Evaluation of trans - and cis -4-[ 18 F]fluorogabapentin for brain PET imaging.

Gabapentin, a selective ligand for the α2δ subunit of voltage-dependent calcium channels, is an anticonvulsant medication used in the treatment of neuropathic pain, focal epilepsy and other neurological conditions. We recently described two radiofluorinated derivatives of gabapentin ( trans- 4-[ 18 F]fluorogabapentin, [ 18 F]tGBP4F, and cis- 4-[ 18 F]fluorogabapentin, [ 18 F]cGBP4F) and showed that these compounds preferentially accumulate in the injured nerves and spinal cord in a rodent model of neuropathic pain. Given the use of gabapentin in brain diseases, we set out to test whether these radiofluorinated derivatives of gabapentin could be used for imaging α2δ receptors in the brain. Specifically, we developed fully automated radiosynthesis methods for [ 18 F]tGBP4F and [ 18 F]cGBP4F and conducted dynamic PET imaging of the brain in two adult rhesus macaques with and without pre-administration of pharmacological doses of gabapentin. These radiotracers showed high metabolic stability, negligible plasma protein binding, moderate-to-low brain penetration and very slow kinetics. Kinetic modeling of brain regional time-activity curves using a metabolite-corrected arterial input function shows that a 1-tissue compartment model accurately fits the data. Graphical analysis via Logan and multilinear analysis 1 produced similar results as compartmental modeling indicating robust quantification. Despite these favorable properties, the limited brain penetration and inability to displace the signal via pharmacological challenge suggests that tracers with higher brain penetration may be needed to accurately image α2δ expression in the brain.