In recent decades, the drugs landscape has changed dramatically, with more aggressive, targeted treatments still being searched for. These new targets were chemokine receptors, a group that is fundamental to inflammation, immune response and cancer. We talk about the new application of chemokine receptors imaging in drug discovery, its applications, technologies, challenges and future in this article.

Information about the Chemokine Receptors and Pathology

Chemokine receptors: a class of GPCRs that regulates the movement of immune cells based on messenger molecules called chemokines. These receptors direct the movement of immune cells, inflammation, wound healing and even cancer. They're mostly present on leukocytes (white blood cells), endothelial cells and other tissues, where they redirect immune cells to sites of infection or injury.

Chemokine receptors are implicated in a whole host of cancer biology, from cell growth at an early stage to spread to distant organs. CXCR4 receptor, for example, is investigated in large quantities in breast cancer, leukemia and lymphoma, facilitating tumour cells' movements to distant sites. CCR5 and CXCR3 were also linked to cancers and inflammatory conditions such as multiple sclerosis and rheumatoid arthritis.

Figure 1. Interplay between oncoviruses and the chemokine system. (Schlecht-Louf G, et al.; 2022)

This is such a generic biological role for chemokine receptors that it's easy to target as a drug candidate. But to get them to do something, there are certain methods of imaging receptor expression and determining how it's really working in practice. That's where chemokine receptor imaging comes in.

Chemokine Receptors Imaging in Drug Design?

Chemokine receptor imaging lets scientists map and count the amount of these receptors that they are present in, express and activate in real-time – crucial to understanding disease development and therapeutic responses. By making it possible to better identify the way receptors behave both in the normal and disease states, chemokine receptor imaging allows for target validation, biomarker identification and drug testing.

Here are the top benefits of imaging chemokine receptors in drug discovery:

• Live Tracking: Imaging can track in real time chemokine receptor activity and expression in organisms. This capacity to monitor changing pharmacokinetic and pharmacodynamic states of receptors is important for drug candidates.
• Non-invasive Diagnostic: Imaging, unlike biopsy, provides a non-invasive way to evaluate receptor activity in tissue, without having to repeat surgery. This is especially useful for longitudinal studies where repeated tissue collections are impossible.
• Knowledge of Drug Mechanisms: Chemokine receptor imaging can be used to reveal the exact nature of the interaction between candidate drugs and molecular targets. It's direct for testing the effect of a drug on receptor expression or activity, which helps you identify promising drug candidates early in the drug discovery process.

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Chemokine Receptors Imaging Analysis

Technologies for Chemokine Receptors Imaging

A variety of imaging methods exist to show chemokine receptors in vivo. These methods use specific ligands or probes that bind to target receptors and then are traced very sensitively. Common imaging techniques include:

1. Positron Emission Tomography (PET)

PET is a powerful imaging method using radioactive tracer material to study molecular activity in living things. When it comes to chemokine receptors, PET tracers can be made to stick to the receptor of interest. Radiolabelled small molecules or peptides that bind to CXCR4 have been created, for instance, to check for receptor activity in cancer and other diseases. PET imaging can be used to obtain spatially and quantitatively detailed information about receptor dynamics both in the laboratory and preclinical trials.

2. Single-Photon Emission Computed Tomography (SPECT)

SPECT is PET-like with gamma-emitting isotopes as opposed to positron emitters. This is the standard way of imaging chemokine receptors since it is so sensitive and cheaper than PET. We have already used SPECT imaging to visualize CCR5 and CXCR4 receptors in disease models such as cancer and cardiovascular disease.

3. Magnetic Resonance Imaging (MRI)

MRI is a general imaging modality that can be applied for both anatomy and function. To image chemokine receptors, MRI can be augmented with superparamagnetic nanoparticles or other receptor-targeting contrast agents. This is possible with MRI because it can provide high-resolution images and can visualize deep tissue, and it's also a good method to track the effect of drugs on receptor expression in the brain or liver.

