Development of new carbon-11 labelled radiotracers for imaging GABA(A)- and GABA(B)-benzodiazepine receptors

作者：Moran Matthew D; Wilson Alan A; Elmore Charles S; Parkes Jun; Ng Alvina; Sadovski Oleg; Graff Ariel; Daskalakis Zafiris J; Houle Sylvain; Chapdelaine Marc J; Vasdev Neil^*

来源：Bioorganic & Medicinal Chemistry, 2012, 20(14): 4482-4488.

DOI：10.1016/j.bmc.2012.05.046

• Radiopharmaceuticals
• Positron emission tomography
• GABA(A) receptors
• GABA(B) receptors
• Carbon-11

Two quinolines identified as positive allosteric modulators of gamma-aminobutyric acid (GABA)(A) receptors containing the alpha(2) 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 GABA(A) receptors with positron emission tomography (PET). Both radiotracers were reliably isolated following reaction of their respective pyridinone/pyridinol tautomeric precursors with [C-11]CH3I in clinically useful, formulated quantities (2.9% and 2.7% uncorrected radiochemical yield, respectively, relative to [C-11]CO2) with high specific activities (>70 GBq mu mol (1); >2 Ci mu mol(-1)) and high radiochemical purities (>95%). The radiosyntheses reported herein represent rare examples of selectively isolating radiolabelled compounds bearing [C-11]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 [C-11]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, 10mg kg (1)) or 5 (5 mg kg (1)) effectively blocked >50% of [C-11]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 [C-11]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, [C-11]5 is worthy of further evaluation in higher species for imaging GABA(A) receptors in the central nervous system. Published by Elsevier Ltd.

• 出版日期2012-7-15