Development and investigation of isotope-labeled ligands for the orexin receptor subtypes OX1R and OX2R

• Applicants: Professor Dr. Peter Gmeiner; Professor Dr. Olaf Prante
• Subject Area: Pharmacy
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 440643129

Orexin receptors with their subtypes OX1R and OX2R, which belong to the class A of G-protein coupled receptors, are considered to be highly interesting pharmaceutical targets. While OX2R is involved in the sleep-wake cycle, OX1R has been implicated in eating disorders, addiction and pain processing. Interestingly, OXR1 is expressed on colon tumor cells and is, in principle, suitable for the development of receptor-mediated radiopharmaceuticals for tumor imaging by positron emission tomography (PET) and tumor radiotherapy. During the first funding period, we discovered and investigated the OX1R-selective lead compound JH112. Guided by a high-resolution crystal structure of the OX1R-JH112 complex, we developed a series of heteroaryl analogs of JH112, including the benzothiazole [18F]KB44, a brain-penetrating PET ligand. We also generated a series of fluorophenyl analogs including the OX1R/OX2R radioligand [18F]KD10 and its OX1R selective derivative [18F]KD23. To access conjugates bearing a metal chelator, we introduced prosthetic groups attached to linkers in position 6' of the phenylene or position 4 of the heteroaryl moiety, providing us with a strategy that will be useful to access orexin receptor-binding radioligands for imaging and therapeutic targeting of peripheral OXR-positive tumors. Based on these investigations, this interdisciplinary project aims to develop and optimize orexin receptor-binding radioligands with favorable in vitro and in vivo pharmacokinetic properties. To achieve this goal, we plan to design and synthesize more hydrophilic radioligands with lower plasma protein binding, optimize conjugates including linkers and chelators to develop high-affinity OX1R radiotherapeutics, extend our studies to a second lead to complement JH112. The ultimate goal of this project is to develop orexin receptor ligands for brain PET imaging with high affinity and favorable pharmacokinetics, and to study preclinical tumor therapy with a promising 161Tb-labeled ligand.

• DFG Programme: Research Grants