购彩中心

Topic: Probe development for systemic molecular imaging of Alzheimer’s disease
Speaker: Dr. Chongzhao Ran, Molecular Imaging Laboratory, Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School
Time: Monday, January 8, 2018, 13:30 PM
Location: Lecture Hall, Chemistry Building A, Room 528 (化学A楼528演讲厅)
Inviter: Prof. Yong Cui (崔勇教授)

Abstract：

Probe development for systemic molecular imaging of Alzheimer’s disease

Chongzhao Ran, Ph. D.

Molecular Imaging Laboratory,

Athinoula A. Martinos Center for Biomedical Imaging,

Department of Radiology,

Massachusetts General Hospital

Harvard Medical School, Boston, MA, 02129

Molecule imaging has been an indispensible tool for diagnosis, pathology investigation and basic mechanism studies in the past decades. For a specific disease, majority of research has been focusing on single-biomarker imaging, which is particularly important for the purpose of diagnosis. However, given the complex nature of diseases, systemic molecular imaging (SYMI) of multi-biomarkers of a single disease can be crucial for understanding the disease, and better designing therapeutics.

Alzheimer’s disease (AD) is a multi-facet neurodegenerative disease, and its biomarkers are also multi-dimensional. Amyloid beta (Aβ) deposits and tau tangles are

the most typical pathological hallmarks of AD, and Aβ species and tau have been considered to be essential dimensions for imaging AD. However, it is very likely that

other biomarkers also highly correlated with the impaired cognitive functions of AD patients. Among them, reactive oxygen species (ROS) have been widely believed to be an important dimension for AD imaging.

In this presentation, I will share our recent results on systemic molecular imaging of AD, particularly on the dimensions of Aβs and ROS. On the dimension of Aβ species, it has been intensely debated which sub-species, including insoluble Aβs and soluble Aβs, could be better biomarkers for AD severity and progression. In the past few years, our research has been concentrated on a trilogy of developing “smart” NIRF probes for various Aβ species. For this trilogy, in episode (I) we have effectively developed NIRF probes for insoluble Aβs. In this episode, we have invented a brand-new family of NIR fluorescent dyes CRANAD-X, and some of them are “smart” probes for the insoluble Aβs. In recent years, mounting evidence indicates that the soluble Aβs are probably the most neurotoxic species.

However, most of the current imaging probes are primarily sensitive for insoluble Aβs. In episode (II), we have successfully developed NIRF probes for both soluble and insoluble Aβ species, and we believe that these probes may have the potential to monitoring the full course of the amyloidosis of AD. For better understanding AD pathology, selectively imaging of the most neurotoxic soluble Aβs is very necessary. In episode (III), we have concentrated our efforts on developing imaging probes selective for soluble Aβs, thus to accomplish early detecting of AD pathology. For the ROS dimension, in the past years, we also have designed several

probes for imaging ROS and H2O2. I will present data to show the correlation of ROS level and the progression of AD.

Reference

a. Ran C, Xu X, Raymond SB, Ferrara BJ, Neal K, Bacskai BJ, Medarova Z, Moore A, J. Amer. Chem. Soc., 2009,131(42):15257-61.

b. Zhang X, Tian Y, Li Z, Tian X, Sun H, Liu H, Moore A, Ran C.*, J. Amer. Chem. Soc., 2013, 135(44):16397-409.

c. Zhang X, Tian Y, Yuan P, Li Y., Yaseen MA, Grutzendler J, Moore A, Ran C.*, Chem. Commun., 2014, 50(78):11550-3.

d. Zhang X, Tian Y, Zhang C, Tian X, Ross AW, Moir RD, Sun H, Tanzi RE, Moore A, and Ran C*, Proc. Natl. Acad. Sci. USA, 2015, 112(31):9734-9.

e. Yang J, Zhang X, Yuan P, Yang J, Xu Y, Grutzendler J, Shao Y, Moore A, Ran C*, Oxalate-curcumin based probe for micro- and macro-imaging of reactive oxygen species in Alzheimer’s disease, Proc. Natl. Acad. Sci. USA, 2017, 114(47):12384- 12389.

个人简历：

Chongzhao Ran, Ph.D.

