Synthesis and Evaluation of Two 18F-Labeled 6-Iodo-2-(4′-N,N-dimethylamino)phenylimidazo[1,2-a]pyridine Derivatives as Prospective Radioligands for β-Amyloid in Alzheimer’s Disease

This study evaluated 18 F-labeled IMPY [6-iodo-2-(4'-N,N-dimethylamino)phenylimidazo[1,2-α]pyridine] derivatives as agents for imaging β-amyloid plaque with positron emission tomography (PET). The precursor for radiolabeling and reference compounds was synthesized in up to five steps from commercially accessible starting materials. One of the two N-methyl groups of IMPY was substituted with either a 3-fluoropropyl (FPM-IMPY) or a 2-fluoroethyl (FEM-IMPY) group. FPM-IMPY and FEM-IMPY were found to have moderate affinity for Aβ-aggregates with K i = 27 ± 8 and 40 ± 5 nM, respectively. A one-pot method for 18 F-2-fluoroethylation and 18F-3-fluoropropylation of the precursor was developed. The overall decay-corrected radiochemical yields were 26-51%. In PET experiments with normal mouse, high uptake of activity was obtained in the brain after iv injection of each probe: 6.4% ID/g for [ 18 F]FEM-IMPY at 1.2 min, and 5.7% ID/g for [ 18 F]FPM-IMPY at 0.8 min. These values were similar to those of [ 123 I/ 125 I]IMPY (7.2% ID/g at 2 min). Polar and nonpolar radioactive metabolites were observed in both plasma and brain homogenates after injection of [ 18 F]FEM or [ 18 F]FPM-IMPY. In contrast to the single-exponential washout of [ 123 I/ 125 I]IMPY, the washouts of brain activity for the two fluorinated analogues were biphasic, with an initial rapid phase over 20 min and a subsequent much slower phase. Residual brain activity at 2 h, which may represent polar metabolites trapped in the brain, was 4.5% ID/g for [ 18 F]FEM-IMPY and 2.1% ID/g for [ 18 F]FPM-IMPY. Substantial skull uptake of [ 18 F]fluoride was also clearly observed. With a view to slow the metabolism of [ 18 F]FEM-IMPY, an analogue was prepared with deuteriums substituted for the four ethyl hydrogens. However, D 4 -[ 18 F]FEM-IMPY showed the same brain uptake and clearance as the protio analogue. Metabolism of the [ 18 F]FEM-IMPY was appreciably slower in rhesus monkey than in mouse. Autoradiography of postmortem brain sections of human Alzheimer's disease patients with [ 18 F]FEM-IMPY showed high displaceable uptake in gray matter and low nonspecific binding in the white matter. This study demonstrates that the IMPY derivatives have favorable in vivo brain pharmacokinetics and a moderate affinity for imaging β-amyloid plaques; however, further improvements are needed to reduce radioactive metabolites, increase binding affinity, and reduce lipophilicity.