4. Optical Imaging

The visualisation of chemokine receptors via optical imaging methods such as fluorescence and bioluminescence imaging can be done inexpensively, in large-scale. Those are typically fluorescent or luminescent probes binding to chemokine receptors. Although optical imaging can only be applied to skin or small animal models, it's time-domain data for drug discovery and screening at a early stage.

5. FACS, Flow Cytometry: Fluorescence-Activated Cell Sorting (FACS) and Flow Cytometry.

For receptor expression on isolated cells, this is often quantified by FACS and flow cytometry. You can use these to monitor chemokine receptor expression on immune cells under various therapeutics. FACS with fluorescently labeled antibodies to individual chemokine receptors is also capable of measuring receptor activity on a single-cell basis and can aid the search for disease-associated biomarkers.

Uses of Chemokine Receptor Imaging for Drug Design

1. Target Identification and Validation

Chemokine receptors are at the centre of a lot of diseases, and therefore very promising targets for drug discovery. Images let scientists determine whether receptors play a role in the pathology and whether they are expressed in other models. If chemokine receptor imaging confirms that a receptor is upregulated or altered during disease states, it will be possible to determine whether treatment by targeting this receptor would help.

2. Therapeutic Monitoring

It's one of the great tribulations of drug discovery: assessing if the drug is hitting the target, is it doing what they're trying to do. Chemokine receptor imaging can also measure drug distribution and action in real-time. An inhibitor of a chemokine receptor, for example, can be evaluated for the inhibition of receptor expression or function in vivo. Image analysis could also track the temporal dynamics of receptor action so that scientists can optimise dosing schedules.

3. Predicting Treatment Response

Imaging chemokine receptors can help us to predict prognosis by showing how receptor expression changes with treatment. This helps scientists determine which patients will benefit from what treatments. For instance, if a cancer drug blocks CXCR4, imaging could tell you if the receptor is sufficiently overexpressed in the tumour to begin therapy, thereby determining individualised treatment.

4. Biomarker Discovery

We can look for new biomarkers of disease or response using chemokine receptor imaging. For instance, changes in chemokine receptor expression during therapy can be predictors of treatment efficacy or failure. These biomarkers can then be used to pick the right patients for clinical trials or to follow treatment performance over time.

5. Drug Discovery and Screening

Chemokine receptor imaging is also used for drug candidate screening. Imaging probes attached to chemokine receptors allow scientists to quickly scan libraries of small molecules, biologics or monoclonal antibodies for molecules that bind and regulate receptor function. This can be a big-time saver in drug discovery, especially when teamed with high-throughput screening technologies.

Challenges and Future Directions

Chemokine receptor imaging is a huge opportunity in drug discovery, but there are a few problems. One of the biggest challenges is the design of targeted, high-affinity imaging probes that can bind to chemokine receptors consistently in the living environment. Then there's a question of whether imaging data accurately capture the actual receptor activity (instead of just binding, off-target effects).

And there are also the technical hurdles with studying deep tissues, such as non-invasive techniques such as PET or MRI. While we have found ways to increase resolution with contrast agents and imaging, it's still difficult to get close enough to show low receptor expression.

Future directions for AI and machine learning can be applied to chemokine receptor imaging – particularly to analysis of big data from imaging systems. AI could optimise the read of an image, spot changes in receptor expression, and anticipate the way certain drugs will react to their targets.

Conclusion

Chemokine receptor imaging is revolutionizing drug development by providing an effective method for determining targets, evaluating treatment and customizing medicine. The further development of imaging technology with drug discovery workflows, the better we can target chemokine receptor therapies. With its ability to transform how we treat diseases from cancer to autoimmune disease, chemokine receptor imaging will be at the centre of the next wave of precision medicine.

1. Schlecht-Louf G, et al.; The Chemokine System in Oncogenic Pathways Driven by Viruses: Perspectives for Cancer Immunotherapy. Cancers (Basel). 2022, 14(3):848.

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