves were fitted well by all models. The two-tissue compartment (2TC) model fits were good, but the 2TC parameters often could not be reliably estimated. There was an excellent correlation of VT between 2TC and one-tissue compartment (1TC) models after excluding unreliable estimates, so the 1TC model was chosen as the most appropriate. The cerebellum showed the lowest VT, consistent with preclinical studies showing little to no specific binding in the region. Further, cerebellar VT did not change between baseline and blocking scans, indicating that the cerebellum is a suitable reference region. The simplified reference tissue model (SRTM) slightly underestimated 1TC BPND and SRTM2 improved BPND estimation. An 80-min scan duration was sufficient to quantify VT and BPND The test-retest study showed excellent absolute test-retest variability for 1TC VT (≤5%) and BPND (≤10%). In the baseline and blocking study, the striatum displayed lower occupancy values than non-striatal regions, which may be attributed to differences in regional acetylcholine concentrations. Conclusion: The 1TC and SRTM2 models are appropriate methods for quantitative analysis of 11C-LSN3172176 imaging data. 11C-LSN3172176 displayed excellent test-retest reproducibility and is a highly promising ligand to quantify M1 receptors in the human brain.