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

Because of its excellent ratio of specific to nondisplaceable uptake, the radioligand ¹¹ 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 ¹⁸ F-labeled TSPO PET radioligand based on ER176 with the potential for broader distribution. This study used generic ¹¹ 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 ¹⁸ F. Methods: Six fluorine-containing analogs of ER176-3 fluoro and 3 trifluoromethyl isomers-were synthesized and labeled by ¹¹ C 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 ¹⁸ F label.
(© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)