Synthesis and evaluation of PET probes for the imaging of I2 imidazoline receptors in peripheral tissues

IntroductionTo explore the possible use of positron emission tomography (PET) probes for imaging of I₂-imidazoline receptors (I₂Rs) in peripheral tissues, we labeled two new I₂R ligands, 2-2-(o-tolyl)vinyl]-4,5-dihydro-1H-imidazole (K_i for I₂Rs, 3.7 nM) and 2-2-(o-tolyl)ethyl]-4,5-dihydro-1H-imidazole (K_i for I₂Rs, 1.7 nM) with ¹¹C (¹¹C]metrazoline and ¹¹C]TEIMD), respectively, and evaluated these ligands and the recently developed I₂R ligand 2-3-fluoro-4-¹¹C]tolyl]-4,5-dihydro-1H-imidazole (¹¹C]FTIMD) by in vivo studies.Methods¹¹C]Metrazoline and ¹¹C]TEIMD were prepared by a palladium-promoted cross-coupling reaction of the tributylstannyl precursor and ¹¹C]methyl iodide. Their biodistribution in mice was investigated by tissue dissection. In addition, PET scans and metabolite analysis were performed.Results¹¹C]Metrazoline and ¹¹C]TEIMD were successfully synthesized with a suitable radioactivity for injection. In the liver and pancreas expressing I₂Rs, coinjection with the high-affinity I₂R ligand, BU224, induced a reduction in the radioactivity level at 30 min after injection of ¹¹C]metrazoline and ¹¹C]FTIMD. However, the radioactivity level after injection of ¹¹C]TEIMD was unchanged. In the PET study, coinjection with BU224 induced a decrease in the radioactivity level in the liver and pancreas after more than 15 min of injection of ¹¹C]metrazoline and ¹¹C]FTIMD as compared with the results obtained for controls. In metabolite analysis, coinjection with BU224 induced a significant reduction in the percentage of unchanged ¹¹C]metrazoline at 30 min after injection as compared with that in the control, although no significant difference was observed in the percentage of unchanged ¹¹C]FTIMD.Conclusion¹¹C]Metrazoline may be a more useful PET probe than ¹¹C]FTIMD for imaging of I₂Rs in peripheral tissues.