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

Transmembrane AMPA receptor regulatory protein γ-8 (TARP γ-8) mediates various AMPA receptor functions. Recently, [¹¹C]TARP-2105 was developed as a PET ligand for TARP γ-8 imaging. We performed a full kinetic analysis of [¹¹C]TARP-2105 using PET with [¹¹C]TARP-2105 for the first time. The distribution volume (V_T), which is a macro parameter consisting of the K₁-k₄ 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) ≈ thalamus (0.5 ± 0.1) > pons (0.4 ± 0.1 mL/cm³). These heterogenous V_T values corresponded with the order of biological distribution of TARP γ-8 in the brain. To validate the reference tissue model, the binding potential (BP_ND) of [¹¹C]TARP-2105 for TARP γ-8 was estimated using general methods (SRTM, MRTM0, Logan reference model, and ratio method). These BP_NDs based on reference models indicated excellent correlation (R² > 0.9) to the indirect BP_NDs based on 2TCM with moderate reproducibility (%variability ≈ 10). PET with [¹¹C]TARP-2105 enabled noninvasive BP_ND estimation and visual mapping of TARP γ-8 in the living rat brain.