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GLP-1Rs expressed in the central nervous system (CNS) regulate appetite and are therefore particularly important in the context of weight loss. There is thus an emerging need for efficient and brain-penetrating Positron Emission Tomography (PET) technologies to study the distribution of GLP-1R in the CNS and facilitate the development of novel GLP-1R-targeted therapeutics. However, currently established GLP-1R PET tracers are peptide-based and exhibit limited blood\u2013brain barrier (BBB) penetration, restricting their use for imaging central GLP-1R expression. V-0219, a small molecule GLP-1R positive allosteric modulator, represents a potential scaffold for the development of BBB-penetrating PET tracers targeting incretin receptor systems in the brain.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Here, we report the radiosynthesis and preclinical evaluation of [\n                      <jats:sup>11<\/jats:sup>\n                      C]Methyl-V-0219, a carbon-11 labelled analogue of V-0219. [\n                      <jats:sup>11<\/jats:sup>\n                      C]Methyl-V-0219 was synthesized using a Pd(0)-mediated Suzuki\u2013Miyaura coupling reaction and obtained with a radiochemical yield of 36\u2009\u00b1\u200918% (n\u2009=\u200916) and radiochemical purity of 98.6\u2009\u00b1\u20091.6% (n\u2009=\u200916). In vitro autoradiography demonstrated retained binding to GLP-1R\u2013positive tissues, although binding to glucose-dependent insulinotropic polypeptide (GIP) and glucagon (GCG) receptors was also observed.\n                    <\/jats:p>\n                    <jats:p>\n                      In vivo PET imaging was performed in rats and pigs and compared with the well-established GLP-1R tracer [\n                      <jats:sup>68<\/jats:sup>\n                      Ga]Ga-DO3A-Exendin-4. Dynamic PET imaging demonstrated rapid brain uptake of [\n                      <jats:sup>11<\/jats:sup>\n                      C]Methyl-V-0219 followed by progressive washout, indicating BBB penetration but limited retention in the brain. In contrast to [\n                      <jats:sup>68<\/jats:sup>\n                      Ga]Ga-DO3A-Exendin-4, [\n                      <jats:sup>11<\/jats:sup>\n                      C]Methyl-V-0219 did not demonstrate detectable retention in GLP-1R\u2013rich tissues, including the pituitary gland and pancreas. Instead, prominent uptake was observed in the liver, intestines, and glandular tissues, consistent with hepatobiliary clearance and nonspecific accumulation of a lipophilic compound. Furthermore, blocking and competition studies did not alter tracer brain kinetics, suggesting no detectable displaceable binding in vivo.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Taken together, these findings demonstrate the feasibility of developing small\u2013molecule\u2013based PET tracers targeting incretin receptor systems, while highlighting the challenges associated with achieving sufficient in vivo specificity for brain GLP-1R imaging.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s41181-026-00486-4","type":"journal-article","created":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T14:14:02Z","timestamp":1786716842000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Radiosynthesis and preclinical evaluation of [11C]Methyl-V-0219, a small molecule glucagon-like peptide-1 allosteric modulator for PET brain imaging"],"prefix":"10.1186","volume":"11","author":[{"given":"Francesco","family":"Lechi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-8567-2277","authenticated-orcid":false,"given":"Amina","family":"Khalil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo Novales","family":"Bautista","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jakob","family":"\u00d6berg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenzo Jacopo Ilic","family":"Balestri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olof","family":"Eriksson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonas","family":"Eriksson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luke R.","family":"Odell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,14]]},"reference":[{"key":"486_CR1","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1007\/s00259-012-2298-2","volume":"40","author":"A Afshar-Oromieh","year":"2013","unstructured":"Afshar-Oromieh A, Malcher A, Eder M, et al. 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