冉崇昭博士

Assistant Professor of Radiology

Martinos Center for Biomedical Imaging

Massachusetts General Hospital

Harvard Medical School

Harvard University

Room 2301, Blg. 149

13th Street, Charlestown, MA, 02129

Tel: 617-643-4886

Email: cran@nmr.mgh.harvard.edu

职位

• Assistant Professor of Radiology: Martinos Center for Biomedical Imaging,

哈佛大学医学院 (2016 - , 分子影像学)

• Instructor of Radiology, Martinos Center for Biomedical Imaging,

哈佛大学医学院 (2009 -2016 , 分子影像学)

教育背景

• 博士后: Martinos Center for Biomedical Imaging,

哈佛大学医学院 (Sept.2006- Oct. 2009, Molecular Imaging)

Ben May Institute for Cancer Research,

芝加哥大学 (2002 ~ 2006, 生物有机化学 与癌症研究)

• 博士: 上海医药工业研究院 (1997.9 ~ 2000.8, 药物化学)

• 硕士: 中国药科大学 (1994.9 ~ 1997.7, 药物化学)

• 本科：中南民族大学 (1990.9 ~ 1994.7, 有机化学)

研究项目

• 开发可⽤于⽼年痴呆早期诊断的分⼦影像技术：⽼年痴呆症是⼀种尚⽆法治愈的神经退⾏性疾病. 随着社会⼈⼝⽼龄化，⽼年痴呆患者将不断的增加，因⽽该疾病将给社会带来沉重的医疗负担。目前，尚⽆药物可以减缓或治愈⽼年痴呆。⽤于临床治疗的药物仅仅可以改善症状，但不能阻⽌该疾病的恶化进程和延⻓⽣命。因⽽，开发可以减缓或治愈⽼年痴呆的药物是⼀项⾮常紧迫的任务。为了有效地开发针对⽼年痴呆的药物，寻找能够跟踪和检测⽼年痴呆病理变化的分⼦影像技术愈发显得重要。

分⼦影像技术是⼀类⾼灵敏和⽆损伤性的活体检测和诊断技术，开发针对⽼年痴呆的荧光分⼦影像探针，PET（正电⼦断层扫描技术）和MRI (核磁共振）分⼦影像探针将有助于加快药物开发的进程和有效性。

该项目以姜⻩素为先导化合物，设计合成了⼀系列荧光分⼦探针并进⾏了活体动物影像实验，发现了⼏个能够有效进⾏在体跟踪⽼年痴呆病理变化的探针 CRANAD-Xs。为了实现临床转化，我们还设计合成了⼀系列18F 标记PET 探针，并进⾏了PET 动物成像实验。实验结果表明其中⼀些PET 探针可以有效区分转基因⽼年痴呆⼩⿏和正常⼩⿏。有关MRI 探针的设计合成正在进⾏之中。我们的实验结果表明所设计的荧光分⼦探针可以有效地跟踪⽼年痴呆模型⿏病程变化，并且能够可靠地监测实验药物的治疗效果。我们认为我们的荧光分⼦影像技术将⼤⼤地提⾼⽼年痴呆药物开发的效率。

• 针对⽼年痴呆的药物开发：该项⺫以姜⻩素为先导化合物，设计合成了⼀系列衍⽣物，并进⾏了⽼年痴呆模型⿏体内药效实验。利⽤我们的荧光分⼦影像技术进⾏跟踪实验，结果表明其中⼀些化合物可以有效地抑制病程发展。我们的成像跟踪结果与传统的病理分析结果⼀致。

• 开发可以监测棕⾊脂肪的分⼦影像技术：近⼏年来，⼤规模的临床试验和统计分析表明棕⾊脂肪与⼈类的体内代谢有着极其重要的关系。与健康试验者相⽐，糖尿病和肥胖患者的棕⾊脂肪重量明显偏低。因⽽有⼈提出增加棕⾊脂肪重量将有利于这些疾病的治疗。但是，能够可靠地监测棕⾊脂肪重量变化的⽅法目前还不成熟。该项⺫通过⼤量筛选荧光分⼦探针发现了CRANAD－2 可以⽤于⼩⿏体内棕⾊脂肪的成像，但是该荧光探针不能够有效地区分棕⾊脂肪和⽩⾊脂肪（有害脂肪）。我们通过对该分⼦的修饰和改造，成功地找到了⼏个⾼选择性⾼灵敏度的荧光分⼦。我们在不同的疾病模型上使⽤这些分⼦，发现这些荧光探针能够有效地监测棕⾊脂肪重量的变化。目前的试验结果表明，我们的技术可以⼲泛⽤于棕⾊脂肪的临床前研究。

