TY - JOUR T1 - In vivo evaluation of six analogs of <sup>11</sup>C-ER176 as candidate <sup>18</sup>F-labeled radioligands for translocator protein 18 kDa (TSPO) JF - Journal of Nuclear Medicine JO - J Nucl Med DO - 10.2967/jnumed.121.263168 SP - jnumed.121.263168 AU - Jae-Hoon Lee AU - Fabrice G. Simeon AU - Jeih-San Liow AU - Cheryl L. Morse AU - Robert L. Gladding AU - Jose Angel Montero Santamaria AU - Ioline D. Henter AU - Sami S. Zoghbi AU - Victor W. Pike AU - Robert B. Innis Y1 - 2022/01/01 UR - http://jnm.snmjournals.org/content/early/2022/01/13/jnumed.121.263168.abstract N2 - 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 &lt; 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. ER -