Evaluation of a novel series of fluorine-18-labeled imidazobenzodiazepines as potential new positron emission tomography radioligands for the GABAA receptor.

Introduction: [(11)C]Flumazenil has been used to study the GABAA receptor in many preclinical and clinical studies, but the short half-life of carbon-11 means that this molecule is restricted to use by investigators with access to on-site cyclotron and radiosynthesis facilities. The radiosynthesis of [(18)F]flumazenil has been evaluated by several groups, but the radiochemical yield can be low and inconsistent. We previously reported a series of fluorine-18-labeled imidazobenzodiazepine-based ligands for the GABAA receptor, which had significantly improved radiosynthesis yields. Here we report the in vivo evaluation and comparison of the distribution, metabolism and specificity of the novel ligands in comparison with [(18)F]flumazenil.

Methods: In vivo biodistribution studies, at time points up to 90min post-injection, were performed in naïve rats to compare the performance of the novel compounds with particular attention paid to regional brain uptake and clearance. In vivo metabolism studies were carried out to determine the percentage of parent compound remaining in the plasma and brain at selected time points. Blocking studies were carried out, using pre-treatment of the test animals with either bretazenil or unlabeled fluorine-19 test compound, to determine the levels of specific and non-specific binding in selected brain regions.

Results: Two of the 12 new compounds were rejected due to poor biodistribution showing significant bone uptake. Some of the compounds showed insufficient whole brain uptake or limited evidence of differential binding to GABAA-rich brain regions to warrant further investigation. Four of the compounds were selected for in vivo metabolism and blocking studies. Overall, the studies indicated that two compounds 3 and 5 showed comparable or improved performance compared with [(18)F]flumazenil, with respect to distribution, metabolic profile and specific binding.

Conclusions: These studies have demonstrated that compounds based on [(18)F]flumazenil, but with alterations to allow improved radiosynthesis, can be prepared which have ideal properties and warrant further evaluation as PET agents for the GABAA receptor. In particular, compounds 3 and 5 show very promising profiles with specific binding and in vivo stability comparable to flumazenil.