Development of tricyclic enzyme inhibitors as PET imaging agents for phosphodiesterase 2A

• Applicants: Professor Detlef Briel; Dr. Matthias Scheunemann
• Subject Area: Pharmacy ; Nuclear Medicine, Radiotherapy, Radiobiology
• Term: from 2017 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 319235997

The phosphodiesterases (PDE) are enzymes which hydrolyze the two cellular messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). So take the eleven different types (isoforms) of PDE influence on the distribution and localization of these second messengers in the central nervous system (CNS) of human. Through the functioning of these on cellular signaling cascades and self-regulation (homeostasis) basic functions such as behavior, learning, memory and recognition are controlled and mental illness are affected.It is presumed that PDE2A is involved in the pathophysiology of neurodegenerative diseases. The specific distribution of PDE2A protein in brain indicates a modulation of important neuronal functions associated to learning and memory. Hence, PDE2A inhibitors are regarded as promising compounds for drug development in treatment of neurological disorders such as Alzheimer´s disease (AD). In addition, this enzyme is highly expressed in certain tumors such as malignant melanoma and mammary carcinoma. The local distribution and function of PDE2A makes molecular imaging by positron emission tomography (PET) promising regarding a better understanding of disorders in humans that are correlated with related diseases.Based on previous results from the Brust research group (HZDR), triazine based tricyclic compounds are to be developed further to gain potent and specific ligands to PDE2A with focus on sufficient metabolic stability of the derived 18F-labeled tracer in vivo. The main synthetic objective of this project for the Briel research group (University of Leipzig) is to develop highly potent triazolopyridopyrazines as candidates for 18F-labeling. These tricyclic compounds are derived from a recent patent (Boehringer 2014) and are currently the most potent PDE2A inhibitors that simultaneously possess a very high selectivity with regard to further PDE enzymes. Three options were selected to find suitable candidates, which will be tested for their binding affinity in cell-based studies. Suitable candidates will be selected for radiolabelling with 18F. Suitable precursors will be synthesized for this purpose and labelling procedures have to be developed. Animal experiments will be performed to investigate the biodistribution and the enzyme binding in vivo of the new radiotracers and to evaluate their potential for neuroimaging with PET. In collaboration with the Yale PET centre the most suitable radioligand(s) will be investigated in monkeys in dynamic PET studies.

• DFG Programme: Research Grants
• International Connection: USA
• Cooperation Partner: Professor Yiyun Henry Huang, Ph.D.