Abstract
Due to its excellent ratio of specific to nondisplaceable uptake, the radioligand 11C-ER176 can successfully image 18kDa translocator protein (TSPO), a biomarker of inflammation, in human brain and accurately quantify target density in homozygous low-affinity binders. Our laboratory sought to develop an 18F-labeled TSPO positron emission tomography (PET) radioligand based on ER176 with the potential for broader distribution. This study used generic carbon-11 labeling and in vivo performance in monkey brain to select the most promising among six fluorine-containing analogs of ER176 for subsequent labeling with longer-lived fluorine-18. Methods: Six fluorine-containing analogs of ER176—three fluoro and three trifluoromethyl isomers—were synthesized and labeled by 11C-methylation at the secondary amide group of the respective N-desmethyl precursor. PET imaging was performed in monkey brain at baseline and after blockade by PK11195. . Uptake was quantified using radiometabolite-corrected arterial input function. The six candidate radioligands were ranked for performance based on two in vivo criteria: 1) ratio of specific to nondisplaceable uptake (BPND), and 2) time stability of total distribution volume (VT), an indirect measure of lack of radiometabolite accumulation in the brain. Results: Total TSPO binding was quantified as VT corrected for plasma free fraction (VT/fP) using Logan graphical analysis for all six radioligands. VT/fP at baseline was generally high (222±178 mL∙cm-3) and decreased by 70–90% after pre-blocking with PK11195. BPND calculated using the Lassen plot was 9.6±3.8; the o-fluoro radioligand exhibited the highest BPND of 12.1, followed by the m-trifluoromethyl (11.7) and m-fluoro (8.1) radioligands. For all six radioligands, VT values reached 90% of the terminal 120-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. Conclusion: All six radioligands had a good ratio of specific to nondisplaceable uptake (BPND) as well as good time stability of total receptor binding (VT). Among them, the o-fluoro, m-trifluoromethyl, and m-fluoro compounds were the three best candidates for development as radioligands with a fluorine-18 label.
- Animal Imaging
- Molecular Imaging
- Neurology
- PET/CT
- Radiopharmaceuticals
- Radiotracer Tissue Kinetics
- neuroinflammation
- positron emission tomography
- radiometabolites
- specific-to-nondisplaceable uptake
- translocator protein
- Copyright © 2022 by the Society of Nuclear Medicine and Molecular Imaging, Inc.