Application of Small Animal Digital PET in Preclinical Research

Application of Small Animal Digital PET in Preclinical Research

Application of Animal Digital PET in Preclinical Research Wenchang Xiao, Ph.D. Wuhan RAYDATA Technology Co., Ltd. Techniques of Molecular Imaging Anatomic Physiologic Metabolic PET/SPECT x-ray CT MRI MR Spectroscopy fMRI ultrasound optical imaging Molecular Preclinical Molecular Imaging Basic research Drug

discovery Target validation Drug development Clinical trail Source of the disease? Monitoring development of disease in vivo. Associated gene, protein and RNA? Measurement from metabolism to gene expression Availability of the inhibitor or analog? Monitoring disease rescue The best candidate? Whole-body pharmacokinetics Effectiveness and safety research in human

Design clinical trail based on preclinical data PET: Functional Imaging Application Oncology Neuroscience Cardiology Metabolism Primary Canc er Neurodegenerative diseases Atherosclerosis Hepatic Adiposis Bone Metabolism Metastatic ca ncer Psychiatric

Disorders Diabetes Arthritis Subcutaneous Cancer Cardiac Infarction Pain Myocardial Metabolism Inflammation Perfusion Stroke Vascular Trauma Neural Circuit

Lipometabolism Bone Others Inflammatory Bowel Disease Pharmacodyn amics Pharmacokine tics Product of Animal Digital-PET Trans-PET BioCaliburn system Derenzo Phantom test Sensitivity: 2.04 % (FOV center, 350 KeV~650 KeV) Spatial Resolution: ~1 mm Luyao Wang, et al., Physics in medicine and biology, 2014. Jun Zhu, et al., Nuclear Instruments & Methods in Physics Research, 2015. Pre-clinical Applications 5 Installation bases Union Hospital in Wuhan (China)

Turku PET center (Finland) Mediterranean Neurological Institute (Italy) University of Illinois at Chicago (USA) University of Wisconsin-Madison (USA) More than 5000 animal experiments Cancer Neurological diseases Cardiovascular diseases Metabolic diseases Etc Mice Rats Rabbits Monkeys Pigs Dozens of publications Nature Medicine Nature Communications Am J Resp Crit Care Med Eur J Nucl Med Mol I Experimental Neurology CNS Neurosci Ther Frontiers in Pharmacology Etc high

Application Cases in Oncology WT Model: C57BL/6 mice with lung cancer. Method: scan. IFN-/- low IL-17-/- Lin H. et al., Am J Respir Crit Care Med. 2014. (IF=13.2) 18 F-FDG-PET/CT, Static Application Cases in Neuroscience Vehicle Don

ST09 high Sham Model: Vascular dementia rat. low Method: 18F-FDG-PET, Static scan. Liu JM. et al., CNS Neurosci Ther. 2016. (IF=3.9) Application Cases in Cardiology Model: Diabetic mice. Method: 18F-FDG-PET, Static scan. Li WJ. et al., Sci Rep. 2017. (IF=4.5) 0-10s 180-240s 900-1200s high

Application Cases in Metabolism Flox Model: Obese mice. Method: scan. low HepKO Wang PX. et al., Nat Med. 2017. (IF=29.9) 18 F-FDG-PET, Dynamic high Application Cases in Pharmacokinetics Model: mice melanoma.

10s 20s 30s 1min with Subcutaneous 2min low Method: 18F-5-FPN-PET, Dynamic scan. 20min 30min 40min 10min 5min Feng H. et al., Eur J Nucl Med Mol Imaging. 2015. (IF=7.3) Publications ORIGINAL ARTICLE

ST09, a Novel Thioester Derivative of Tacrine, Alleviates Cognitive Decits and Enhances Glucose Metabolism in Vascular Dementia Rats Jian-Min Liu,1 , * Peng-Fei Wu,1 , 2 , 3 Jing Rao,4 Jun Zhou,1 Zu-Cheng Shen,1 Han Luo,1 Jian-Geng Huang,4 Xiao Liang,5 Li-Hong Long,1 , 2 , 3 Qing-Guo Xie,5 Feng-Chao Jiang,6 Fang Wang1 , 2 , 3 & Jian-Guo Chen1 , 2 , 3 , 7 1 Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China 2 The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China 3 Laboratory of Neuropsychiatric Diseases, The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan, China 4 Department of Pharmaceutics, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China 5 Wuhan National Laboratory for Optoelectronics, Huazhong University of Science and Technology, Wuhan, China 6 Department of Medicinal Chemistry, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China 7 The Collaborative Innovation Center for Brain Science, Wuhan, China Keywords Acetylcholinesterase; Glucose Metabolism; Tacrine; Thioester Derivative; Vascular Dementia. Correspondence J.-G. Chen, or F. Wang, Department of Pharmacology, Tongji Medical College, HUST, #13, Hangkong Road, Wuhan, Hubei 430030, China. Tel.: +86-27-83692636; Fax: +86-27-83692608; E-mail: [email protected], or [email protected] Received 18 June 2015; revision 30 October

