[¹¹C]RO6899880, a novel agonist PET radioligand for the GABA_A receptor

Objectives A PET radioligand with high sensitivity to GABA levels may facilitate understanding of neuropsychiatric disorders. Available radioligands for the GABA_A receptor are antagonists or inverse agonists. On the contrary, binding of agonists is more vulnerable to GABA levels in vitro. Here we prepared a novel GABA_A receptor agonist PET radioligand, [¹¹C]RO6899880, and compared its binding with [¹¹C]Suriclone (Frost et al, 1986) in the non-human primate brain.

Methods [¹¹C]RO6899880 and [¹¹C]Suriclone were both prepared from their corresponding desmethyl precursor. Baseline PET measurements were conducted to compare whole brain uptake and receptor binding kinetics. On a second experimental day a flumazenil (1.0 mg/kg) displacement study was performed, with i.v. administration 20-25 min after injection of [¹¹C]RO6899880. The specific binding in the occipital cortex was defined by using the pons as reference region and the binding potential (BP_ND) was estimated using SRTM. Venous blood samples were obtained to assess radioligand metabolism in plasma using radio-HPLC.

Results [¹¹C]RO6899880 and [¹¹C]Suriclone were produced with high incorporation yield (30-85%), radiochemical purity (>99%) and specific radioactivity (>5000 Ci/mmol). Both radioligands displayed adequate brain uptake, with a regional distribution consistent with binding to GABA_A receptors. The peak in specific binding for [¹¹C]RO6899880 was achieved after 30-40 min, while [¹¹C]Suriclone binding did not reach equilibrium during the PET measurement. The BP_ND was 1.6 for [¹¹C]RO6899880. Administration of flumazenil reduced [¹¹C]RO6899880 binding in all brain regions to the approximate level as in pons.

Conclusions [¹¹C]RO6899880 is a highly promising PET radioligand for evaluation of agonist GABA_A receptor binding in the living primate brain. Evaluation of the sensitivity of [¹¹C]RO6899880 binding to endogenous GABA levels is currently planned.

Research Support The research leading to these results has received support from the Innovative Medicine Initiative Joint Undertaking under grant agreement n115008 of which resources are composed of EFPIA in-kind contribution and financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013).