In vitro and in vivo evaluation of [¹¹C]MPEPy as a potential PET ligand for mGlu₅ receptors

Excessive activation via the metabotropic glutamate receptor subtype 5 (mGluR₅) has been implicated in depression, neuropathic pain and other psychiatric, neurological and neurodegenerative diseases. A mGluR₅ radioligand for in vivo quantification by positron emission tomography (PET) would facilitate studies of the role of this receptor in disease and treatment. 3-Methoxy-5-pyridin-2-ylethynylpyridine (MPEPy), a selective and high-affinity antagonist at the mGluR₅ receptor was selected as a candidate ligand; a recent publication by Yu et al. [Nucl Med Biol 32 (2005) 631-640] presented initial micro-PET results for [¹¹C]MPEPy with enthusiasm. Building on their efforts, we report as unique contributions (1) an improved chemical synthesis method, (2) the first data using human tissue, (3) phosphor images for rat brain preparations, (4) a novel comparison of anesthetic agents and (5) in vivo data in baboon. In vitro phosphor imaging studies of this ligand using human and rat brain tissue demonstrated high specific binding in the hippocampus, striatum and cortex with minimal specific binding in the cerebellum. In contrast, in vivo micro-PET studies in rats using urethane anesthesia, PET studies in baboons using isoflurane anesthesia and ex vivo micro-PET studies in unanesthetized rats each showed little specific binding in the brain. Despite the promising in vitro results, the low signal-to-noise ratio found in vivo does not justify the use of [¹¹C]MPEPy as a PET radiotracer in humans.