Nondisplaceable Binding Is a Potential Confounding Factor in ¹¹C-PBR28 Translocator Protein PET Studies

Abstract

The PET ligand ¹¹C-PBR28 (N-((2-(methoxy-¹¹C)-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 outcome 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 V_S. Data from 4 previously published ¹¹C-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.