Hydroxytryptamine receptors (or serotonin receptors) are members of a class of central G-protein coupled receptors (GPCRs) that modulate hundreds of physiological processes in the CNS and elsewhere. They are receptors for gut mood, cognition, perception and intestinal function. Depression, anxiety, schizophrenia and Parkinson's are all afflicted with serotonin-receptor inhibitors, and because they are central to so many neurological and psychiatric conditions.

Figure 1. Structure Ligands of 5-Hydroxytryptamine 2B Receptor. (Wang Q, et al.; 2021)

Imagery of HTRs was now an essential means of teaching about the action of the receptors in the living world. Modern imaging tools reveal distribution, expression and activity of serotonin receptors in real-time – which is incredibly useful for drug discovery and development. In this article, we describe how serotonin receptor imaging is currently used, what its applications in drug discovery look like, and their challenges and possibilities.

Overview of Hydroxytryptamine Receptors

There are seven families of serotonin receptors (5-HT1- to 5-HT7), plus many subtypes that signal in various ways. Such receptors appear everywhere in the brain (and subtypes even in the periphery). Among the most intensively researched serotonin receptors for drug discovery:

1. 5-HT1 Receptors: These receptors are mostly affecting the mood, anxiety, and pain states. They're called antidepressants and anxiolytics.

2. 5-HT2 Receptors: They're involved in mood disorder, psychosis and vasoconstriction. They become the victims of antipsychotics and antidepressants.

3. 5-HT3 Receptors: Required for nausea and vomiting, they're targets of antiemetic medication in chemotherapy.

4. 5-HT4 Receptors: The same receptors are also found in gut movements and are turned on during irritable bowel syndrome (IBS).

Serotonin receptors are also especially useful for drug development because of their physiological heterogeneity, especially for neuropsychiatric and gastrointestinal diseases.

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5-Hydroxytryptamine Receptors Imaging Analysis

Imaging Technologies for Hydroxytryptamine Receptors

Imaging of hydroxytryptamine receptors is part of the drug-development process and allows scientists to see and measure the distribution and activity of the receptors in vivo. It's possible to study HTRs with several imaging modalities, each of which is helpful and problematic.

1. Positron Emission Tomography (PET) Imaging

It is one of the most popular methods to study HTRs in vivo, and PET scans are very common. Through the ligands of serotonin receptors radiolabeled, PET can non-invasively observe receptor distribution and densities in living systems. Specific radiotracers for different subtypes of serotonin receptor allow scientists to trace the receptors' locations in the brain and their involvement in a variety of neurological disorders.

Advantages:

• High sensitivity and resolution.
• Measurement of binding and dispersion of receptors.
• Enables longitudinal testing in wild animals and people.

Challenges:

• Needs radiolabelled ligands for each receptor subtype developed.
• The method is not cheap and takes expensive instruments.

But, even in the face of these difficulties, PET scans have played an important part in the understanding of serotonin receptors in psychiatric conditions, allowing us to view receptor activity in states of disease and discover drug targets.

2. SPECT (Single Photon Emission Computed Tomography)

SPECT imaging is PET but using radionuclides emitting gamma instead of positrons. It's often a cheaper substitute for PET, but slightly less detailed and sensitive. Serotonin receptors have been analyzed using SPECT, and in the clinic for evaluating receptor binding in neuropsychiatric patients.

Advantages:

• More accessible than PET.
• Lower prices and quicker access to SPECT scanners in the clinic.

Challenges:

• Less spatial resolution than PET.
• Requires radiotracers (never readily available).

SPECT is especially useful for the clinical research that doesn't have PET available. It's a feasible means of monitoring receptor-based drug therapies in the clinic.

3. MRI and Functional MRI (fMRI) MRI: Magnetic resonance imaging (MRI) and Functional MRI.

MRI and fMRI are not just for imaging brain function, they are a must-have. Although MRI does not image receptors by itself, functional MRI (fMRI) can be combined with other methods to infer serotonin receptor function indirectly, by monitoring brain blood flow that reflects neuronal activity.

Advantages:

• Non-invasive and widely available.
• High spatial resolution for brain images.

