The sigma-2 (s2) receptors play a role in anxiety, depression, movement disorders and psychostimulant abuse. These important aspects of their CNS pharmacology remain relatively unexplored. In part, this is a consequence of the lack of radioligands for in vivo studies of s2 receptors in animal models and for non- invasive brain PET imaging. Thus, it is not surprising that the NIH CNS Radiotracer Table lists C-11 SA4503 is an available s1 receptor probe for PET, while none are listed for the s2 receptor. We recently reported that cocaine's locomotor stimulatory effects in mice are attenuated by administration of a highly s2 receptor-selective tetrahydroisoquinolinyl benzamide. We could not demonstrate a direct interaction of cocaine with s2 receptors in vivo in brain because there are no appropriate radioligands. Our central hypothesis is that novel radioligands can be developed that will display high s2 receptor affinity and selectivity, and will emerge as leading candidates for brain PET imaging of s2 receptors. A systematic medicinal radiochemistry approach that has served as a successful paradigm for the development of other PET imaging radiotracers serves as the framework for our proposal.
Our specific aims are: 1) the evaluation of the pharmacokinetics, pharmacology, metabolic stability and PET imaging potential of [18F]-labeled s2 receptor ligands in vivo in normal mouse and 2) the preparation of novel [18F]-labeled ligands that bind with high affinity and selectivity to s2 receptors. The specific innovation in this proposal derive from recognition of key chemical structural modifications that, when combined into new molecules, should lead to optimized radioligands. This proposal is submitted in response to PAR-13-282: Development and Application of PET and SPECT Imaging Ligands as Biomarkers for Drug Discovery and for Pathophysiological Studies of CNS Disorders (R21). At the end of the R21 funding period, we fully anticipate that one or more of the [18F]-labeled radioligands will display high s2 receptor affinity and selectivity, proven specific binding in viv, appropriate pharmacokinetics, good metabolic stability, and utility for micro-PET brain imaging. The development of such radioligands will provide new and unique opportunities for the discrimination of s2 receptor-mediated activities in the CNS, and facilitate the development of s2 receptor ligands as therapeutics for CNS disorders. Furthermore, optimal s2 receptor ligands for brain PET might also have great utility in the oncology realm.
Radioligands for Sigma-2 receptor Studies in the CNS by PET Public Health Relevance: In the brain there are proteins called sigma receptors. These receptors play a role in anxiety, depression, movement disorders and psychostimulant abuse; however, we do not have a clear understanding of how they function. We propose to synthesize new biomarkers that are specific for these receptors and that contain a radioactive tag. Non-invasive imaging by positron emission tomography (PET) would help us 'see' these receptors and how they interact in the presence of legal and illegal drugs in healthy and sick individuals. From these studies, we could learn more about these receptors and design new medicines that could be helpful treating people.
| Lever, Susan Z; Fan, Kuo-Hsien; Lever, John R (2017) Tactics for preclinical validation of receptor-binding radiotracers. Nucl Med Biol 44:4-30 |
