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. <b>Methods:</b> 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 <i>N</i>-desmethyl precursor. PET imaging of the monkey brain was performed at baseline and after blockade by <i>N</i>-butan-2-yl-1-(2-chlorophenyl)-<i>N</i>-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 [<i>BP</i>_ND]) and the time stability of total distribution volume (<i>V</i>_T), an indirect measure of lack of radiometabolite accumulation in the brain. <b>Results:</b> Total TSPO binding was quantified as <i>V</i>_T corrected for plasma free fraction (<i>V</i>_T/<i>f</i>_P) using Logan graphical analysis for all 6 radioligands. <i>V</i>_T/<i>f</i>_P was generally high at baseline (222 ± 178 mL·cm^-3) and decreased by 70%-90% after preblocking with PK11195. <i>BP</i>_ND calculated using the Lassen plot was 9.6 ± 3.8; the <i>o</i>-fluoro radioligand exhibited the highest <i>BP</i>_ND (12.1), followed by the <i>m</i>-trifluoromethyl (11.7) and <i>m</i>-fluoro (8.1) radioligands. For all 6 radioligands, <i>V</i>_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. <b>Conclusion:</b> All 6 radioligands had good <i>BP</i>_ND and good time stability of <i>V</i>_T Among them, the <i>o</i>-fluoro, <i>m</i>-trifluoromethyl, and <i>m</i>-fluoro compounds were the 3 best candidates for development as radioligands with an ¹⁸F label.