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

Abstract Introduction To explore the possible use of positron emission tomography (PET) probes for imaging of I2 -imidazoline receptors (I2 Rs) in peripheral tissues, we labeled two new I2 R ligands, 2-[2-( o -tolyl)vinyl]-4,5-dihydro-1 H -imidazole ( Ki for I2 Rs, 3.7 nM) and 2-[2-( o -tolyl)ethyl]-4,5-dihydro-1 H -imidazole ( Ki for I2 Rs, 1.7 nM) with11 C ([11 C]metrazoline and [11 C]TEIMD), respectively, and evaluated these ligands and the recently developed I2 R ligand 2-[3-fluoro-[4-11 C]tolyl]-4,5-dihydro-1 H -imidazole ([11 C]FTIMD) by in vivo studies. Methods [11 C]Metrazoline and [11 C]TEIMD were prepared by a palladium-promoted cross-coupling reaction of the tributylstannyl precursor and [11 C]methyl iodide. Their biodistribution in mice was investigated by tissue dissection. In addition, PET scans and metabolite analysis were performed. Results [11 C]Metrazoline and [11 C]TEIMD were successfully synthesized with a suitable radioactivity for injection. In the liver and pancreas expressing I2 Rs, coinjection with the high-affinity I2 R ligand, BU224, induced a reduction in the radioactivity level at 30 min after injection of [11 C]metrazoline and [11 C]FTIMD. However, the radioactivity level after injection of [11 C]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 [11 C]metrazoline and [11 C]FTIMD as compared with the results obtained for controls. In metabolite analysis, coinjection with BU224 induced a significant reduction in the percentage of unchanged [11 C]metrazoline at 30 min after injection as compared with that in the control, although no significant difference was observed in the percentage of unchanged [11 C]FTIMD. Conclusion [11 C]Metrazoline may be a more useful PET probe than [11 C]FTIMD for imaging of I2 Rs in peripheral tissues.