Nondisplaceable Binding Is A Potential Confounding Factor In C-11-Pbr28 Translocator Protein Pet Studies

The PET ligand C-11-PBR28 (N-((2-(methoxy-C-11)-phenyl)methyl)-N-(6-phenoxy-3-pyridinyl)acetamide) binds to the 18-kDa translocator protein (TSPO), a biomarker of glia. In clinical studies of TSPO, the ligand total distribution volume, V-T, is frequently the reported out come measure. Since V-T is the sum of the ligand-specific distribution volume (V-S) and the nondisplaceable-binding distribution volume (V-ND), differences in V-ND across subjects and groups will have an impact on V-T. Methods: Here, we used a recently developed method for simultaneous estimation of V-ND (SIME) to disentangle contributions from V-ND and VS. Data from 4 previously published C-11-PBR28 PET studies were included: before and after a lipopolysaccharide challenge (8 subjects), in alcohol use disorder (14 patients, 15 controls), in first-episode psychosis (16 patients, 16 controls), and in Parkinson disease (16 patients, 16 controls). In each dataset, regional V-T estimates were obtained with a standard 2-tissue-compartment model, and brain-wide V-ND was estimated with SIME. V-S was then calculated as V-T - V-ND. V-ND and V-S were then compared across groups, within each dataset. Results: A lower V-ND was found for individuals with alcohol-use disorder (34%, P = 0.00084) and Parkinson disease (34%, P = 0.0032) than in their corresponding controls. We found no difference in V-ND between first-episode psychosis patients and their controls, and the administration of lipopolysaccharide did not change V-ND. Conclusion: Our findings suggest that in TSPO PET studies, nondisplaceable binding can differ between patient groups and conditions and should therefore be considered.