In Vivo Evaluation of 6 Analogs of ¹¹C-ER176 as Candidate ¹⁸F-Labeled Radioligands for 18-kDa Translocator Protein

Abstract

Because of its excellent ratio of specific to nondisplaceable uptake, the radioligand ¹¹C-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 ¹⁸F-labeled TSPO PET radioligand based on ER176 with the potential for broader distribution. This study used generic ¹¹C 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 ¹⁸F. Methods: Six fluorine-containing analogs of ER176—3 fluoro and 3 trifluoromethyl isomers—were synthesized and labeled by ¹¹C methylation at the secondary amide group of the respective N-desmethyl precursor. PET imaging of the monkey brain was performed at baseline and after blockade by N-butan-2-yl-1-(2-chlorophenyl)-N-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 [BP_ND]) and the time stability of total distribution volume (V_T), an indirect measure of lack of radiometabolite accumulation in the brain. Results: Total TSPO binding was quantified as V_T corrected for plasma free fraction (V_T/f_P) using Logan graphical analysis for all 6 radioligands. V_T/f_P was generally high at baseline (222 ± 178 mL·cm⁻³) and decreased by 70%–90% after preblocking with PK11195. BP_ND calculated using the Lassen plot was 9.6 ± 3.8; the o-fluoro radioligand exhibited the highest BP_ND (12.1), followed by the m-trifluoromethyl (11.7) and m-fluoro (8.1) radioligands. For all 6 radioligands, V_T 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. Conclusion: All 6 radioligands had good BP_ND and good time stability of V_T. Among them, the o-fluoro, m-trifluoromethyl, and m-fluoro compounds were the 3 best candidates for development as radioligands with an ¹⁸F label.