Kinetic modeling and test-retest variability of the M1 muscarinic acetylcholine receptor PET radiotracer 11C-LSN3172176 in humans

499 Objectives: The M1 muscarinic acetylcholine receptor (M1 mAChR) is an important therapeutic target for Alzheimer’s disease and other neurodegenerative disorders. A novel PET radiotracer, 11C-LSN3172176, was developed to quantify M1 mAChR, and was previously shown to have favorable kinetics and high specific binding in monkey studies. The aim of this work was to evaluate modeling methods and test-retest variability of 11C-LSN3172176 in humans. Methods: Six healthy subjects (3M/3F) completed a test-retest protocol. The test and retest scans were 5.8 ± 0.9 hours apart. An additional four healthy subjects (3M/1F) completed a scopolamine blocking protocol. The blocking scan was conducted 24 h after a scopolamine patch was placed. Acquisitions were 2-hour dynamic scans with an HRRT after injection of 11C-LSN3172176. Arterial blood samples were collected for measurement of tracer free fraction and the arterial input function. Using the AAL template and individual MR images, regions of interest (ROIs) were defined including striatum, neocortical regions, and cerebellum, to generate time-activity curves (TACs). Regional distribution volumes (VT) and binding potential (BPND) were calculated using one- and two-tissue compartment models (1TC and 2TC) and multilinear analysis-1 (MA1). The simplified reference tissue model (SRTM) was also used to estimate BPND. The cerebellum was used as a reference region, as it was the region with the lowest uptake and preclinical studies showed little to no specific binding. The absolute test-retest variability (aTRV) of VT and BPND were calculated as 100 [asterisk] |test - retest| / ((test + retest) / 2). M1 mAChR occupancy by scopolamine and non-displaceable distribution volume (VND) were estimated from the occupancy plot. Results: Highest uptake of 11C-LSN3172176 was seen in the striatum, followed by neocortical regions, with lowest uptake in the cerebellum. Regional TACs were fitted well with all models, with a slight lack of fit for 1TC and MA1. Although the 2TC fits were good, the 2TC parameters often could not be reliably estimated (relative standard error of VT > 10% in 75% of fits) due to numerical identifiability problems. 1TC mean K1 values (mL/cm3/min) ranged from 0.18 (centrum semiovale) to 0.49 (putamen). 1TC mean VT values (mL/cm3) ranged from 5.0 (cerebellum) to 48.7 (ventral striatum). There was an excellent correlation of VT between 2TC vs. 1TC (VT (1TC) = 1.00[asterisk]VT (2TC) - 1.07, R2 = 0.99) after excluding estimates with large standard errors. MA1 VT values (t[asterisk]=10 min) matched well with those of 1TC (VT (MA1, t[asterisk]=10 min) = 1.00[asterisk]VT (1TC) + 0.17, R2 = 1.00). SRTM BPND values were well correlated with those from 1TC, but were slightly underestimated (BPND (SRTM) = 0.90[asterisk]BPND (1TC) + 0.17, R2 = 0.97). The aTRV of VT (1TC) was excellent (mean: 4%, range: 1-7%) in all regions. The aTRV of BPND (1TC) was also excellent (mean: 6%, range: 4-10%), but the aTRV of BPND (SRTM) was somewhat higher (mean: 9%, range: 5-13%). In occupancy plots for the scopolamine study, the striatum and pallidum regions followed a different regression line than the other regions. Mean occupancy values were 44 ± 7% (striatum and pallidum) and 31 ± 8% (other regions), with mean VND of 5.2 ± 0.7 mL/cm3, which was similar to the cerebellum VT (mL/cm3) values (baseline, 4.9 ± 0.5; blocking, 5.1 ± 0.5). Regional differences in occupancy may be attributable to differences in regional acetylcholine concentrations. Conclusion: The 1TC and MA1 are appropriate models for analysis of 11C-LSN3172176 imaging data. The cerebellum appears to be a suitable reference region given its lowest VT and negligible change in VT between baseline and blocking scans. SRTM is also a useful alternative model for analysis. 11C-LSN3172176 brain PET showed excellent test-retest variability and thus this tracer is likely to be highly useful for quantification of M1 ACh receptors in humans. Research Support: Eli Lilly and Company