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

Abstract

The positron emission tomography (PET) ligand 11 C-PBR28 binds to the 18kDa translocator protein (TSPO), a biomarker of glia. In clinical studies of TSPO, the ligand total distribution volume, VT, is frequently the reported outcome measure. Since VT is the sum of the ligand specific (VS) and non-displaceable binding (VND), differences in VND across subjects and groups will have an impact on VT.Methods: Here, we used a recently developed method for simultaneous estimation of VND (SIME) to disentangle contributions from VND and VS. Data from four previously published 11 C-PBR28 PET studies were included: (i) before and after a lipopolysaccharide challenge (8 subjects), (ii) in alcohol use disorder (14 patients, 15 controls), (iii) in first-episode psychosis ( 16patients, 16 controls), and (iv) in Parkinson's disease (16 patients, 16 controls). In each dataset, regional VT estimates were obtained with a standard two-tissue compartment model, and brainwide VND was estimated with SIME. VS was then calculated as VT-VND. VND and VS were then compared across groups, within each dataset.Results: A lower VND was found for individuals with alcohol use disorder (34%, p=0.00084) and Parkinson's disease (34%, p=0.0032), when compared to their corresponding controls. We found no difference in VND between first-episode psychosis patients and their controls, and the administration of lipopolysaccharide did not change VND. Conclusion:Our findings suggest that in TSPO PET studies, non-displaceable binding can differ between patient groups and conditions and should therefore be taken into account.

Specific and non-specific binding of a tracer for the translocator-specific protein in schizophrenia: an [11C]-PBR28 blocking study

“…This mismatched between SIME and Lassen plot estimates has been already shown by Schain and colleagues [35], who reported similar V ND values for both healthy controls (mean±sd: 1.45 ± 0.56 mL/cm 3 ) and Alzheimer disease patients (mean±sd: 1.36 ± 0.40 mL/cm 3 ). In a recent study, comparing SIME V ND estimates across different populations, Laurell and colleagues found a mean value of 1.12 mL/cm 3 for a group of 6 HABs first-episode psychosis patients, very well aligned with the SIME V ND estimate obtained in our sample [25].…”

Molecular Imaging in Parkinsonian Disorders—What’s New and Hot?

“…Using 18F-DPA714, elevated binding was found in the midbrain and putamen, but also frontal cortex in PD patients with mixed or high-affinity [ 159 ]. Interestingly, elevated 11C-PBR28 binding with hotspots in the cerebellar white matter and lentiform nucleus clearly separated patients with MSA from PD patients [ 160 ], although binding may be biased by group differences of non-displaceable binding [ 161 ].…”

Characterization of neuroinflammatory positron emission tomography biomarkers in chronic traumatic encephalopathy

“… 29 There is also high variability in non-displaceable binding across patient populations that needs to be considered for designing and interpreting TSPO-PET studies. 30 Another short-coming of TSPO-PET is the sensitivity of second-generation radiotracers to the TSPO single-nucleotide polymorphism (SNP), rs6971, resulting in low-, mixed- and high-affinity binders which requires genetic profiling before imaging with these radiopharmaceuticals.…”