所获荣誉

• 1993 Top Student, South-Central University for Nationalities, Wuhan, China

• 1994 Honored Student, South-Central University for Nationalities, Wuhan,

• 1996 Jiuhuan Award, China Pharmaceutical University, Nanjing, China

• 2008 Travel Award, World Molecular Imaging Congress, 2008, Nice, France

• 2010 Career Development award from NIH/NIA

专利申请

1. Ran, C., Moore, A., 2008, Difluoroboron-derivated Curcumin as a near infrared probe, PCT Int.Appl. (2010), WO 2010017094 A2 20100211.

2. Xie, M. Ran, C., Ming, Y., 2008, Tetrahydroisoquinoline as potential antiarrhythamic agent ,CN101619038.

3. Ran, C., Moore, A., 2009, Methods and system for detecting soluble amyloid-β, PCT Int.Appl. (2011), WO 2011014648 A2 20110203.

4. Ran, C., Moore, A., 2013, Methods and system for imaging Brown Adipose Tissue, US Patent No.:US 14/916,779, PCT/US2014/054012.

5. Ran, C., Moore, A., 2012, Rational design curcumin analogues to attenuate copper induced crosslinking of amyloid beta, US Patent number: 9738623.

6. Ran, C., Yang, J., Moore, A., 2016, Half-curcuminoids as potential amyloid-beta PET imaging agents (MGH Invention No. 24074)

发表学术论文（部分论文）

1) Yang J, Zhang X, Yuan P, Yang J, Xu Y, Grutzendler J, Shao Y, Moore A, Ran C*, Oxalate-curcumin based probe for micro- and macro-imaging of reactive oxygen species in Alzheimer’s disease, Proc.Natl. Acad. Sci. USA, 2017, 114(47):12384-12389.

2) Yang J, Zhang X, Zhu Y, Lenczowski E, Tian Y, Yang J, Zhang C, Hardt M, Qiao C, Tanzi RE, Moore A, Ye H, Ran C*, A double-edged role of copper in the fate of amyloid beta in the presence of antioxidants,Chemical Science, 2017, 8: 6155-6164.

3) Li Y, Yang J, Liu H, Yang J, Du L, Feng H, Tian Y, Cao J, Ran C*, Tuning Stereo-hindrance of Curcumin Scaffold for Selective Imaging of Soluble Forms of Amyloid Beta Species, Chemical Science, 2017, 8:7710-7717.

4) Shen S, Lim G, You Z, Ding W, Huang P, Ran C, Doheny J, Caravan P, Tate S, Hu K, Kim H, McCabe M, Huang B, Xie Z, Kwon D, Chen L, Mao J, Gut microbiota is critical for the induction of chemotherapy-induced pain, Nature Neuroscience, 2017, 20(9):1213-1216.

5) Zhang X, Tian Y, Zhang H, Kavishwar A, Lynes M, Brownell AL, Sun H, Tseng YH, Moore A, and Ran C*, Curcumin analogues as selective fluorescence imaging probes for brown adipose tissue and monitoring browning, Scientific Reports, 2015, 5: 13116, doi:10.1038/srep13116.

6) Zhang X, Tian Y, Zhang C, Tian X, Ross AW, Moir RD, Sun H, Tanzi RE, Moore A, and Ran C*, Near‐infrared fluorescence molecular imaging of amyloid beta species and monitoring therapy in animal models of Alzheimer's disease, Proc. Natl. Acad. Sci. USA, 2015, 112(31):9734-9. PMID: 26199414.

7) Zhang X, Tian Y, Yuan P, Li Y., Yaseen MA, Grutzendler J, Moore A, Ran C.*, A bifunctional curcumin analogue for two-photon imaging and inhibiting crosslinking of amyloid beta in Alzheimer's disease, Chem. Commun., 2014, 50(78):11550-3. PMID: 25134928.

8) Zhang X, Tian Y, Li Z, Tian X, Sun H, Liu H, Moore A, Ran C.*, Design and Synthesis of Curcumin Analogues for in Vivo Fluorescence Imaging and Inhibiting Copper-Induced Cross-Linking of Amyloid Beta Species in Alzheimer's Disease, J. Amer. Chem. Soc., 2013, 135(44):16397-409.

