Development of new carbon-11 labelled radiotracers for imaging GABAA- and GABAB-benzodiazepine receptors

Two quinolines identified as positive allosteric modulators of γ-aminobutyric acid (GABA)A receptors containing the α2 subunit, 9-amino-2-cyclobutyl-5-(6-methoxy-2-methylpyridin-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-b]quinolin-1-one (4) and 9-amino-2-cyclobutyl-5-(2-methoxypyridin-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-b]quinolin-1-one (5), were radiolabelled at the methoxy position with carbon-11 (half-life = 20.4 min). These quinolines represent a new class of potential radiotracers for imaging the benzodiazepine site of GABAA receptors with positron emission tomography (PET). Both radiotracers were reliably isolated following reaction of their respective pyridinone/pyridinol tautomeric precursors with [11C]CH3I in clinically useful, formulated quantities (2.9% and 2.7% uncorrected radiochemical yield, respectively, relative to [11C]CO2) with high specific activities (>70 GBq μmol−1; >2 Ci μmol–1) and high radiochemical purities (>95%). The radiosyntheses reported herein represent rare examples of selectively isolating radiolabelled compounds bearing [11C]2-methoxypyridine moieties. Although both radiotracers demonstrated promising imaging characteristics based on preliminary ex vivo biodistribution studies in conscious rodents, higher brain uptake was observed with [11C]5 and therefore this radiotracer was further evaluated. Carbon-11 labelled 5 readily penetrated the brain (>1 standard uptake value in cortical regions at 15 min post-injection of the radiotracer), had an appropriate regional brain distribution for GABAA receptors that appeared to be reversible, and did not show any appreciable radiometabolites in rat brain homogenates up to 15 min post-injection. Preadministration of flumazenil (1, 10 mg kg−1) or 5 (5 mg kg−1) effectively blocked >50% of [11C]5 binding to the GABAA receptor-rich regions, thereby suggesting that this radiotracer is worthy of further evaluation for imaging GABAA receptors. Additionally (R,S)-N-(1-(3-chloro-4-methoxyphenyl)ethyl)-3,3-diphenylpropan-1-amine, 6, an allosteric modulator of GABAB receptors, was efficiently labelled in one step using [11C]methyl iodide. Ex vivo biodistribution studies in conscious rats showed low brain uptake, therefore, efforts are underway to discover alternative radiotracers to image GABAB. In conclusion, [11C]5 is worthy of further evaluation in higher species for imaging GABAA receptors in the central nervous system.

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