In an attempt to search for and cure multisystemic neurological and psychiatric disease, scientists have turned to brain neurotransmitters. And the most powerful of those, N-methyl-D-aspartate (NMDA) receptors, are those governing synaptic plasticity, memory and neurodevelopment. Alzheimer's, schizophrenia, depression and pain are induced by NMDA receptor deletion. And that has fuelled a lot of work to create medicines that bind to these receptors. Some additional information is being given to us here from new imaging approaches that enable us to observe NMDA receptors in the living brain, and the process of drug development can continue.

Understanding NMDA Receptors

NMDA receptors are the basal receptors of glutamate receptors, the central nervous system's chief excitatory neurotransmitter receptors. They're rare receptors because two molecules need to trigger them: glutamate and either glycine or D-serine. And NMDA receptors are voltage-gated, so the ion channel opens only after the postsynaptic neuron has depolarised enough. And that double activation requirement is what gives them synaptic plasticity and memory.

Figure 1. NMDAR subunit composition, structure, and pharmacology. (Zhang W, et al.; 2022)

NMDA receptors are complexes of different subunits: GluN1, GluN2 (A-D) and GluN3 (A-B). The individual chemistry of these subunits can affect where the receptor resides, what pharmacology and how it operates at the synapses. Modifications of the NMDA receptor are known to be involved in several neurological and psychiatric disorders and make good drug targets.

Imaging and NMDA Receptor Study: What You Need to Know?

Image analysis that lets scientists see NMDA receptors in the brain is changing the way we understand these proteins. Such methods not only can help explain how NMDA receptors normally work but also how their dysregulation leads to disease. Imaging is also crucial for the creation and validation of NMDA receptor drugs.

1. Positron Emission Tomography (PET)

The imaging of NMDA receptors in the living brain is best carried out by Positron Emission Tomography (PET). PET uses radiolabeled ligands that are reacted directly to NMDA receptors so that their spatial and density can be determined live. Such a technique can tell us a great deal about receptor vulnerability, binder preference and the effects of treatments.

And in the latest PET scans, more potent radioligands have hit NMDA receptors. [18F]GE-179, for instance, one promising PET radioligand, blocks the PCP site of the NMDA receptor. We have already used this ligand to map the localisation of NMDA receptors in healthy individuals and neurological patients, to better characterise the mechanisms of diseases such as schizophrenia and Alzheimer's. And let's compare PET occupancy of NMDA receptor-binding ligands by NMDA receptor-binding ligands, too. This is important when you are calculating the dosage to take in a clinical trial, because you can estimate how much of a drug you need to achieve a therapeutic result without overkill.

2. Magnetic Resonance Imaging (MRI)

PET is super-specific and sensitive, while MRI is spatially precise and doesn't emit ionising radiation. We were able to study NMDA receptors because they are more easily investigated using the newer methods for MRI – functional MRI (fMRI) and magnetic resonance spectroscopy (MRS).

And this may have something to do with neurons, too – fMRI detects brain activity by tracking blood flow. fMRI doesn't photograph NMDA receptors, but it can be used to explore functional consequences of NMDA receptor modulation. We might, for example, inject NMDA receptor agonists or antagonists, and then see what happens to brain activity, which was direct proof of receptor function and spread.

MRS, however, can estimate the amount of some brain metabolites that depend on the firing of the NMDA receptor. MRS can record fluctuations in glutamate and its co-factors, for example, and tell us something about the metabolisms that govern the functions and antagonistic effects of NMDA receptors.

3. Single-Photon Emission Computed Tomography (SPECT)

One nuclear scan, called single-photon emission computed tomography (SPECT) – which, like PET, bombards radioligands onto NMDA receptors – also has a nuclear scan. SPECT tends to be not quite as spatially precise as PET but is less expensive and accessible. NMDA receptor distribution and density have been measured by SPECT imaging in a number of neurological disorders. For example, radiolabelled ligands binding to the NMDA receptor complex have been explored for its function in epilepsy, and we now know how the density of NMDA receptors shifts with seizure activity.

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NMDA Receptors Imaging Analysis

Applications in Drug Development

NMDA receptor imaging is not only transforming our view of the brain but is also central to the research on new treatments. In offering a non-invasive approach to the brain, imaging helps scientists test potential drugs against NMDA receptors.

1. Target Identification and Validation

Imaging is applied early in drug development to characterise and confirm NMDA receptors as targets. It is possible to look at the distribution and density of NMDA receptors in disease states to see whether they would be suitable targets for intervention. NMDA receptor density in specific brain regions, for instance, might indicate their contribution to the pathophysiology of a disease, which is reason enough to engineer NMDA receptor modulators.

2. Preclinical Evaluation

Preclinical research employs imaging also widely in testing whether new drugs will interfere with NMDA receptor function. The experimental development of therapeutics tends to be based on animal models of neurological and psychiatric disorders. The bind-rate of radiolabelled drugs to NMDA receptors can be quantified using PET and SPECT imaging to ascertain pharmacokinetic and pharmacodynamic activity.

Imaging can also identify off-target and toxicological profiles, assisting in fine tuning potential drugs before going to the clinical stage. This is the last resort to make sure that only the most promising and safe compounds make it into human trials.

3. Clinical Trials

NMDA receptor imaging gives us crucial drug-effect and safety information in clinical trials. Receptor occupancy in patients can be measured using PET/SPECT scans to figure out the best dosing schedule. These are the information needed to keep the therapeutic benefit from the side-effects.

The brain activity is also monitored by functional imaging, like fMRI, with NMDA receptor-targeting agents. fMRI changes to brain activity can give an early warning that a drug is potentially curative, before the clinical symptoms are even better. This speeds up drug development through early proof-of-concept data.

4. Biomarker Development

Photosynthesis of NMDA receptors helps in creating biomarkers for neurological and psychiatric disorders too. Biomarkers are objective measures of disease state or drug response, and are extremely useful in clinical trials for stratification and treatment response.

We might use for instance an NMDA receptor densities or activity alteration in PET imaging to serve as biomarkers for schizophrenia or Alzheimer's. Such biomarkers can be used to determine which patients will be most benefitted by NMDA receptor-targeted medications, making clinical trials more accurate and outcomes more likely.

Challenges and Future Directions

Imaging NMDA receptors is promising, but there are still a number of challenges. A big hurdle is the ability to make highly selective and sensitive radioligands that discriminate among different subtypes of NMDA receptors. Since NMDA receptor subunits are all so different, ligands that bind to subunit groups would give us more accurate information on receptor activity and drug effects.

A second problem is that we want multimodal imaging methods that bring together all the good aspects of multiple methods. For instance, PET-MRI fusion can offer both molecular and anatomical data, so that it has a broader picture of how NMDA receptor's function and fail.

Our studies of NMDA receptors will be improved with imaging technologies, like the new high-resolution PET scanners and MRI sequences. And the interrogation of imaging data with other modalities like electrophysiology and genomics will allow us to understand NMDA receptor-mediated disorders from a more holistic perspective and to design more promising treatments.

Conclusion

Imaging NMDA receptors is changing neuropharmacology, by unlocking insights about their functions in health and illness like never before. By PET, MRI and SPECT, scientists can see how NMDA receptors operate in the human brain, which means we can develop more precisely targeted drugs.

1. Zhang W, et al.; Targeting NMDA receptors in neuropsychiatric disorders by drug screening on human neurons derived from pluripotent stem cells. Transl Psychiatry. 2022, 12(1):243.

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