Introduction

Finding the drug targets and confirming them is the art of drug discovery in the therapy field. Most prominent among these are nuclear receptors (NRs), proteins that tell genes what small molecules are doing, be it a hormone, metabolite or drug. They're implicated in every physiologic function, from metabolism and immune function to cell growth. Due to their role in disease process, nuclear receptors have been selected for therapy in a vast array of therapeutic areas – cancer, metabolic diseases, cardiovascular disease, autoimmune diseases, just to name a few. Even therapeutic ones are difficult to develop though: specificity of target and better knowledge of how NRs operate in the body are all barriers to making drugs that target NRs.

Figure 1. Nuclear receptor transcriptional activation. (Avior Y, et al.; 2013)

Then we could look at nuclear receptors in living creatures thanks to modern imaging methods. Nuclear receptors imaging analysis can be used to monitor the activity of receptors in real time, candidate drug movement and find out molecular mechanisms of how drugs interact with receptors. I'll go over the role of the nuclear receptor for drug discovery, and how imaging can speed up the search for new drugs that depend on these essential proteins in this post.

What are Nuclear Receptors?

Nuclear receptors are a multifactorial set of transcription factors that are induced by ligands including hormones (oestrogen, thyroid hormones), vitamins (vitamin D) and signaling molecules. Such receptors could even attach themselves to DNA in the cell's nucleus and switch certain metabolism, growth and immunity genes on or off.

There are two types of nuclear receptors: cellular and nucleotide.

1. Receptors of Steroid Hormones – These receptors are activated by steroid hormones like glucocorticoids, oestrogens and androgens. Estrogen receptor (ER), androgen receptor (AR) and glucocorticoid receptor (GR).
2. Molecules That Interact with Nuclear Metabolic and Immune Modulators–Molecular messengers such as retinoic acid, thyroid hormone and bile acids activate these receptors. These are retinoic acid receptor (RAR), peroxisome proliferator-activated receptors (PPARs) and liver X receptors (LXRs).

The nuclear receptor is induced and, depending on which receptor is induced and which ligand is induced, gene expression is stimulated or suppressed. And nuclear receptors have been hot drug targets too, given their ubiquitousness as cause-and-effect proxies of illness.

Challenges in Targeting Nuclear Receptors

Drugs do not work in isolation on nuclear receptors. Although NRs provide numerous therapeutic possibilities, they can be as positive or negative, given their pleiotropic nature (multiplicity-based regulation of many genes). That is why it is important to know the exact function of each receptor in relation to particular diseases. What's more, the construction of selective agonists or antagonists for single nuclear receptors that are not cross-reactive with other receptors is a difficult problem.

Candidates for drug must be as specific as possible, as well as as low as possible toxic. The fluidity of nuclear receptor activation, and the multi-molecular web that they interact with, make finding effective, safe drugs even harder. And this is where imaging technologies come in.

Nuclear Receptor Drug Design

There are a few main advantages of imaging to drug development for targets such as nuclear receptors. Through imaging, scientists can learn more about how nuclear receptors are distributed, localised and activated within living cells. It's with this live monitoring that we can better design, optimize and monitor therapeutic effects.

1. Imaging of Nuclear Receptor Expression

But a difficult part of the work on nuclear receptors is to figure out their expression in various tissues and organs. Fluorescence imaging, positron emission tomography (PET) and single-photon emission computed tomography (SPECT) are non-invasive imaging techniques that can track receptor expression and distribution. Tag a ligand or antibody that targets a nuclear receptor of interest, and you can see exactly where and when a receptor is activated in real time. It determines which tissues are best for drug delivery and tracks the pharmacokinetics of drug candidates.

2. Receptor Binding and Ligand Interaction

If you want to develop a drug, you have to know how a drug behaves toward the target. Images like PET or SPECT radiolabeled to monitor the drug's adhesion to its target nuclear receptor. Such techniques can show the receptor-ligand interactions live, and can reveal important information about drug binding, preference and distribution. Moreover, fluorescent probes and bioluminescence can be used to understand the binding profiles of drug candidates in living systems, which can aid scientists in determining when and for how long receptors are active.

3. Real-Time Monitoring of Receptor Activation

Entrainment of nuclear receptors requires multi-step signalling networks that ultimately result in gene expression changes. The imaging is done in real-time so researchers can observe receptor activation and its consequences. This matters particularly for assessing the role of nuclear receptor activation in the body, and how drugs modulate it. By way of example, fluorescent reporters coupled to gene promoters could track how many particular nuclear receptors get activated and look for changes in gene expression under the influence of a drug. This can help you to better know how the drug works and how it does.

4. Imagery of Drug Spread and Activity Imaging

Imagery is also used to monitor the movement and activity of molecules against nuclear receptors. By using PET, SPECT and magnetic resonance imaging (MRI), one can track how a drug candidate spreads through the body and whether it gets to the target tissues. This enables drug delivery systems to be optimised, with researchers able to determine which formulations work best for delivery specifically to nuclear receptor-containing tissues, like the liver or brain.

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Nuclear Receptors Imaging Analysis

Application of Nuclear Receptor Imaging in Drug Design

The use of nuclear receptor imaging in drug design has been successful across several therapeutic lines:

1. Cancer Therapy

A large number of cancers are motivated by abnormally modulated nuclear receptors, including estrogen receptors in breast cancer and androgen receptors in prostate cancer. Such receptor imaging may identify patients who are most vulnerable to receptor therapy. What's more, in real time imaging of receptor binding can reveal how drug efficacy is shifting and guide clinicians in modifying therapy. By way of illustration, we can measure the amount of time an anti-estrogen drug adheres to oestrogen receptors in breast cancer patients via PET images.

2. Metabolic Disorders

Inflammatory nuclear receptors, including peroxisome proliferator-activated receptors (PPARs) and liver X receptors (LXRs), control lipid metabolism and glucose metabolism. In the context of diabetes, obesity and cardiovascular disease, we are making medicines for these receptors. Imaging tools can help scientists detect receptor expression in target tissues, track drug candidate distribution and measure treatment effects metabolically. This can help to make drug development much faster and better for patients.

3. Autoimmune Diseases and Inflammation

There are also nuclear receptors involved in modifying immune responses, and some are involved in inflammatory activity. For instance, GR are at the heart of the actions of corticosteroids that are prescribed for autoimmune disorders such as rheumatoid arthritis. Imaging can let scientists see immune cells and tissues in the path of treatment for glucocorticoids to better understand their efficacy and search for novel therapies.

Future Directions and Conclusion

As nuclear receptor imaging becomes more refined, imaging technology should enable even finer and more ebb-and-flow measurements of nuclear receptor biology. High-resolution imaging, new radiotracers and molecular reporters in real time will help us still further decipher the role of nuclear receptors and drugs.

Nuclear receptors are potential – and problem – in the drug development world. Now that we can visualise receptor expression, ligand binding, activation and post-hoc effects in organisms, imaging analysis could be used to revolutionise the discovery and development of nuclear receptor-targeted treatments. As they offer better knowledge of drug candidates' pharmacokinetics and pharmacodynamics, imaging tools will make future drugs that target nuclear receptors safer, more efficacious, and more specific to patients.

1. Avior Y, et al.; Flavonoids as dietary regulators of nuclear receptor activity. Food Funct. 2013, 4(6):831-44.

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