Highly potent binding molecules improve imaging and activation of lab-designed neuronal receptors

2019

Challenge

Chemogenetic technologies such as Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are used in hundreds of laboratories around the world to control neuronal activity in freely moving animals. These technologies are currently being developed for use in humans as a next-generation therapeutic. However, the technology is limited by the fact that currently available ligands — the synthetic molecules that bind to these lab-designed receptors — are either weak or bind to other receptors in addition to their target receptor, leading to undesired side-effects.

Advance

A team of IRP researchers and outside collaborators led by Mike Michaelides, Ph.D., developed the first novel series of DREADD ligands that exhibit a high propensity to bind to their target receptor and are highly potent in rodents and nonhuman primates. The team also developed the first DREADD ‘radioligand,’ a ligand labeled with a radioactive tracer that enables scientists to use non-invasive positron emission tomography (PET) imaging to visualize DREADD receptor localization in the brain and track it over time. The new radioligand is labeled with a radioactive isotope that lasts longer in the body than other radioligands — about two hours rather than 20 minutes. This feature makes the technology commercially viable because it allows the radioligand to be shipped to and used in labs that lack certain specialized equipment for synthesizing and viewing radioactive molecules.

Impact

With these refined tools, chemogenetic technologies such as DREADDs can now be used in laboratory animals, including nonhuman primates, and potentially in humans, with greater ease of use and increased sensitivity. The new PET radioligand also permits, for the first time, anatomical visualization of cell type-specific neural pathways in a non-invasive manner over time. This will greatly facilitate future research into how specific brain circuits contribute to behavior, health, and disease, and it is also expected to open the door for potential human applications.

Publications

Bonaventura J, Eldridge MAG, Hu F, Gomez JL, Sanchez-Soto M, Abramyan AM, Lam S, Boehm MA, Ruiz C, Farrell MR, Moreno A, Faress IMG, Andersen N, Lin JY, Moaddel R, Morris PJ, Shi L, Sibley DR, Mahler SV, Nabavi S, Pomper MG, Bonci A, Horti AG, Richmond BJ, Michaelides M. (2019). High-potency ligands for DREADD imaging and activation in rodents and monkeys. Nat Commun. Oct 11;10(1):4627.