In vivo evaluation of a new 18F-labeled PET ligand, [18F]FEBU, for the imaging of I2-imidazoline receptors

IntroductionThe functions of I2-imidazoline receptors (I2Rs) are unknown, but evidence exists for their involvement in various neuropsychiatric disorders. Although a few positron emission tomography (PET) I2R ligands have been developed, of which [11C]FTIMD and [11C]BU99008 were evaluated as PET I2R imaging ligands in monkeys, no human PET imaging study using an I2R-selective PET ligand has been conducted yet. Thus, we synthesized an 18F-labeled I2R-selective ligand (BU99018 or FEBU, Ki for I2Rs = 2.6 nM), and evaluated its application using rodents in PET imaging in vivo toward the development of a clinically-useful I2R PET imaging ligand.Methods[18F]FEBU was synthesized by the reaction of its precursor and [18F]fluoroethyl bromide. A biodistribution and brain PET study were conducted in mice and rats respectively.Results[18F]FEBU was successfully synthesized yielding a radioactivity suitable for injection (10.1 ± 5.3% at the end of the irradiation (n = 10) based on 18F−). The specific activity at end of synthesis (EOS) was 40–147 TBq/mmol (n = 10). The radiochemical purity was > 99% at EOS and remained > 99% for 90 min after EOS. In mice brain uptake was relatively high. In the blocking study with the co-injection of the high-affinity I2R ligand BU224 (1 mg/kg b.w.) brain uptake was significantly decreased 30 min post-injection. In the PET studies the radioactivity was highly accumulated in the I2R-rich hypothalamus. Pretreatment with BU224 (1 mg/kg b.w.) significantly decreased the radioactivity in the hypothalamus to 23% of that of the control from 60 to 90 min post-injection.Conclusion[18F]FEBU was sufficiently stable as a PET ligand and had a relatively high specific binding affinity for I2Rs in rats and mice.