G protein coupled receptors (GPCRs) play an important role in cell signal transduction and are important targets for many drugs. Cannabinoid type I receptor (CB1R) is one of the most highly expressed GPCRs in the central nervous system, mainly expressed in the brain tissue, and mostly located in the presynaptic membrane of nerve endings to regulate the release of neurotransmitters. CB1R is involved in a wide range of biological functions, including the regulation of learning cognition, energy balance, pain, addiction, neuroprotection and other physiological and pathological processes. Much can be learned about the role of the receptor by determining its localization. Although techniques for mapping CB1 receptor in the nervous system have seen substantial advances in recent years, such as quantitative autoradiography, in situ hybridization, and immunocytochemistry. However, these techniques can only observe a small portion of tissues and are invasive, and cannot directly measure large-volume CB1 receptors dynamics in intact tissues in vivo. Several in vivo neuroimaging techniques, such as positron emission tomography (PET), single photon emission computed tomography (SPECT), and magnetic resonance imaging (MRI), allow non-invasive imaging within living brain. These techniques are well developed; however, in vivo imaging of cannabinoid systems is in a very preliminary state. There is a growing need for measurement methods that can record comprehensive information about the living brains. MRI is a special tool in this regard, which can offer an attractivecombination of minimal invasiveness, ability to monitor large fields of view, and relatively high resolution for studies(~10 μm in high magnetic field scanners). Compared to microscopy and optical methods, MRI can image the entire brain and is noninvasive; Compared to PET, spatial and temporal resolution is much better and exist no radioactivity. Its technique and applications are somewhat different from those of both autoradiography and other in vivo imaging strategies such as PET and SPECT. Rather than detection of radioactivity, MRI involves detection of spin properties of hydrogen nuclei, “protons,” which depend on their physical-chemical environments. The development of these imaging methods for cannabinoid receptors may help our understanding of mental diseases, and produce useful leads for the development of drug therapies for these illnesses as well as helping us understand mechanisms of addiction. A better understanding of the cannabinoid receptor system might produce more useful therapeutic drugs with less abuse potentia. Based on these, we still need to develop an in vivo neuroimaging ligand suitable for the cannabinoid system, and here we use Rimonabant, an antagonist that selectively acts on the CB1R. By chemically conjugating Rimonabant to the gadolinium chelate, we sought to create a novel paramagnetic probe with suitable lipophilicity, high sensitivity and affinity for CB1R. In order to achieve excellent sensitivity at lower concentrations, the initial molecular design for the targeted probe was to conjugate rimonabant to Gd-DOTA in a ratio of 1:3. However, this kind of probe showed relatively weak binding activity with CB1R. Next we continue to modify the structure of the probe. By synthesizing several probes with different structures, mainly change the connection part between contrast agent Gd-DOTA and Rimonabant, we can determine which structure is more suitable for the following imaging experiments. Introduction of the probe into mouse brains furthermore permits MRI-based measurement. The specificity of Rimonabant binding to CB1R and the contrast generated by gadolinium chelate in MRI were used to investigate the distribution of CB1R in real time in vivo.

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References

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