First-in-Human Assessment of 11C-LSN3172176, an M1 Muscarinic Acetylcholine Receptor PET Radiotracer

This was a first-in-human study of the PET radiotracer C-11-LSN3172176 for the muscarinic acetylcholine receptor subtype M1. The objectives of the study were to determine the appropriate kinetic model to quantify binding of the tracer to M1 receptors, and the reliability of the chosen quantification method. Methods: Six healthy subjects completed the test-retest protocol, and 5 healthy subjects completed the baseline-scopolamine blocking protocol. Multiple modeling methods were applied to calculate total distribution volume (V-T) and nondisplaceable binding potential (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 nondisplaceable distribution volume. 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 2-tissue-compartment (2TC) model fits were good, but the 2TC parameters often could not be reliably estimated. Because V-T correlated well between the 2TC and 1-tissue-compartment (1TC) models after exclusion of unreliable estimates, the 1TC model was chosen as the most appropriate. The cerebellum showed the lowest V-T, consistent with preclinical studies showing little to no specific binding in the region. Further, cerebellar V-T 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 the simplified reference tissue model 2 (SRTM2) improved BPND estimation. An 80-min scan was sufficient to quantify V-T and BPND. The test-retest study showed excellent absolute test-retest variability for 1TC V-T (<= 5%) and BPND (<= 10%). In the baseline and blocking studies, occupancy values were lower in the striatum than in nonstriatal regions, as may be attributed to differences in regional acetylcholine concentrations. Conclusion: The 1TC and SRTM2 models are appropriate for quantitative analysis of C-11-LSN3172176 imaging data. C-11-LSN3172176 displayed excellent test-retest reproducibility and is a highly promising ligand to quantify M1 receptors in the human brain.

Automated summary

This study investigated the PET radiotracer C-11-LSN3172176 for M1 muscarinic acetylcholine receptors in healthy participants, finding that the 1TC and SRTM2 models are most suitable for quantitative analysis. The cerebellum was identified as a suitable reference region for the tracer. Overall, C-11-LSN3172176 demonstrated excellent test-retest reproducibility and holds promise for quantifying M1 receptors in the human brain.