PDE4D PET Ligand for Psychiatric Disease

利乐发现伙伴公司是NIH蓝图神经治疗网络奖的获得者，该奖项旨在开发磷酸二酯酶-4D(PDE4D)阴性变构调节剂(NAMS)，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年底进入人类第一阶段临床试验。通过与NIMH内部计划的Robert Inris博士和Victor Pike博士达成的合作研究和开发协议(CRADA)，该公司一直在并行开发用于在人脑中对PDE4亚型进行成像的新型PET配体。拟议的第一阶段SBIR的目标是开发一种可用于评估Tetra-NIH Blueprint药物在人类第一阶段临床试验中的目标占有率的PDE4D PET配体，以及一种可用于评估精神和神经疾病患者的PDE4D水平的PET配体。 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进行了遗传学验证，这些儿童患上了一种被称为肢端营养不良2型的超罕见疾病(ACRDY2；MIM 600129)。ACRDY2是一种发育障碍，以智力残疾、短指、鼻部发育不良和身材矮小为特征。患有肢端骨质疏松症的儿童智商只有50-80。因此，PDE4D是果蝇PDE4基因的人类同源基因，其中Dunce突变是在模式生物中发现的第一个学习突变。罗利普兰和其他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前认知作用，而敲除或敲除小鼠PDE4D基因也可以改善学习和记忆。 我们的NIMH合作者英尼斯和派克已经证明，在重度抑郁症患者中，PDE4PET成像发生了改变。这些研究使用C-11(R)-罗利普兰作为评估PDE4水平的PET配体，然而，罗利普兰同样与大脑中表达的不同PDE4亚型(PDE4A、PDE4B和PDE4D)结合。因此，我们想要了解在严重的抑郁症和其他精神疾病中，PDE4D水平是否发生了变化。 在第一阶段的SBIR中，利乐公司将优化有效和选择性的PDE4D NAMS，由将进行活体PET成像研究的英尼斯和派克进行C-11或F-18标记。如果找到合适的PDE4D PET配体，这种显像剂可能会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.