Abstract
Using a molecular modeling approach for Tau-binding sites, we modified our previously reported imaging agent, [(125)I]INFT, for the potential improvement of binding properties to Tau in an Alzheimer's disease (AD) brain. Two new derivatives, namely [(125)I]ISAS and [(125)I]NIPZ, were designed, where binding energies at site 1 of Tau were -7.4 and -6.0 kcal/mole, respectively, compared to [(125)I]INFT (-7.6 kcal/mole). The radiosynthesis of [(125)I]ISAS and [(125)I]NIPZ was carried out by using iodine-125 and purified chromatographically to achieve >90% purity. In vitro binding affinities (IC(50)) for Tau were as follows: INFT = 7.3 × 10(-8) M; ISAS = 4.7 × 10(-8) M; NIPZ > 10(-6) M. The binding of [(125)I]ISAS to gray matter (GM) correlated with the presence of Tau in the AD brain, confirmed by anti-Tau immunohistochemistry. [(125)I]NIPZ did not bind to Tau, with similar levels of binding observed in GM and white matter (WM). Four radiotracers were compared and the rank order of binding to Tau was found to be [(125)I]IPPI > [(125)I]INFT > [(125)I]ISAS >>> [(125)I]NIPZ with GM/WM ratios of [(125)I]IPPI = 7.74 > [(125)I]INFT = 4.86 > [(125)I]ISAS = 3.62 >> [(125)I]NIPZ = 1.24. The predictive value of Chimera-AutoDock for structurally related compounds binding to the Tau binding sites (measured as binding energy) was good. A binding energy of less than -7 kcal/mole is necessary and less than -8 kcal/mole will be more suitable for developing imaging agents.