Challenges:

• Not as good at directly measuring serotonin receptors.
• Offers no molecular-level information.

We've been studying the functional effects of serotonin receptor activation in various parts of the brain with fMRI. In depression, for example, 5-HT receptor activation can be associated with diminished brain function in certain parts of the brain.

4. Fluorescence Microscopy and Optical Imaging

We used fluorescence microscopy and optical imaging for in vitro and ex vivo analyses of the serotonin receptor. With fluorescently labelled ligands or genetically engineered receptor templates, they enable you to see where receptors are located at high resolution in tissue samples.

Advantages:

• High spatial resolution.
• Imaging the dynamic of receptors in real-time on the cell and subcellular level.

Challenges:

• Ex vivo/slim animal research only.
• Requires specialized fluorescence equipment.

Fluorescence imaging allows for insights into serotonin receptor expression in cells and animals in culture, and to determine how drug candidates affect receptor localisation and transport.

Hydroxytryptamine Receptor Imaging in Drug Design

Receptor imaging has changed the drug development landscape – especially in the field of neuropsychiatric conditions. Serotonin receptors are central to many neurological processes, and the role they play in disease is important for targeted therapy. Here are some of the main therapeutic uses of HTR imaging:

1. Target Identification and Validation

Analyses of serotonin receptors can identify which receptor subtypes are responsible for specific disorders and then tailor drugs to target these receptors. We use PET imaging to monitor changes in 5-HT1A and 5-HT2A receptor binding in depression and schizophrenia, for example. By mapping receptor density and activity, imaging data allows us to confirm receptor targets so that drugs can be designed for the most promising ones.

2. Pharmacokinetic and Pharmacodynamic Studies

Serotonin receptor-targeted treatments have pharmacokinetics (how a drug goes down, through its system and out the door) and pharmacodynamics (how a drug acts on the body), which can be measured by imaging. It's also recorded with PET and SPECT scans, which determine in vivo how drug candidates attach to serotonin receptors. This means the drugs can be used at the optimal dosages, at the optimal efficacy, and at the least side-effect because the drug binds to the target receptor, and not against it.

3. Patient Stratification and Personalized Medicine

Imaging serotonin receptors might help to categorize patients, so that we know which ones have a certain receptor change and are candidates for certain therapies. Patients with low 5-HT2A receptor density, for instance, might be less responsive to antipsychotic drugs. Personalized therapy may be directed by objective evaluation of receptor status in individual patients using receptor imaging.

4. Monitoring Treatment Response

Through a change in receptor binding over time, clinicians can observe how patients are responding to drug treatment. This can be useful especially in chronic clinical trials or in conditions like depression or anxiety, where treatment response is variable.

5. Verification of Drug Safety and Adverse Effects

Imaging serotonin receptor interaction can also help assess the safety of new drugs. We can detect the effects of a drug on receptor density and activity, so that side effects like off-target binding can be identified very early in development. This saves drugs from having unintended side effects on other biological systems.

Challenges and Future Directions

Though serotonin receptor imaging is helping to drive drug development, there are still a few issues. It is also a problem to find high-affinity ligands for each serotonin receptor subtype because the existing tracers may not always be selectively binding or sensitivity-improving. Then there is the difficulty and cost of imaging technologies such as PET and SPECT, especially in the very early stages of drug discovery.

But future imaging technology, including more selective radiolabelled tracers and molecular imaging resolution, promises to fix all of this. And, when stacked with other technologies (like genetic and proteomic profiling), imaging might offer a richer view into receptor biology and the drug action.

Conclusion

Hydroxytryptamine receptor imaging is now the gold standard in the pharmaceutical development, especially for neuropsychiatric disorders. Imaging technology enables scientists to design better and more specific treatments by giving real-time access to receptor distribution, expression and activity. It will be difficult to design imaging agents and refine imaging methods for clinical application, but the role of serotonin receptor imaging in drug development has tremendous promise for personalised medicine and for improving treatment for patients with various neurological and psychiatric conditions.

1. Wang Q, et al.; Structure, Function, and Pharmaceutical Ligands of 5-Hydroxytryptamine 2B Receptor. Pharmaceuticals (Basel). 2021, 14(2):76.

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