Development of radiotracers for PET imaging of GABA-B receptors

An imbalance in excitatory/inhibitory transmission, due to alterations in GABAergic signaling, has been suggested as an underlying cause of autism. These studies argue that the GABAergic system represents a viable therapeutic target for autism. Indeed, the GABA-B receptor agonist R-baclofen has been shown to ameliorate social deficits and repetitive behaviors in two mouse models of autism¹. However, baclofen is known to exhibit relatively poor blood-brain-barrier permeability, arguing for the development of drug treatments more accessible to the central nervous system. Yet such drug discovery efforts are complicated by a lack of suitable radiotracers for imaging GABA-B receptors.

Dean Wong and Andrew Horti propose to develop radiotracers for in vivo imaging of cerebral GABA-B receptors. A highly potent GABA-B ligand has been described in the literature but its binding affinity has not been determined².  Wong and Horti will synthesize this compound and fluoro derivatives, and assess whether their inhibition binding affinities are adequate to serve as potential positron emission tomography (PET) radiotracers. The compound with the best binding affinity will be radiolabeled and evaluated in non-human primate PET studies.