9) Xueli Zhang, Chaincy Kuo, Anna Moore, C Ran*, In Vivo Optical Imaging of Interscapular Brown Adipose Tissue with 18F-FDG via Cerenkov Luminescence Imaging, PLOS One, 2013, 8(4): e62007.

10) C Ran, Anna Moore, Spectral Unmixing Imaging of Wavelength-Responsive Fluorescent Probes: An Application for the Real-Time Report of Amyloid Beta Species in Alzheimer's Disease, Mol. Imaging and Biology, 2012,14(3): 293-300.

11) C Ran, Xiaoyin Xu, Pamela Pantazopoulos, Zdravka Medarova, Brian J. Bacskai, Anna Moore, Design, Synthesis and Testing of Curcumin Based “Smart” Near Infrared Probes for in vivo Detection of Amyloid-β Plaques in Transgenic Animal Model, J. Amer. Chem. Soc., 2009, 131(42):15257-61.

12) C Ran, Qing Dai, and Ronald G. Harvey, Strategies for Synthesis of Adducts of o-Quinone Metabolites of Carcinogenic Polycyclic Aromatic Hydrocarbons with 2'-Deoxyribonucleosides, J. Org. Chem., 2008,73 (3), 992 -1003.

13) C Ran, Pamela Pantazopoulos, Zdravka Medarova, Anna Moore, Synthesis and Testing of Beta-Cell-Specific Streptozotocin-Derived Near-Infrared Imaging Probes, Angewandte Chemie International Edition, 2007, 46(47): 8998-9001.

14) C Ran, Qing Dai, Ronald G. Harvey, Efficient synthesis of N6-aryl-2'-deoxyadenosines via coppermediated direct coupling of aryl halide with 2'-deoxyadenosine. J. Org. Chem., 2005, 70(9): 3724-26.

15) Qing Dai, C Ran, Ronald G. Harvey, Synthesis of adducts of o-quinone metabolites of Carcinogenic polycyclic aromatic hydrocarbons with 2’-deocyadenosine and 2’-deoxyuanosine. Organic Letters, 2005, 7(6): 999-1002.

会议报告 （部分报告）

1) Xueli Zhang, Anna Moore, C Ran*, Curcumin analogues for fluorescence imaging and inhibiting cross-linking of amyloid beta of Alzheimer’s disease. New Advances in optical imaging in cell and organism, 2013, Cold Spring Harbor Laboratory Meeting, Asia, Suzhou (Contribution Presentation).

2) Xueli Zhang, Anna Moore, C Ran*, Imaging Brown Adipose Tissue with Cerenkov Luminescence Imaging, World Molecular Imaging Congress, 2012, Dublin, Ireland ((Selected Oral Presentation by the Committee).

3) C Ran, Anna Moore, Smart optical imaging probes for AD detection, World Molecular Imaging Congress, 2010, Kyoto, Japan (Selected Oral Presentation by the Committee).

4) C Ran, Anna Moore, Non-conjugated small molecular FRET for differentiating Abeta species, World Molecular Imaging Congress, 2010, Kyoto, Japan ((Selected Oral Presentation by the Committee).

5) C Ran, Xiaoyin Xu, Anna moore, Design, synthesis, and testing of difluoroboron derivated curcumins as “Smart” Near Infrared Probes for in vivo detection of amyloid-β deposits, World Molecular Imaging Congress, Nice, France, 2008 (Selected Oral Presentation by the Committee).

邀请报告 （部分报告）

2010 Shanghai Jiaotong University, Shanghai, China

Molecular Imaging in detection of pathology of Alzheimer’s disease

2010 Shandong University, Jinan, China

Molecular Imaging and Chemical Biology

2011 South-Central University for Nationalities, Wuhan, China

Molecular Imaging in detection of pathology of Alzheimer’s disease

2012 Caliper Lifescience, MA, USA (Workshop at Yale University)

Fluorescence imaging of Alzheimer’s disease

2013 Martinos Center for Biomedical Imaging, MGH/Harvard Medical School

Near-infrared “smart” fluorescent imaging probes for amyloidosis of Alzheimer’s disease

2013 Pfizer Pharmaceuti