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

Abstract Two quinolines identified as positive allosteric modulators of γ-aminobutyric acid (GABA) A receptors containing the α 2 subunit, 9-amino-2-cyclobutyl-5-(6-methoxy-2-methylpyridin-3-yl)-2,3-dihydro-1 H -pyrrolo[3,4- b ]quinolin-1-one ( 4 ) and 9-amino-2-cyclobutyl-5-(2-methoxypyridin-3-yl)-2,3-dihydro-1 H -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 GABA A receptors with positron emission tomography (PET). Both radiotracers were reliably isolated following reaction of their respective pyridinone/pyridinol tautomeric precursors with [ 11 C]CH 3 I in clinically useful, formulated quantities (2.9% and 2.7% uncorrected radiochemical yield, respectively, relative to [ 11 C]CO 2 ) 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 [ 11 C]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 [ 11 C] 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 GABA A 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 [ 11 C] 5 binding to the GABA A receptor-rich regions, thereby suggesting that this radiotracer is worthy of further evaluation for imaging GABA A receptors. Additionally ( R , S )- N -(1-(3-chloro-4-methoxyphenyl)ethyl)-3,3-diphenylpropan-1-amine, 6 , an allosteric modulator of GABA B receptors, was efficiently labelled in one step using [ 11 C]methyl iodide. Ex vivo biodistribution studies in conscious rats showed low brain uptake, therefore, efforts are underway to discover alternative radiotracers to image GABA B . In conclusion, [ 11 C] 5 is worthy of further evaluation in higher species for imaging GABA A receptors in the central nervous system.