PDE4D PET Ligand for Psychiatric Disease

Tetra Discovery Partners是NIH Blueprint Neurotherapeutics Network奖的获得者，该奖项旨在开发磷酸二酯酶-4D（PDE 4D）负变构调节剂（NAM），用于治疗受精神和神经疾病影响的患者的记忆丧失。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博士和维克托Pike博士的合作研究和开发协议（CRADA），该公司一直在平行开发用于成像人脑中PDE 4亚型的新型PET配体。拟议的I期SBIR的目标是开发一种PDE 4D PET配体，用于评估Tetra-NIH Blueprint药物的人体I期临床试验中的靶点占有率，以及一种PET配体，用于评估精神病和神经系统疾病患者的PDE 4D水平。 PDE 4D作为改善人类认知的靶点，通过对患有PDE 4D基因突变的儿童的研究进行了遗传学验证，这些儿童患有一种称为肢端发育不全2型（ACRDY 2; MIM 600129）的超罕见疾病。ACRDY 2是一种发育障碍，其特征在于智力残疾、短指、鼻发育不全和身材矮小。患有肢端骨发育不全的儿童智商只有50-80。因此，PDE 4D是果蝇PDE 4基因的人类直系同源物，其中Dunce突变是在模式生物中鉴定的第一个学习突变。Rolipram和其他PDE 4抑制剂已被证明在许多学习和记忆的动物模型中具有广泛的促认知作用，而敲除或敲低小鼠PDE 4D基因也可改善学习和记忆。 我们的NIMH合作者Innis和Pike已经表明，重度抑郁症患者的PDE 4 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PDE 4水平，然而，咯利普兰等同地结合脑中表达的PDE 4的不同亚型（PDE 4A、PDE 4 B和PDE 4D）。因此，我们想了解PDE 4D水平在重度抑郁症和其他精神疾病中是否会改变。 在I期SBIR中，Tetra将优化Innis和Pike进行的C-11或F-18标记的有效和选择性PDE 4D NAM，Innis和Pike将进行体内PET成像研究。如果一个合适的PDE 4D PET配体被确定，成像剂可以迅速进入人体临床试验。

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.