Small-animal PET study for noninvasive quantification of transmembrane AMPA receptor regulatory protein gamma-8 (TARP gamma-8) in the brain

Transmembrane AMPA receptor regulatory protein gamma-8 (TARP gamma-8) mediates various AMPA receptor functions. Recently, [C-11]TARP-2105 was developed as a PET ligand for TARP gamma-8 imaging. We performed a full kinetic analysis of [C-11]TARP-2105 using PET with [C-11]TARP-2105 for the first time. The distribution volume (V-T), which is a macro parameter consisting of the K-1-k(4) rate constants in the two-tissue compartment model analysis, exhibited the following rank order: hippocampus (1.4 +/- 0.3) > amygdala (1.0 +/- 0.2) > frontal cortex (0.9 +/- 0.2) > striatum (0.8 +/- 0.2) >> cerebellum (0.5 +/- 0.1)asymptotic to thalamus (0.5 +/- 0.1) > pons (0.4 +/- 0.1 mL/cm(3)). These heterogenous V-T values corresponded with the order of biological distribution of TARP gamma-8 in the brain. To validate the reference tissue model, the binding potential (BPND) of [C-11]TARP-2105 for TARP gamma-8 was estimated using general methods (SRTM, MRTM0, Logan reference model, and ratio method). These BP(ND)s based on reference models indicated excellent correlation (R-2 > 0.9) to the indirect BP(ND)s based on 2TCM with moderate reproducibility (%variability asymptotic to 10). PET with [C-11]TARP-2105 enabled noninvasive BPND estimation and visual mapping of TARP gamma-8 in the living rat brain.