2015; accepted 18 November 2015 *Present address: Wuhan NO. 1 hospital, Wuhan, Hubei, 430022, China SUM MARY A ims: Chemical entities containing mercapto group have been increasingly attractive in the therapy of central nerve system (CNS) diseases. In the recent study, we screened a series of mercapto-tacrine derivatives with synergistic neuropharmacological proles in vitro. M ethods: We investigated the effect and mechanism of ST09, a thioester derivative of tacrine containing a potential mercapto group, on the vascular dementia (VaD) model of rat induced by bilateral common carotid arteries occlusion (2-VO). Results: ST09 and itsactive metabolite ST10 retained excellent inhibition on acetylcholinesterase (AChE) activity. ST09 signicantly attenuated the 2-VO-induced impairment in spatial acquisition performance and inhibited the 2-VO-induced rise of AChE activity. In the VaD model, ST09 attenuated the oxidative stress and decreased the apoptosis in the cortex and hippocampus. Compared with donepezil, ST09 exhibited a better effect on the regeneration of free thiolsin 2-VO rats. Interestingly, ST09, not donepezil, greatly improved glucose metabolism in various brain regions of 2-VO rats using functional imaging of 1 8 F-labeled uoro-deoxyglucose (FDG) positron emission tomography (PET). Conclusions: ST09 may serve as a more promising agent for the therapy of VaD than tacrine owing to the introduction of a potential mercapto group into the parent skeleton. doi: 10.1111/cns.12495 The rst two authors contributed equally to this work. Introduction Vascular dementia (VaD) is considered as a second most common

cause of dementia after Alzheimers dementia (AD) [1]. The cognitive impairment of VaD is mainly attributed to cerebrovascular pathology [2]. After cerebral hypoperfusion, a series of factors, including metabolism impairment, excitotoxicity, oxidative stress, and cholinergic decit, are involved in the progression of 2016 John Wiley & Sons Ltd secondary cognitive impairment [3,4]. Although some drugs have been approved as moderate therapy for VaD [2,59], none of the clinic drugs show a signicant therapeutic effect on VaD yet. By recognizing the multifactorial nature of VaD, single chemical entity with the ability to modulate multiple targets may offer a promising approach for the treatment of dementia. Tacrine, the rst AChEI approved by the Food and Drug Administration (FDA) for Alzheimers disease (AD), exhibits a CNS Neuroscience & Therapeutics (2016) 110 1 Guang-Nian Zhao, et al., Tmbim1 is a multivesicular body regulator that protects against non-alcoholic fatty liver disease in mice and monkeys by targeting the lysosomal degradation of Tlr 4, Nature Medicine, 2017 (IF=29.9) Pi-Xiao Wang, et al., Targeting CASP8 and FADD-like apoptosis regulator ameliorates nonalcoholic steatohepatitis in mice and nonhuman primates, Nature Medicine, 2017 (IF=29.9)

Ying Yang, et al., Opposite monosynaptic scaling of BLPvCA1 inputs governs hopefulness- and helplessness-modulated spatial learning and memory, Nature Communications, 2016 (IF= 12.1) Hua Lin, et al., Interplay of Th1 and Th17 Cells in Murine Models of Malignant Pleural Effusion, American Journal of Respiratory and Critical Care Medicine, 2014 (IF=13.118) Hongyan Feng, et al., Imaging malignant melanoma with 18F-5-FPN, European Journal of Nuclear Medicine and Molecular Imaging , 2015 (IF= 7.3) Mohamed A A Ahmed, et al., New approach for simultaneous respiratory and cardiac motion correction in cardiac PET (NAMC-CPET), Physics in Medicine and Biology, 2015 IF=2.76 1 Jian-Min Liu, et al., ST09, a novel thioester derivative of tacrine, alleviates cognitive deficits and enhances glucose metabolism in vascular dementia rats, CNS Neuroscience & Therapeutic s, 2016 (IF= 4.019) Our Group 2018.6 Philadelphia, USA SNMMI

2019.1 2018.6 Prague, Czech IUPESM Acknowledgments Huazhong University of Sci. & Tech. Qingguo Xie, Prof. Peng Xiao, Prof. Xiao Liang Raydata Technology Co., Ltd.(Wuhan) Lu Wan, PhD Huanhuan Yan, PhD Raycan Technology Co., Ltd.(Suzhou) Fang Chen Yuexuan Hua Department of Nuclear Medicine, Union Hospital, Tongji Medical College Prof. Xiaoli Lan Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College Prof. Xiaoping Chen State Key Laboratory of Molecular Oncology Prof. Qimin Zhan Thank you for your attention!

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