Prostanoid receptors are G protein-coupled receptors (GPCRs) whose roles vary widely across the body and in pathology. These receptors control prostanoids, active lipids from arachidonic acid. Prostanoids act on inflammation, pain, circulation, immune system and even cancer - so prostanoid receptors are ripe for the wringer.

Figure 1. Structural basis for ligand recognition and activation of the prostanoid receptors. (Li X, et al.; 2024)

Real-time imaging and tracking of these receptors opened up entirely new dimensions of how they work and could be treated. In this article, we discuss prostanoid receptor imaging as a drug development technology, what's in use, what's limited, and the newest technologies pushing this area forward.

Prostanoid Receptors and How They Work in Biology

They divide prostatenoid receptors into subtypes based on their molecular structure and signalling circuits. They are thromboxane (TP), prostacyclin (IP), prostaglandin (EP) and prostanoid D (DP) receptors. The tissue distributions and physiology of all subtypes differ.

• IP receptors: First a target for vasodilation and platelet deposition, IP receptors have now been discovered as targets in hypertension and cardiovascular disease.
• Thromboxane (TP) receptors: also cause vasoconstriction and platelet adhesion, thrombosis, atherosclerosis, and other inflammation.
• EP-receptors: These control inflammation, pain, immune system and even cancer pathophysiology. All of the subtypes (EP1, EP2, EP3 and EP4) have different functions, more function of EP2 and EP4 resides in inflammation and tumorigenesis.
• Prostanoid D (DP) receptors: The receptors are stimulated by immune control, inflammation and relaxation of smooth muscle.

And in other tissues and organs as well: brain, heart, kidneys, lungs, gut. They're involved in so many systems in health and disease, that they're familiar target. But the expression is cellular and even tissue-specific, and drug design has been hard.

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Prostanoid Receptors Imaging Analysis

The Impact of Imaging on Prostanoid Receptor Targeting

This is one of the biggest problems in designing drugs for prostanoid receptors - there isn't any good, non-invasive way to assess receptor expression and activity in the body. Image-based technologies that allow scientists to see and measure prostanoid receptor activity in living cells are lifesaving for studying receptor dynamics and how therapies work.

The presence of prostanoid receptors needs to be detected in particular for several reasons:

1. Monitor Expression and Localization of Prostanoid Receptors: Prostanoid receptor expression varies with tissue and disease type. In cancer, for example, some prostanoid receptors might be hyper-reactive in tumour tissue. By imaging, scientists can track the movement of these receptors in real time, and target treatments more precisely.
2. Track Drug Response: Being able to measure the interaction between drugs and prostanoid receptors in vivo is important to better tailor therapy. Imaging can indicate if a drug effectively reaches its target, if it crosses the blood-brain barrier (in the case of central nervous system targets), and if it generates the receptor-mediated effect intended.
3. Assessment of Therapeutic Action: Prostanoid receptor-targeted medications are frequently used to control specific receptor circuits in diseases such as inflammation, pain or cancer. Imaging lets scientists observe the behaviour of receptors in real-time while treating, monitoring how well the drug works.
4. Illustration of Pathologic Change: Imaging prostanoid receptors in diseased tissues may shed light on the dynamic shifts in receptor expression seen in cancer, cardiovascular disease and neurodegenerative disorders. It's using this knowledge to design medications to act directly on different receptor profiles.

Novel Imaging Approaches for Prostanoid Receptor Research

Recent imaging advances have made it easier than ever to study prostanoid receptors in living people. Different molecular and functional strategies are now being looked at to detect these receptors.

1. Positron Emission Tomography (PET) Imaging

PET is a non-invasive technique, which has been invaluable in molecular imaging of GPCRs, such as prostanoid receptors. By radiolabelled ligands for the prostanoid receptors, PET scans can track receptor binding and activity in real time in human patients. This strategy yields quantitative data about receptor density, binding affinity to ligand receptors and drug candidates' pharmacokinetics.

