In Vivo Evaluation of 6 Analogs of C-ER176 as Candidate F-Labeled Radioligands for 18-kDa Translocator Protein.

Because of its excellent ratio of specific to nondisplaceable uptake, the radioligand C-ER176 can successfully image 18-kDa translocator protein (TSPO), a biomarker of inflammation, in the human brain and accurately quantify target density in homozygous low-affinity binders. Our laboratory sought to develop an F-labeled TSPO PET radioligand based on ER176 with the potential for broader distribution. This study used generic C labeling and in vivo performance in the monkey brain to select the most promising among 6 fluorine-containing analogs of ER176 for subsequent labeling with longer-lived F. Six fluorine-containing analogs of ER176-3 fluoro and 3 trifluoromethyl isomers-were synthesized and labeled by C methylation at the secondary amide group of the respective -desmethyl precursor. PET imaging of the monkey brain was performed at baseline and after blockade by -butan-2-yl-1-(2-chlorophenyl)--methylisoquinoline-3-carboxamide (PK11195). Uptake was quantified using radiometabolite-corrected arterial input function. The 6 candidate radioligands were ranked for performance on the basis of 2 in vivo criteria: the ratio of specific to nondisplaceable uptake (i.e., nondisplaceable binding potential []) and the time stability of total distribution volume (), an indirect measure of lack of radiometabolite accumulation in the brain. Total TSPO binding was quantified as corrected for plasma free fraction (/) using Logan graphical analysis for all 6 radioligands. / was generally high at baseline (222 ± 178 mL·cm) and decreased by 70%-90% after preblocking with PK11195. calculated using the Lassen plot was 9.6 ± 3.8; the -fluoro radioligand exhibited the highest (12.1), followed by the -trifluoromethyl (11.7) and -fluoro (8.1) radioligands. For all 6 radioligands, reached 90% of the terminal 120-min values by 70 min and remained relatively stable thereafter, with excellent identifiability (SEs < 5%), suggesting that no significant radiometabolites accumulated in the brain. All 6 radioligands had good and good time stability of Among them, the -fluoro, -trifluoromethyl, and -fluoro compounds were the 3 best candidates for development as radioligands with an F label.