TY - JOUR T1 - In vivo evaluation of six analogs of <sup>11</sup>C-ER176 as candidate 18F-labeled radioligands for translocator protein 18 kDa (TSPO) JF - Journal of Nuclear Medicine JO - J Nucl Med SP - 1 LP - 1 VL - 62 IS - supplement 1 AU - Jae-Hoon Lee AU - Fabrice Simeon AU - Jeih-San Liow AU - Cheryl Morse AU - Robert Gladding AU - Jose Angel Montero Santamaria AU - Sabrina Taliani AU - Federico Da Settimo AU - Ioline Henter AU - Sami Zoghbi AU - Victor Pike AU - Robert Innis Y1 - 2021/05/01 UR - http://jnm.snmjournals.org/content/62/supplement_1/1.abstract N2 - 1Objectives: 11C-ER176 can successfully image TSPO, a biomarker of inflammation, in human brain because it has an excellent ratio of specific to nondisplaceable uptake and can accurately quantify target density in homozygous low-affinity binders. We aim to develop an 18F-labeled TSPO PET radioligand based on ER176 with potential for wider distribution. This study used generic carbon-11 labeling and in vivo performance in monkey brain to select the most promising of six fluorine-containing analogs of ER176 for subsequent 18F-radiolabeling. Methods: Six 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 precursors. PET imaging was performed in monkey brain at baseline and after administration of nonradioactive PK11195, and uptake was quantified using metabolite-corrected arterial input function. The six candidate radioligands were ranked based on two in vivo performance criteria: 1) BPND (ratio of specific to nondisplaceable uptake), and 2) time stability of the calculated target density (VT); time stability is an indirect measure of lack of radiometabolite accumulation in the brain. Results: Total TSPO binding was well identified as VT using Logan graphical analysis (standard errors &lt; 10%) for all six radioligands. VT at baseline was generally high (12-41 mL∙cm-3) and decreased by 70-90% after pre-blocking with nonradioactive PK11195. BPND calculated using the Lassen plot ranged from 3.7 to 11.6; the m-trifluoromethyl radioligand exhibited the highest BPND of 11.6, followed by the o-fluoro (9.6) and p-fluoro (5.9) radioligands. For all six radioligands, VT values reached 90% of 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. Conclusions: The results demonstrate that all six radioligands have a good ratio of specific to nondisplaceable uptake (BPND) as well as good time stability of total receptor binding (VT). Among them, the m-trifluoromethyl, o-fluoro, and p-fluoro compounds were the three best candidates for future radiolabeling with 18F. ER -