PDE4D PET Ligand for Psychiatric Disease

用于精神疾病的 PDE4D PET 配体

基本信息

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
项目类别：
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

项目摘要

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是NIH蓝图神经疗法网络奖的接受者，以开发磷酸二酯酶4D（PDE4D）阴性变构调节剂（NAMS），用于治疗受精神病和神经疾病影响的患者的记忆力丧失。 TETRA-NIH蓝图药物预计将于2015年底进行人类I期临床试验。通过与NIMH壁内计划的Robert Innis博士和Victor Pike博士的合作研究与发展协议（CRADA），该公司一直在与人类脑中成像PDE4子类型的新颖PET PET GITS合作。拟议的I期SBIR的目的是开发一种PDE4D PET配体，可用于评估人类I期tetra-NIH蓝图药物的I期临床试验以及PET配体，以及一种可用于评估精神病和神经疾病患者中PDE4D水平的PET配体。 PDE4D作为改善人类认知的靶点，通过对患有PDE4D基因突变的儿童的研究，他们形成了一种被称为AcrodySostosis-2型的超稀有疾病（Acrdy2; mim 600129）。 Acrdy2是一种发育障碍，其特征是智力障碍，脑力症，鼻腔发育不全和身材矮小。肢体肌生造成病的儿童只能达到50-80的智商。因此，PDE4D是果蝇PDE4基因的人类直系同源物，其中dunce突变是模型生物体中第一个鉴定出的学习突变。在许多学习和记忆的动物模型中，Rolipram和其他PDE4抑制剂已被证明是广泛的认知，而小鼠PDE4D基因的敲除或敲除也可以改善学习和记忆。我们的NIMH合作者Innis和Pike表明，重度抑郁症患者的PDE4 PET成像正在改变。这些研究使用C-11（r） - 罗里普拉姆作为宠物配体来评估PDE4水平，但是，rolipram与在脑中表达的PDE4的不同亚型平均结合（PDE4A，PDE4B，PDE4B＆PDE4D）。因此，我们想了解在严重抑郁症和其他精神病疾病中PDE4D水平是否改变。在I期SBIR中，TETRA将优化Innis和Pike的C-11或F-18标记的有效和选择性PDE4D NAM，他们将在体内宠物成像研究中进行。如果确定合适的PDE4D PET配体，成像剂可以快速前进到人类的临床试验中。