报告题目：Development of second generation of molecular imaging probes for Amyloid beta
报 告 人：Chongzhao Ran（冉崇昭）博士（麻省总院/哈佛大学医学院）
Amyloid beta (Ab) deposits and Tau tangles are the two characteristic biomarkers for Alzheimer’s disease (AD). In the progression of AD, various Ab subtypes, including soluble and insoluble Abs, co-exist, but soluble Abs are the dominant species at the pre-symptomatic stage. Studies show that soluble Aβs such as oligomers are more neurotoxic than insoluble deposits (fibrils and plaques) and can serve as biomarkers for the pre-symptomatic stages of AD. Notably, recent evidence indicates that Aβ species are the key initiator for AD pathology; therefore, for early/pre-symptomatic imaging, Aβs are the very ideal targets. Additionally, it is well-established that abnormal levels of Abs in the brain appear 30 years before symptom starts in humans. However, the current probes (the first generation (1stG)) can only detect the abnormal Ab deposits around 5 years before the clinical syndrome, leaving a 25-year gap between the early pathogenesis and the imaging detection. In the past years, my research group has been focusing on developing 2ndG (second generation) imaging probes, which are defined as probes that are highly sensitive for both soluble and insoluble Abs and can be used to fill the 25-year gap that cannot be reported by the 1stG probes.
Most of the 1stG tracers are based on the scaffold of thioflavin and styrene, whose intrinsic limitations are their insensitivity to soluble Abs, the high toxicity species and likely biomarkers for the pre-symptomatic stage. To overcome the intrinsic limitation of the 1st G probe, we have systematically investigated near infrared fluorescent (NIRF) curcuminoids as the new scaffold for detecting Abs. In this presentation, I will also discuss our tracer design half-curcuminoids as the novel second generation of PET tracers for Abs. With the optimized PET tracers, we will discuss results from preclinical PET imaging with mice. For a long term, we will advance the probes for future translational studies.
Chongzhao Ran, Ph.D., is an Assistant Professor in Radiology, Massachusetts General Hospital and Harvard Medical School. He received Master Degree in Medicinal Chemistry from China Pharmaceutical University, and Ph.D. in Medicinal Chemistry from Shanghai Institute of Pharmaceutical Industry, China. He did his postdoctoral training at University of Chicago and Harvard Medical School. Dr. Ran’s research focuses on the development of molecular imaging probe and imaging technologies. Dr. Ran has published nearly 60 papers in the fields of chemistry and molecular imaging, some in high-ranking journals such as PNAS and J. Amer. Chem. Soc.. Since 2010, Dr. Ran’s research has been continuously supported by multiple NIH grants from NIA, NIDDK and other foundations. In the past years, his research group has successfully developed numerous near-infrared fluorescence (NIRF) imaging probes, which revolve around their own brand CRANAD-X, for in vivo detection of amyloid beta in mouse models of Alzheimer’s disease (AD). Particularly, Dr. Ran’s research has been focusing on seeking “smart” NIR probes for soluble amyloid beta species, which are widely believed to be the most neurotoxic species at the early stage of AD. Recently, his research group has been successfully designed and synthesized 2nd generation PET tracers for amyloid beta species. In addition, his research group has discovered several NIRF probes and PET tracers for imaging brown adipose tissue. These probes have remarkable potential for future diagnosis and monitoring the efficacy of drugs for Alzheimer’s disease, diabetes and obesity in preclinical studies and clinical trials.