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However, the absence of a suitable positron emission tomography (PET) radioligand has precluded non-invasive quantification of TAAR1 expression and drug-receptor interactions in vivo. In this study, we report the preclinical development of [\n                      <jats:sup>18<\/jats:sup>\n                      F]TAAR1-2203, a fluorine-18 labeled PET ligand suitable to image TAAR1 expression in peripheral tissues.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      [\n                      <jats:sup>18<\/jats:sup>\n                      F]TAAR1-2203 ([\n                      <jats:sup>18<\/jats:sup>\n                      F]RO5263397) was obtained via copper-mediated radiofluorination. In vitro stability was assessed in formulation, serum and using liver microsomes. Specific binding was evaluated by in vitro autoradiography, ex vivo biodistribution, and PET imaging under baseline and blockade conditions with structurally distinct TAAR1 agonists, as well as in TAAR1 knockout (KO) mice. Receptor occupancy studies were conducted in the pancreas \u2013 a peripheral organ with high physiological TAAR1 expression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      TAAR1-2203 exhibited high TAAR1 affinity in competition binding assays across species, with K\n                      <jats:sub>i<\/jats:sub>\n                      values of 0.9 nM (mouse) and 5.7 nM (human). Tracer stability was corroborated by cross-species microsomal incubations and ex vivo radiometabolite analyses in mice. In peripheral tissues with known TAAR1 expression, [\n                      <jats:sup>18<\/jats:sup>\n                      F]TAAR1-2203 displayed robust signal intensity that was significantly reduced under pharmacological blockade or in TAAR1 KO mice, thus confirming specific receptor binding. Although [\n                      <jats:sup>18<\/jats:sup>\n                      F]TAAR1-2203 appeared to cross the blood-brain barrier based on brain time-activity curves and ex vivo radiometabolite analysis, no specific binding was observed in the CNS. Target occupancy studies in the pancreas demonstrated dose-dependent blockade, with a calculated D\n                      <jats:sub>50<\/jats:sub>\n                      of 0.67 \u00b5mol\/kg for a structurally distinct potent TAAR1 agonist.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      [\n                      <jats:sup>18<\/jats:sup>\n                      F]TAAR1-2203 represents the first PET radioligand for TAAR1 imaging with favorable in vitro and in vivo performance characteristics, enabling non-invasive assessment of receptor expression and drug occupancy in peripheral TAAR1-expressing tissues. [\n                      <jats:sup>18<\/jats:sup>\n                      F]TAAR1-2203 holds promise for translational application in various drug development programs.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00259-025-07564-w","type":"journal-article","created":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T07:35:08Z","timestamp":1762414508000},"page":"2540-2553","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Preclinical development of [18F]TAAR1-2203 as a PET radioligand for imaging TAAR1 expression and receptor occupancy"],"prefix":"10.1007","volume":"53","author":[{"given":"Achi","family":"Haider","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiwei","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiahui","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie K.","family":"Pfister","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinlong","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmad","family":"Chaudhary","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunyu","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Rong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Axel","family":"Paehler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne","family":"Mohr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger D.","family":"Norcross","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Honer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linjing","family":"Mu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Gobbi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger","family":"Schibli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marius C.","family":"Hoener","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven H.","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,6]]},"reference":[{"key":"7564_CR1","doi-asserted-by":"publisher","first-page":"866","DOI":"10.1007\/s11481-011-9321-4","volume":"7","author":"MW Panas","year":"2012","unstructured":"Panas MW, Xie Z, Panas HN, Hoener MC, Vallender EJ, Miller GM. 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