Development of SPECT Probes for In Vivo Imaging of β-Amyloid and Tau Aggregates in the Alzheimer's Disease Brain

Alzheimer's disease (AD) is the most common form of irreversible dementia among elderly people. In the postmortem brains of AD patients, the deposition of senile plaques composed of beta-amyloid (A beta) peptides and neurofibrillary tangles composed of highly phosphorylated tau proteins are two neuropathological hallmarks. Therefore, the in vivo imaging of A beta and tau aggregates with positron-emission tomography (PET) or single-photon emission computed tomography (SPECT) would promote drug development, early diagnosis, and monitoring of the disease status in AD patients. In this study, we designed and synthesized novel A beta and tau imaging probes for SPECT. [I-125] PBOX-3, developed as an A beta imaging probe, showed high affinity for A beta aggregates in vitro. A SPECT/CT study with [I-123] PBOX-3 revealed a higher level of radioactivity in a Tg2576 mouse, which is the AD model mouse, than in a wild-type mouse. In addition, ex vivo autoradiograms of brain sections from a Tg2576 mouse after the injection of [I-123] PBOX-3 showed the selective binding of A beta plaques. BIP-NMe2, developed as a tau imaging probe, showed high and selective affinity for tau aggregates in AD brain sections. In addition, [I-125] BIP-NMe2 displayed high initial uptake into, and fast washout from, the normal mouse brain, suggesting that [I-125] BIP-NMe2 has favorable pharmacokinetics for the in vivo imaging of tau aggregates. Taken together, we successfully developed an A beta imaging probe, PBOX-3, and a tau imaging probe, BIPNMe2. These probes may be used to develop novel methods for the diagnosis, treatment and monitoring of AD progression.