TSPO circadian pattern: a test-retest study of [¹¹C]ER176

Purpose: Mitochondrial translocator protein 18 kDa (TSPO), expressed by brain cells involved in immunity, has been a positron emission tomography (PET) target in numerous neurological and psychiatric studies. TSPO PET ligand binding is influenced by the single nucleotide polymorphism rs6971, dividing the population into three groups: high-affinity binders (HAB), mixed-affinity binders (MAB), and low-affinity binders (LAB). Unlike most “second generation” TSPO ligands, [¹¹C]ER176 allows imaging of even LAB. This study examines the yet unstudied test-retest reproducibility of [¹¹C]ER176 binding in all TSPO genotypes. Methods: Twelve healthy participants were studied. Seven had two [¹¹C]ER176 PET scans in the same day, morning and afternoon; five of these had a third PET scan on a separate morning. Five additional controls underwent two scans on separate mornings. Metabolite-corrected arterial input function (AIF) was used to calculate total distribution volume (V_T) with a two-tissue compartment model. Results: V_T showed showed excellent reproducibility for scans performed at the same time of day: for AM scans, whole-brain variability, excluding an outlier, was 12.4 ± 6.0%. The intraclass correlation coefficient was excellent, at 0.92. However, V_T showed a significant diurnal effect: [¹¹C]ER176 parent SUV was higher in all subjects in AM compared to PM, while brain V_T was lower in AM. HABs and MABs showed greater V_T increases: whole-brain V_T variability for AM versus PM was 8.5 ± 5.8% / 28.4 ± 4.5% / 28.5 ± 8.0% for LAB/MAB/HAB. Conclusion: [¹¹C]ER176 brain V_T has good reproducibility across days for scans performed in the morning. However, V_T shows diurnal effects, which must be accounted for in study design.