Radiosynthesis and in-vivo evaluation of [¹¹C]VU0361737, a positive allosteric modulator, for metabotropic glutamate receptor subtype 4 (mGluR4)

Objectives The recent brain research has shown that mGluR are involved in several neurological disorders including Parkinson’s disease and drug addiction. We have shown earlier that deficit in dopamine transporter function is accompanied with enhanced expression of mGluR5. However, glutamate as well as dopamine is released from the presynaptic site of the neuron, making presynaptically located mGluR4 more important contributor for glutamate neurotransmission. To investigate it, we synthesized N-(3-methoxy-4-chlorophenyl)-2-picolinamide (VU0361737, EC₅₀ = 110 nM) and its nor-precursor as a lead compound to image neuronal mGluR4 with PET.

Methods Nonradioactive VU0361737 and nor-precursor were synthesized by amide bond reaction. [¹¹C]VU0361737 was labeled with [¹¹C]CH₃I mediated by 5 M KOH. The radioactive product was injected to five female rats. Two rats were used for baseline study, and the other two were treated with 5 mg/kg of nonradioactive VU0361737 one minute before [¹¹C]VU0361737 injection for blocking study. The last one was treated with 10 mg/kg of MTEP, an mGluR5 inhibitor for selectivity study. Dynamic PET images of rat brain were obtained from 0 to 90 minutes.

Results [¹¹C]VU0361737 was obtained with 27% decay corrected RCY from [¹¹C]CO₂. Its specific activity was 2.72 Ci/μmol at EOS, and radiochemical purity was over 98%. Total synthesis time was 41 minutes. Major uptake was observed in hippocampus, thalamus, and striatum. Time-activity curves of these brain regions revealed fast uptake and washout within 20 minutes after injection. The average uptake between 0 to 20 minutes from baseline and blocking studies displayed 15-31% blocking effect in major ROIs. Co-injection with MTEP also reduced uptake in C-11 by 5-33%.

Conclusions [¹¹C]VU0361737 demonstrated a potential as PET radiotracer for mGluR4 with modest specificity and selectivity. Further characterization of this compound and its related derivatives is in process.

Research Support NIBIB-R01EB012864 and NIMH-R01MH91684 to AL