Radiosynthesis and evaluation of an 18F-labeled radioligand for imaging metabotropic glutamate receptor 3 with positron emission tomography

The metabotropic glutamate receptor 3 (mGluR3) is a G-protein-coupled receptor (GPCR) involved in modulating glutamatergic neurotransmission and maintaining neural homeostasis. By inhibiting adenylyl cyclase activity, mGluR3 negatively modulates the activity of adenylyl cyclase via Gi/o protein coupling, reducing cyclic AMP (cAMP) levels and modulating downstream signaling pathways. Dysfunction of mGluR3 is associated with a range of neurological and psychiatric disorders, including depression, autism, cognitive impairment, bipolar affective disorder, schizophrenia, and neurodegenerative diseases. Despite its therapeutic relevance, no selective mGluR3 positron emission tomography (PET) radioligand is currently available to image this target <i>in vivo</i>. In this study, we report the radiosynthesis and preclinical evaluation of [¹⁸F]VU6010572 - a novel PET tracer based on a therapeutical drug candidate. VU6010572 exhibits potent binding affinity (IC₅₀ = 39.9 nM) and exceptional selectivity (>100-fold over other mGluR subtypes). Radiolabeling with fluorine-18 yielded [¹⁸F]VU6010572 with high radiochemical yield (48%, decay-corrected) and molar activity (59 GBq/µmol). While <i>in vitro</i> autoradiography demonstrated heterogeneous brain distribution, dynamic PET imaging in rodents revealed reasonable brain uptake <i>in vivo</i> yet modest binding specificity and rapid brain washout. While these findings support the potential of [¹⁸F]VU6010572 as a lead structure, further medicinal chemistry optimization is warranted to enhance the metabolic and pharmacokinetic properties.