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Radiosynthesis and Preclinical Evaluation of ¹¹C-ABP688 as a Probe for Imaging the Metabotropic Glutamate Receptor Subtype 5

¹ Center for Radiopharmaceutical Science of ETH, PSI and USZ and Department of Chemistry and Applied Biosciences of ETH, Zurich, Switzerland; ² PET Center, Division of Nuclear Medicine, University of Zurich, Zurich, Switzerland; and ³ Novartis Institutes for Biomedical Research Basel, Novartis Pharma AG, Basel, Switzerland

Correspondence: For correspondence or reprints contact: Simon M. Ametamey, PhD, Center for Radiopharmaceutical Science of ETH, PSI and USZ, ETH-Hönggerberg, D-CHAB IPW HCI H427, Wolfgang-Pauli-Strasse 10, CH-8093 Zurich, Switzerland. E-mail: simon.ametamey{at}pharma.ethz.ch

¹¹C-ABP688 (3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone-O-¹¹C-methyl-oxime), a noncompetitive and highly selective antagonist for the metabotropic glutamate receptor subtype 5 (mGluR5), was evaluated for its potential as a PET agent. Methods: ABP688 was radiolabeled with ¹¹C by reacting ¹¹C-methyl iodide with the sodium salt of desmethyl-ABP688 (3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone oxime). The affinity of ¹¹C-ABP688 for mGluR5 was determined by Scatchard analysis using rat whole-brain membranes (without cerebellum). Ex vivo autoradiography, biodistribution, and PET studies with ¹¹C-ABP688 were performed on rats, wild-type mice, and mGluR5-knock-out mice. Results: The overall synthesis time was 45–50 min from the end of radionuclide production. ¹¹C-ABP688 was obtained in good radiochemical yield (35% ± 8%, n = 17, decay corrected), and the specific radioactivity was 150 ± 50 GBq/µmol (n = 17) at the end of the synthesis. Scatchard analysis revealed a single high-affinity binding site with a dissociation constant of 1.7 ± 0.2 nmol/L and a maximum number of binding sites of 231 ± 18 fmol/mg of protein. Ex vivo autoradiography in wild-type mice and rats showed a heterogeneous distribution pattern consistent with the known distribution of mGluR5 in the brain, with the highest uptake in hippocampus, striatum, and cortex. Blocking studies by coinjection of ¹¹C-ABP688 and unlabeled 2-methyl-6-(3-methoxyphenyl)ethynyl-pyridine (1 mg/kg), an antagonist for mGluR5, revealed up to 80% specific binding in rat brain. In mGluR5-knock-out mouse brain, a homogeneous and markedly reduced accumulation of ¹¹C-ABP688 was observed. PET studies on rats and mice using a small-animal PET scanner also demonstrated radioactivity uptake in the brain regions known to be rich in mGluR5. In contrast, radioactivity uptake in mGluR5-knock-out mice was fairly uniform, substantiating the specificity of ¹¹C-ABP688 binding to mGluR5. Conclusion: ¹¹C-ABP688 is a selective tracer for imaging mGluR5 in vivo in rodents and may offer a future tool for imaging mGluR5 in humans using PET.

Key Words: metabotropic glutamate receptor subtype 5 • ¹¹C-ABP688 • mGluR5-knock-out mice • biodistribution

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