Daisaku Nakamura

Design, Synthesis, and Preliminary Evaluation of SPECT Probes for Imaging β-Amyloid in Alzheimer’s Disease Affected Brain

In this study, we synthesized of a series of 2-phenyl- and 2-pyridyl-imidazo[1,2- a]pyridine derivatives and examine their suitability as novel probes for single-photon emission computed tomography (SPECT)-based imaging of β-amyloid (Aβ). Among the 11 evaluated compounds, 10 showed moderate affinity to Aβ(1-42) aggregates, exhibiting half-maximal inhibitory concentrations (IC50) of 14.7 ± 6.07-87.6 ± 39.8 nM. In vitro autoradiography indicated that 123I-labeled triazole-substituted derivatives displayed highly selective binding to Aβ plaques in the hippocampal region of Alzheimers disease (AD)-affected brain. Moreover, biodistribution studies performed on normal rats demonstrated that all 123I-labeled probes featured high initial uptake into the brain followed by a rapid washout and were thus well suited for imaging Aβ plaques, with the highest selectivity observed for a 1 H-1,2,3-triazole-substituted 2-pyridyl-imidazopyridine derivative, [123I]ABC577. This compound showed good kinetics in rat brain as well as moderate in vivo stability in rats and is thus a promising SPECT imaging probe for AD in clinical settings.

P2-086: Synthesis and evaluation of novel amyloid binding compounds as PET/SPECT imaging agents for amyloid plaques

Background: Non-invasive -amyloid imaging technique with positron emission tomography (PET) or single photon emission computed tomography (SPECT) is believed to be effective in both the early diagnosis of Alzheimer’s disease (AD) and the monitoring of anti-amyloid therapy. Methods: The objective is to identify novel -amyloid imaging tracers for clinical use. For the purpose, we designed imidazopyridine-phenol derivatives as candidates and identified several desirable amyloid-binding compounds (ABCs). In this study, ABCs were radio-labeled and conducted biological evaluation. Results: Radio-labeling (F or I) of ABCs was respectively achieved based on each precursor and moderate level of yield was obtained. Consequently ABCs showed high binding affinity for A (142) fibrils in vitro assay and moderate blood-brain barrier penetration was observed in normal rodents. On the other hand, in vitro autoradiography studies showed that ABCs clearly demonstrated not only specific binding to amyloid plaques, but also very low nonspecific binding to white matter in postmortem AD brain sections and transgenic mouse model (Tg2576). In addition, the binding affinity of ABCs to ninety-one types of receptors and transporters (e.g., DA, 5-HT, GABA, Histamine) resulted to be lower than 1/1000 worth the maximum affinity for amyloid. These findings indicate that ABCs can provide specific PET or SPECT images with low background noise. Also safety studies such as single-dose toxicity study or genotoxicity test demonstrated safety of ABCs. Conclusions: These results suggest that ABCs will be potential compounds as novel PET or SPECT tracers for clinical use.