Translational Evaluation of PET Radiotracers

National Institute Of Mental Health

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Abstract

For several years, we have focused on developing much-needed, effective, sensitive, and reliable radioligands to image neuroinflammation. 18kDA translocator protein (TSPO) is the most frequently studied target of neuroinflammation using positron emission tomography (PET), but its limitations have spurred the molecular imaging community to find more promising targets. Thus, we turned our attention to 18F-SF51, which was previously found to have high binding affinity and selectivity for TSPO in mouse brain. Our study sought to further evaluate the suitability of 18F-SF51 for absolute quantification of TSPO in monkey brain. PET imaging was performed in three monkeys at baseline and after blockade with the TSPO ligand PK11195. The concentration of parent radioligand was measured in concurrent arterial blood samples. TSPO binding was calculated as total distribution volume corrected for free parent fraction in plasma (VT/fP) using a two-tissue compartment model (2TCM). 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. We found that, after 18F-SF51 injection, the concentration of brain radioactivity peaked at 2.0 SUV at 10 minutes and declined to 30% of the peak at 180 minutes. VT/fP at baseline was generally high (190 13 mL cm-3) and decreased by 80% after blocked with PK11195. BPND of the whole brain was 7.3 4.5. VT values reached the similar level of 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. Furthermore, radiolabeling with 18F renders this ligand suitable for widespread use. Taken together, these findings suggest that 18F-SF51 is a promising next-generation TSPO PET ligand and that further evaluation in humans is warranted.