Brain metabotropic subtype 1 (mGlu1) receptors have been implicated in several neuropsychiatric disorders, including pain, anxiety, mood disorders, schizophrenia, cerebellar ataxia, extrapyramidal motor dysfunction, fear, excitotoxicity, and epilepsy. Consequently, these receptors are considered to be a target for drug development. A means to image and quantify human brain mGlu1 receptors with PET would be valuable for drug development and for understanding better the role of these receptors in pathophysiology. However, unlike for human brain mGlu5 receptors, satisfactory radioligands for quantifying human brain mGlu1 receptors with PET have been lacking. Our goal was to develop such a radioligand. Candidate ligands for PET imaging of brain receptors should present a variety of features, among which are, importantly, high affinity, high selectivity, moderate lipophilicity, and amenability to labeling with a positron-emitter, which is usually carbon-11 (t1/2 = 20.4 min) or fluorine-18 (t1/2 = 109.7 min). Early efforts to develop an effective mGlu1 receptor PET radioligand have explored several candidates among a variety of structural classes, most of which have proved unpromising in animal PET studies. Exceptionally, we more recently developed [11C]LY2428703, which appeared promising in rat. However, this radioligand failed to give a receptor-specific signal in human subjects, primarily because of a significantly lower affinity and plasma free fraction in human than in rat. Subsequently, we selected 4-fluoro‑N‑methyl‑N‑(4-(6-(methylamino)pyrimidin-4-yl)thiazol-2-yl)benzamide (FIMX) for development as a potential PET radioligand, based on its reported high affinity for human mGlu1 receptors, high binding selectivity and moderate lipophilicity. The labeling of FIMX with carbon-11 or fluorine-18 was challenging but was eventually met by applying new 11C-carboxyation chemistry and the synthesis of a diaryl hypervalent precursor for radiofluorination. In monkey, [18F]FIMX was found to show excellent properties for PET imaging of brain mGlu1 receptors, including moderately high brain, and high reversible receptor-specific signal, which is noticeably most prominent in cerebellum. [18F]FIMX was therefore advanced to evaluation in human subjects where it shows similar high performance for imaging and quantifying brain mGlu1 receptors. [18F]FIMX is expected to be a valuable tool for drug development and for studies of pathophysiology.

Development of PET radioligands for imaging brain mGlu1 receptors

249th National Meeting (2015)

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