A major advantage of PET is that it is very sensitive and granular, so tiny changes in receptor expression can be detected in tissues. PET imaging in drug development could optimise dosing, track the outcome of therapy, and monitor how medications move across different tissues.

2. SPECT (Single Photon Emission Computed Tomography)

Like PET, SPECT scans receptor activity using radiolabelled substances in real time. SPECT usually lacks PET's resolution, but is cheaper and has more possibilities. Prostanoid receptors are being probed with their own radiotracers and SPECT allows for monitoring receptor occupancy and distribution in the clinic.

3. Bioluminescence and Fluorescence Imaging

In cell- or sub-cellular molecular imaging, bioluminescence and fluorescence-based techniques are standard. Both methods are done using reporter genes that light up when a target receptor is coupled. Fluorescent or luminescent molecules applied to prostanoid receptors let researchers track receptor activity in animal or cell cultures.

That's where fluorescence imaging is helpful: you can watch what happens to receptors in real time, at a high spatial resolution. Then there's the multiplex imaging that can let you see more than one kind of receptor or more than one therapeutic target all at once, in one system - which paints a much clearer picture of how drugs work on receptors.

4. Magnetic Resonance Imaging (MRI)

MRI could be a revolution in prostanoid receptor imaging with new contrast agents targeting prostanoid receptors. While MRI is more often applied to anatomical scans, with functional MRI (fMRI) one can monitor changes in tissue metabolism and receptor function, giving immediate feedback on therapeutic effects.

5. Optical Coherence Tomography (OCT)

OCT is an in-situ imaging procedure for eye diseases. But it's also had efficacy imaging prostanoid receptors in tissues like the retina. OCT can offer high-resolution images of receptor activity and localisation in tissues, and with the help of biomarkers, it could be used to study the effects of prostanoid receptors in conditions such as macular degeneration.

Challenges in Prostanoid Receptor Imaging

Even with these imaging breakthroughs, some of the difficulties for researchers working on prostanoid receptors remain.

1. Ligand Selection & Species: One of the biggest issues is to create ligands that are very specific and selective for the different prostanoid receptors. Since most prostanoid receptors are essentially identical in structure and signalling pathways, it's difficult to develop imaging agents that bind only to the target receptor and not any other receptors.
2. Expression of Different Tissues: Prostanoid receptors are expressed differently for different tissues, disease and even in response to the clock. It's imperative to create imaging techniques capable of reproducing these dynamic dynamics if we are to understand the full extent of receptor signalling during disease and treatment.
3. Sensitivity and Resolution: While the sensitivity and resolution of imaging techniques such as PET and fluorescence imaging have improved considerably, there's still much to learn about. Measurements of tiny modulations in receptor activity, or recording the way drugs act on low-level receptors in live models, require sophisticated instruments and computational computing.
4. Accessibility & Cost: High-tech imaging procedures, such as PET, SPECT, MRI, can be costly and demand specialized machines. This could hinder their adoption, especially in preclinical studies or crowded areas.

Conclusion

The prostanoid receptors are a rich and important group of drug targets. The in vivo imaging of these receptors has radically changed how we perceive their biology, and provided a path for targeted therapy. Images of the receptors — through PET and SPECT to fluorescence and bioluminescence — are now enabled by imaging techniques that had not been available before.

It's not over yet, but the ongoing work on highly targeted ligands, better imaging, and increased sensitivity will be the focus of the next wave of drug discovery for prostanoid receptors. Such advancements will not only make it easier to diagnose diseases caused by these receptors but enable more targeted and effective therapeutics. If the science behind prostanoid receptor imaging improves, it can revolutionise the way we approach drug development - more accurate, effective, and ultimately more successful at treating all manner of disease states.

1. Li X, et al.; Structural basis for ligand recognition and activation of the prostanoid receptors. Cell Rep. 2024, 43(3):113893.

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