Imaging of I2-imidazoline receptors by small-animal PET using 2-(3-fluoro-[4-11C]tolyl)-4,5-dihydro-1H-imidazole ([11C]FTIMD)

IntroductionImidazoline receptors (IRs) have been established as distinct receptors, and have been categorized into at least two subtypes (I1R and I2R). I2Rs are associated with depression, Alzheimer's disease, Huntington's disease and Parkinson's disease. A few positron emission tomography (PET) probes for I2Rs have been synthesized, but a selective PET probe has not been evaluated for the imaging of I2Rs by PET. We labeled a selective I2R ligand 2-(3-fluoro-4-tolyl)-4,5-dihydro-1H-imidazole (FTIMD) with 11C and performed the first imaging of I2Rs by PET using 2-(3-fluoro-[4-11C]tolyl)-4,5-dihydro-1H-imidazole ([11C]FTIMD).Methods[11C]FTIMD was prepared by a palladium-promoted cross-coupling reaction of the tributylstannyl precursor and [11C]methyl iodide in the presence of tris(dibenzylideneacetone)dipalladium(0) and tri(o-tol)phosphine. Biodistribution was investigated in rats by tissue dissection. [11C]FTIMD metabolites were measured in brain tissues and plasma. Dynamic PET scans were acquired in rats, and the kinetic parameters estimated.Results[11C]FTIMD was successfully synthesized with a suitable radioactivity for the injection. Co-injection with 0.1 mg/kg of cold FTIMD and BU224 induced a significant reduction in the brain-to-blood ratio 15 and 30 min after the injection. In metabolite analysis, unchanged [11C]FTIMD in the brain was high (98%) 30 min after the injection. In PET studies, high radioactivity levels were observed in regions with a high density of I2R. The radioactivity levels and VT values in the brain regions were prominently reduced by 1.0 mg/kg of BU224 pretreatment as compared with control.Conclusion[11C]FTIMD showed specific binding to I2Rs in rat brains with a high density of I2R.