{"doi":"10.2967/jnumed.121.263168","title":"In Vivo Evaluation of 6 Analogs of <sup>11</sup>C-ER176 as Candidate <sup>18</sup>F-Labeled Radioligands for 18-kDa Translocator Protein","abstract":"Due to its excellent ratio of specific to nondisplaceable uptake, the radioligand <sup>11</sup>C-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 <sup>18</sup>F-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. <b>Methods:</b> Six fluorine-containing analogs of ER176—three fluoro and three trifluoromethyl isomers—were synthesized and labeled by <sup>11</sup>C-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 (BP<sub>ND</sub>), and 2) time stability of total distribution volume (V<sub>T</sub>), an indirect measure of lack of radiometabolite accumulation in the brain. <b>Results:</b> Total TSPO binding was quantified as V<sub>T</sub> corrected for plasma free fraction (V<sub>T</sub>/f<sub>P</sub>) using Logan graphical analysis for all six radioligands. V<sub>T</sub>/f<sub>P</sub> at baseline was generally high (222±178 mL∙cm-3) and decreased by 70–90% after pre-blocking with PK11195. BP<sub>ND</sub> calculated using the Lassen plot was 9.6±3.8; the o-fluoro radioligand exhibited the highest BP<sub>ND</sub> of 12.1, followed by the m-trifluoromethyl (11.7) and m-fluoro (8.1) radioligands. For all six radioligands, V<sub>T</sub> 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. <b>Conclusion:</b> All six radioligands had a good ratio of specific to nondisplaceable uptake (BP<sub>ND</sub>) as well as good time stability of total receptor binding (V<sub>T</sub>). 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.","journal":"Journal of Nuclear Medicine","year":2022,"id":268810,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":18,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9604,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":523452,"name":"Fabrice G. Siméon","orcid":"0000-0003-1337-5832","position":1,"is_corresponding":false},{"id":394486,"name":"Jeih‐San Liow","orcid":"0000-0002-7878-1076","position":2,"is_corresponding":false},{"id":394488,"name":"Cheryl L. Morse","orcid":"0000-0001-6213-3560","position":3,"is_corresponding":false},{"id":349533,"name":"Robert L. Gladding","orcid":null,"position":4,"is_corresponding":false},{"id":348142,"name":"Jose A. Montero Santamaria","orcid":"0000-0003-0069-7445","position":5,"is_corresponding":false},{"id":237391,"name":"Ioline D. Henter","orcid":"0000-0002-2379-2413","position":6,"is_corresponding":false},{"id":342708,"name":"Sami S. Zoghbi","orcid":"0000-0001-5613-8314","position":7,"is_corresponding":false},{"id":342697,"name":"Victor W. Pike","orcid":"0000-0001-9032-2553","position":8,"is_corresponding":false},{"id":237392,"name":"Robert B. Innis","orcid":"0000-0003-1238-7209","position":9,"is_corresponding":false},{"id":353941,"name":"Jae‐Hoon Lee","orcid":"0000-0002-9898-9886","position":0,"is_corresponding":true}],"reference_count":23,"raw_metadata":null,"created_at":"2026-07-19T00:27:14.088663Z","pmid":"35027372","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}