In vivo evaluation of a novel 18F-labeled PET radioligand for translocator protein 18kDa (TSPO) in monkey brain

Abstract

Abstract Purpose: 18F-SF51 was previously found to have high binding affinity and selectivity for 18kDa translocator protein (TSPO) in mouse brain. This study sought to further evaluate the suitability of 18F-SF51 for absolute quantification of TSPO in monkey brain. Methods: Positron emission tomography (PET) imaging was performed in monkey brain (n=3) at baseline and after pre-blockade with the TSPO ligands PK11195 and PBR28. TSPO binding was calculated as total distribution volume corrected for free parent fraction in plasma (VT/fP) using a two-tissue compartment model. Receptor occupancy and nondisplaceable uptake were determined via Lassen plot. Binding potential (BPND) was calculated as the ratio of specific binding to nondisplaceable uptake. Time stability of VT was used as an indirect probe to detect radiometabolite accumulation in the brain. In vivo and ex vivo experiments were performed in mice to determine the distribution of the radioligand. Results: After 18F-SF51 injection, the concentration of brain radioactivity peaked at 2.0 standardized uptake value (SUV) at ~10 minutes and declined to 30% of the peak at 180 minutes. VT/fP at baseline was generally high (203±15 mL· cm-3) and decreased by ~90% after blockade with PK11195. BPND of the whole brain was 7.6 ± 4.3. VT values reached levels similar to terminal 180-minute values by 70 minutes and remained relatively stable thereafter with excellent identifiability (standard errors < 5%), suggesting that no significant radiometabolites accumulated in the brain. Ex vivo experiments in mouse brain showed that 96% of radioactivity was parent. No significant uptake was observed in the skull, suggesting a lack of defluorination in vivo. Conclusion: The results demonstrate that 18F-SF51 is an excellent radioligand with a good ratio of specific to nondisplaceable uptake as well as good time stability of total receptor binding. Collectively, the results suggest that 18F-SF51 warrants further evaluation in humans.