RT Journal Article SR Electronic T1 In vivo evaluation of six analogs of 11C-ER176 as candidate 18F-labeled radioligands for translocator protein 18 kDa (TSPO) JF Journal of Nuclear Medicine JO J Nucl Med FD Society of Nuclear Medicine SP 1 OP 1 VO 62 IS supplement 1 A1 Jae-Hoon Lee A1 Fabrice Simeon A1 Jeih-San Liow A1 Cheryl Morse A1 Robert Gladding A1 Jose Angel Montero Santamaria A1 Sabrina Taliani A1 Federico Da Settimo A1 Ioline Henter A1 Sami Zoghbi A1 Victor Pike A1 Robert Innis YR 2021 UL http://jnm.snmjournals.org/content/62/supplement_1/1.abstract AB 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 < 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 < 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.