11C-BF-227

Molecular imaging is a visualization of quantity and dynamics of molecules to understand the process of gene regulation and physiological function of the proteins in living tissue or cells. Examples of the research include the development and application of fluorescent proteins, quantum dots, nanoparticles for optical imaging, micro bubbles for ultrasound, ferromagnetic compounds for MRI and radiopharmaceuticals for positron emission tomography (PET). PET is most promising in this field, because of its high sensitivity of the measurement and easy applicability to humans. In this general remark, the topics will be concentrated on molecular imaging with PET for the diagnosis of Alzheimer's disease (AD) in early stage. 11C-MP4P (N-methlpiperidyl-4-propionate), is a probe for the measurement of acetylcholine esterase (AchE) activity in the human brain by PET. The AchE activities (k3) in early onset AD measured with PET was low in hippocampus, amygdale and wide spread neocortex including parietal and temporal cortex compared to those in age-matched control. The results indicated that the decrease of AchE activities is preceded by the decrease of blood flow. One of the topics in this research field is an imaging of aggregated amyloid Abeta in the AD brain. Kudo et al, screened more than 2,600 compounds and found several good probes for amyloid Abeta imaging, including BF-168 and BF-227. Okamura demonstrated that BF-168 specifically bind to the amyloid plaques in the brain of a transgenic mouse (PS1/APPsw). Furumoto et al successfully labeled BF-227 with C-11, and clinical PET studies using 11C-BF-227 is now ongoing at Tohoku University. Preliminary clinical study revealed that the compound accumulated in the tempo-parietal region of the brain in AD patient, although non-specific accumulation in the thalamus, basal ganglia and white matter was observed. The goal of this project is to detect AD at pre-clinical stage.

Progressive accumulation of senile plaques (SPs) is one of the major neuropathological features of Alzheimer's Disease (AD) that precedes cognitive decline. Noninvasive detection of SPs could, therefore, be a potential diagnostic test for early or presymptomatic detection of AD patients. For this purpose, many attempts have been made to visualize AD-specific pathological changes in the living brain. Currently, a most practical method for the in vivo measurement of SP depositions is using positron emission tomography (PET) and contrast agent that specifically label SPs. We have developed a novel compound 2-[2-(2-dimethylaminothiazol-5-yl) ethenyl]-6-[2-(fluoro)ethoxy] benzoxazole (BF-227) as a candidate for an amyloid imaging probe for PET. BF-227 displayed high affinity to synthetic amyloid beta fibrils and clearly stained both SPs and diffuse plaques in AD brain sections. Intravenous administration of [11C]BF-227 into normal mice indicated that this labeled tracer readily penetrated the blood brain barrier (BBB) and was washed out quickly from brain tissue. Currently, we have investigated the clinical trial of [11C]BF-227 in healthy subjects and AD patients.