Radiosynthesis and preclinical evaluation of [C]Methyl-V-0219, a small molecule glucagon-like peptide-1 allosteric modulator for PET brain imaging

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Background Glucagon-like peptide-1 receptor (GLP-1R) is a clinically validatedtherapeutic target for the treatment of obesity and type 2 diabetes. GLP-1Rs expressedin the central nervous system (CNS) regulate appetite and are therefore particularlyimportant in the context of weight loss. There is thus an emerging need for efficientand brain-penetrating Positron Emission Tomography (PET) technologies to studythe 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–brain barrier (BBB) penetration, restricting their use forimaging central GLP-1R expression. V-0219, a small molecule GLP-1R positive allostericmodulator, represents a potential scaffold for the development of BBB-penetrating PETtracers targeting incretin receptor systems in the brain. Results Here, we report the radiosynthesis and preclinical evaluation of [11C]Methyl-V-0219, a carbon-11 labelled analogue of V-0219. [11C]Methyl-V-0219 wassynthesized using a Pd(0)-mediated Suzuki–Miyaura coupling reaction and obtainedwith a radiochemical yield of 36 ± 18% (n = 16) and radiochemical purity of 98.6 ± 1.6%(n = 16). In vitro autoradiography demonstrated retained binding to GLP-1R–positivetissues, although binding to glucose-dependent insulinotropic polypeptide (GIP) andglucagon (GCG) receptors was also observed. In vivo PET imaging was performed in rats and pigs and compared with thewell-established GLP-1R tracer [68Ga]Ga-DO3A-Exendin-4. Dynamic PET imagingdemonstrated rapid brain uptake of [11C]Methyl-V-0219 followed by progressivewashout, indicating BBB penetration but limited retention in the brain. In contrastto [68Ga]Ga-DO3A-Exendin-4, [11C]Methyl-V-0219 did not demonstrate detectableretention in GLP-1R–rich 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 brainkinetics, suggesting no detectable displaceable binding in vivo. Conclusion Taken together, these findings demonstrate the feasibility of developingsmall–molecule–based PET tracers targeting incretin receptor systems, whilehighlighting the challenges associated with achieving sufficient in vivo specificity forbrain GLP-1R imaging.

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