Unlocking the Multifaceted Role of CB<sub>1</sub>R in the Endocannabinoid System with Labeled Chemical Probes

The endocannabinoid system is a key homeostatic regulator that influences multiple physiological processes across nervous, immune, and metabolic systems in humans. Despite decades of pharmaceutical research, only a few clinically relevant outcomes have been achieved. This limited success is partly attributed to the exceptional complexity and signaling promiscuity of endogenous cannabinoids acting through the cannabinoid receptor types 1 and 2. Here, we review the development, application, and potential of labeled small molecules as tool compounds, with a specific focus on cannabinoid receptor type 1 research, the most abundant G-proteincoupled receptor in the mammalian brain. Technical and scientific advancements in spectroscopy have enabled the application of radionuclide and fluorescent probes with improved spatial and temporal resolution. In parallel, interdisciplinary collaboration, cross-validation, and rigorous pharmacological characterization established highquality standards for the development of labeled probes. Together, these developments open up new avenues for probe-based investigations of cannabinoid receptor type 1 biology and molecular pharmacology.