Synthesis and biological evaluation of 123I-labeled pyridyl benzoxazole derivatives: novel β-amyloid imaging probes for single-photon emission computed tomography

Abstract

In vivo imaging of β-amyloid (Aβ) plaques by non-invasive techniques such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT) may facilitate early diagnosis and drug discovery for the treatment of Alzheimer's disease (AD). SPECT is known as a more useful modality than PET in terms of routine diagnostic use, but there have been no reports on attractive probes in clinical studies. In this study, we synthesized and evaluated novel ¹²³I-labeled pyridyl benzoxazole (PBOX) derivatives as SPECT probes for imaging Aβ plaques in vivo. The PBOX derivatives showed affinity for Aβ(1–42) aggregates in vitro (K_i = 6.9–138 nM). In biodistibution experiments in normal mice, all these derivatives showed high initial uptake into (4.6–6.6% ID g⁻¹ at 2 min) and rapid clearance (0.3–1.3% ID g⁻¹ at 60 min) from the brain. Furthermore, [¹²⁵I]9 clearly labeled Aβ plaques in in vitro autoradiography of postmortem AD brain sections. SPECT/CT study with [¹²³I]9 displayed higher radioactivity in Tg2576 mice than wild-type mice. In addition, ex vivo autoradiograms of brain sections from Tg2576 mice after the injection of [¹²³I]9 showed selective binding of Aβ plaques. In conclusion, [¹²³I]9 may be a potential SPECT probe for imaging Aβ plaques in AD brain.