Pharmacological MRI

Outline of the module
The imaging technique of choice for drug discovery and testing is positron-emission tomography (PET) as medical compound can be selectively labelled radioactive. However, MRI is more and more recognised as an alternative to PET as it does not involve radioactivity or ionising radiation. The use of MRI in the field of pharmacology is manifold: For neurological effects of drugs, cerebral blood flow – measured during resting using either intra-vascular contrast agents or arterial spin labelling – is a marker of the tissue state. In addition, functional MRI involving tasks has been more and more used to probe which brain areas changed their activity as compared to prior to drug intake. To assess metabolic effect of drugs, MR spectroscopy is an excellent tool as the concentration of various biochemical compounds (i.e. glutamate, NAA, ATP, etc.) can be non-invasively assessed. Although neurology is the major field of pharmacological MRI, these techniques can also be applied to other parts of the body. For example, blood flow can also be used during a cardiac stress paradigm.

In this module, the different MRI techniques specific to pharmacological MRI will be introduced. In addition, the most relevant pharmacological compounds studied with MRI and their effects on the body will be discussed. Finally, the use and limitations of animal models for drug development and testing is an essential part of the module and will be exemplified throughout each topic.


Learning objectives
At the end of the module, students will have expert knowledge about the following topics:
• 
Drug effects on metabolism, structure and function on various body parts
• Various phases for drug discovery and legal regulations for drug release
• MRI techniques assessing metabolism, structure and function (MRS, contrast agents, ASL, fMRI, anatomical MRI, diffusion MRI)
• Use and limitation of animal models for drug discovery and evaluation
• The most important drugs and experimental designs in the fields of neurology, oncology, and cardiology
• Other imaging technologies (i.e. PET) and multi-modal imaging for drug discovery
• Recognising drug effects from imaging data
• Data acquisition criteria and protocols and data analysis for pharmacological MRI


Content
The social costs and reduced individual life quality is increasing with ever aging populations in the industrialised world. Thus, drug discovery for remedying diseases and malfunctions is an important industry and will become even more important in the following years and decades. Beside genetic and invasive methods, imaging techniques are recognised to be essential for drug development and evaluation. Most prominently, positron-emission tomography (PET) is utilised in this context as drugs and targeted molecules can be radioactively labelled and their fate in the organism studied. However, MRI presents alternative as it is non-invasive and can be used for longitudinal studies without being limited by radiation exposure. MRI techniques to assess tissue states are continuously evolving and so the potential of MRI for pharmacology is expected to flourish in the near future.

The most relevant MRI techniques for pharmacology are: MR spectroscopy, functional MRI, anatomical MRI, blood flow methods. For example, the development of molecular imaging methods, such as MR spectroscopy (MRS), as allowed the further elucidation of multiple mutations and dysregulatory effects of pathways leading to oncogenises. It is of crucial importance to develop imaging methods to optimise the design, dosage and schedule of novel therapeutic and pharmacological approaches. An aberrant choline phospholipid metabolism and enhanced flux of glucose derivatives through glycolysis, which sustain the redirection of mitochondrial ATP to glucose phosphorylation, are two major hallmarks of cancer cells. MRS provides an excellent tool to monitor these processes and the effect of anticancer drugs as choline, phosphor, ATP and other metabolites are measured with this technique both in vivo and in vitro.

Another emerging field of pharmacological MRI is functional MRI in neurology. Functional neuroimaging has the potential to improve the decision-making process in the development of new drugs. It probes the neuronal activity following a behavioural task and the alteration of neuronal activity following a drug administration. With the high cost of failure of compounds in later stages of development, there is a need to establish, early in humans, reliable measures of drug activity and efficacy in the brain. FMRI is helping us to understand therapeutic mechanisms and can provide clinically relevant markers of disease responses to drugs. Thus, for the field of diseases in the central nervous system, fMRI can add additional information to evaluate drug effects on cognitive and sensory brain functions.

Measuring blood flow in the brain but also in other body parts (heart, kidney) using contrast agent techniques or arterial spin labelling provides information about the level of metabolism and blood vessel integrity. Thus, these methods provide valuable information for the effect and efficacy of drug actions.

To summarise, this module will provide an overview and introduction into established and emerging MRI techniques which are relevant for drug development and evaluation of drug effects. In addition, it will be shown why MRI is useful for specific pharmacological applications which cannot be provided by other techniques.

Overview of tasks and lectures
There will be 10 lectures of 2 hours distributed over 5 days.
• Introduction into drug chemistry and pharmacology
• MRI sequences and parameters for pharmacology
• MR spectroscopy in pharmacology
• Functional MRI in pharmacology
• Assessing cerebral blood flow in pharmacology I (contrast agent techniques)
• Assessing cerebral blood flow in pharmacology I (arterial spin labeling) 
• Neurology and pharmacological MRI
• Body imaging and pharmacological MRI
• Multi-modal imaging for drug discovery
• Summary and Introduction of post-module assignments 

Position within the programme
This module is most closely related to the clinical modules. Other modules will lay the foundation for pharmacological MRI. However, this is a stand-alone module which does not require much knowledge from other modules. This module will introduce scientist-practitioners to the complexities pharmacological MRI and its role in drug discovery and testing.


Teaching format

Structure
The module is a one week-long residential module consisting of 10 lectures of 2 hours. Each day, the students will in addition perform data acquisition on the MRI scanners to get acquainted to pharmacological protocols using MRI. In addition, students will learn to extract pharmacologically relevant information from various MRI modalities. Furthermore, the residential part is combined with a preparatory reading phase and post-module marked assignments.

Grading
Passing the module requires an 85% attendance to the lectures and practical sessions, and a satisfactory completion of the practical sessions and the module assignments The module assignments will be summarised by the students in a written form which will be evaluated by the module coordinator(s).


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