PDE4D PET Ligand for Psychiatric Disease

用于精神疾病的 PDE4D PET 配体

• 批准号: 8904221
• 负责人: Mark E Gurney
• 金额: $ 34.62万
• 依托单位: TETRA DISCOVERY PARTNERS, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8904221
• 关键词: Acrodysostosis; Active Sites; Address; Affect; Amino Acids; Animal Model; Award; Binding; Binding Sites; Brain; Child; Clinical Trials; Cognition; Cognitive; Cooperative Research and Development Agreement; Databases; Disease; Drosophila genus; Enzymes; Funding; G Protein-Coupled Receptor Genes; Gene Mutation; Genes; Genetic; Goals; Health; Human; Image; Impaired cognition; Inhibitory Concentration 50; Intellectual functioning disability; Intramural Research Program; Ion Channel; Knock-out; Label; Lead; Learning; Ligands; Major Depressive Disorder; Memory; Memory Loss; Mental disorders; Metabolic Activation; Monkeys; Mus; Mutation; National Institute of Mental Health; Neurologic; Nose; Orthologous Gene; PDE4B; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phenylalanine; Pike fish; Plasma; Plasma Proteins; Positron-Emission Tomography; Protein Binding; Rare Diseases; Rattus; Rolipram; Small Business Innovation Research Grant; Structure; Testing; Tyrosine; United States National Institutes of Health; Validation; Work; design; developmental disease; genotoxicity; imaging agent; improved; in vivo; inhibitor/antagonist; knock-down; novel; phosphodiesterase 4D

Tetra Discovery Partners is the recipient of an NIH Blueprint Neurotherapeutics Network award to develop phosphodiesterase-4D (PDE4D) Negative Allosteric Modulators (NAMs) for treating memory loss in patients affected by psychiatric and neurologic diseases. The Tetra-NIH Blueprint drug is projected to reach human Phase I clinical trials in late 2015. Through a Cooperative Research and Development Agreement (CRADA) with Dr Robert Innis and Dr Victor Pike of the NIMH Intramural Program, the company has been working in parallel to develop novel PET ligands for imaging PDE4 subtypes in the human brain. The goal of the proposed Phase I SBIR is to develop a PDE4D PET ligand useful for assessing target occupancy in human Phase I clinical trials of the Tetra-NIH Blueprint drug as well as a PET ligand that will be useful for assessing PDE4D levels in patients with psychiatric and neurologic disease. PDE4D as a target for improving cognition in humans has genetic validation through studies of children with PDE4D gene mutations who develop an ultra-rare disorder known as acrodysostosis type-2 (ACRDY2; MIM 600129). ACRDY2 is a developmental disorder characterized by intellectual disability, brachydactyly, nasal hypoplasia and short stature. Children with acrodysostosis only achieve an IQ of 50-80. Thus, PDE4D is the human ortholog of the Drosophila PDE4 gene in which the Dunce mutation was the first learning mutation identified in a model organism. Rolipram and other PDE4 inhibitors have been shown to be broadly pro-cognitive in numerous animal models of learning and memory, while knock-out or knock-down of the mouse PDE4D gene also improves learning and memory. Our NIMH collaborators, Innis and Pike, have shown that PDE4 PET imaging is altered in patients with major depression. Those studies used C-11 (R)-rolipram as a PET ligand for assessing PDE4 levels, however, rolipram binds equally to the different subtypes of PDE4 expressed in brain (PDE4A, PDE4B & PDE4D). We therefore want to understand if PDE4D levels are altered in major depression and other psychiatric diseases. In the Phase I SBIR, Tetra will optimize potent and selective PDE4D NAMs for C-11 or F-18 labelling by Innis and Pike who will conduct in vivo PET imaging studies. Should a suitable PDE4D PET ligand be identified, the imaging agent could rapidly advance into human clinical trials.

Tetra Discovery Partners 荣获 NIH Blueprint Neurotherapeutics Network 奖，开发磷酸二酯酶 4D (PDE4D) 负变构调节剂 (NAM)，用于治疗精神和神经系统疾病患者的记忆丧失。 Tetra-NIH Blueprint 药物预计将于 2015 年底进入人体 I 期临床试验。通过与 NIMH 校内项目的 Robert Innis 博士和 Victor Pike 博士签订的合作研究与开发协议 (CRADA)，该公司一直在并行开发新型 PET 配体，用于对人脑中的 PDE4 亚型进行成像。拟议的 I 期 SBIR 的目标是开发一种 PDE4D PET 配体，可用于评估 Tetra-NIH Blueprint 药物的人体 I 期临床试验中的靶点占据率，以及一种 PET 配体，可用于评估精神科和神经系统疾病患者的 PDE4D 水平。 PDE4D 作为改善人类认知的目标，通过对患有 PDE4D 基因突变的儿童的研究得到了遗传验证，这些儿童患上了一种极其罕见的疾病，称为 2 型肢端骨质疏松症 (ACRDY2；MIM 600129)。 ACRDY2 是一种发育障碍，其特征是智力障碍、短指、鼻发育不全和身材矮小。患有肢端骨质疏松症的儿童智商只能达到 50-80。因此，PDE4D 是果蝇 PDE4 基因的人类直系同源物，其中 Dunce 突变是在模型生物体中发现的第一个学习突变。咯利普兰和其他 PDE4 抑制剂已被证明在许多学习和记忆动物模型中具有广泛的促认知作用，而小鼠 PDE4D 基因的敲除或敲低也能改善学习和记忆。 我们的 NIMH 合作者 Innis 和 Pike 表明，重度抑郁症患者的 PDE4 PET 成像发生了改变。这些研究使用 C-11 (R)-咯利普兰作为 PET 配体来评估 PDE4 水平，然而，咯利普兰与大脑中表达的 PDE4 的不同亚型（PDE4A、PDE4B 和 PDE4D）同等结合。因此，我们想了解重度抑郁症和其他精神疾病中 PDE4D 水平是否发生变化。 在 I 期 SBIR 中，Tetra 将优化有效且选择性的 PDE4D NAM，以便 Innis 和 Pike 进行 C-11 或 F-18 标记，他们将进行体内 PET 成像研究。如果找到合适的 PDE4D PET 配体，该显像剂可以迅速进入人体临床试验。