· Review of PET and pharmacologic MRI (phMRI) studies to study in vivo drug delivery

· State-of-the-art imaging tools and methods to study drug delivery and function, with an emphasis on combined PET/fMRI and imaging drug delivery to the brain

· Overview of models that integrate drug function, occupancy and yield quantitative biomarkers

· Future directions

· Definition of PET, fMRI, phMRI in the context of imaging drug delivery

· Understand concepts of pharmacokinetics and pharmacodynamics and what parameters we can assess using PET imaging or pharmacologic MRI

· Appreciate how combined PET and fMRI measures can advance our knowledge on drug delivery and in vivo drug properties, and allows us to classify drugs in vivo

· Learn how quantitative modeling (including pharmacokinetic modeling) can consolidate findings, support a mechanistic hypothesis or develop new biomarkers

The specific binding of a drug to its target in tissue can be directly measured by PET (and autoradiography). With dynamic acquisitions, the timecourse of radiotracer binding to the tissue is observed and in vivo drug binding properties can then be quantified using measures of binding potential (BP), which represents the product of B_max (=total number of receptors) and the affinity 1/K_D of the drug to its target (K_D = dissociation constant). This quantification requires the analysis of dynamic time activity curves (TAC) using kinetic models that need to be validated according to which radiotracer is used. With a good radiotracer, meaning it is specific to its target and has favorable kinetics, PET imaging yields highly specific information about drug binding to its target. However, PET is limited by its relatively low temporal resolution and care must be taken not to interpret drug binding as a direct measure of efficacy.

Drug delivery can also be assessed indirectly by imaging with fMRI during a pharmacologic challenge, which is also referred to as pharmacologic MRI (phMRI). Unlike in conventional task-based fMRI, where it is challenging to disentangle specific molecular components to the hemodynamic response, phMRI can employ drugs that are known to target specific receptor classes and is thus able to interpret the distribution and duration of fMRI signal changes due to a pharmacological challenge in light of receptor distributions and the pharmacokinetic profile of the drug. Due to the fact that phMRI is a downstream measure of receptor occupancy, it provides complementary information to PET imaging: (i) It is able to image functional effects of drugs and (ii) it can do so at a higher temporal resolution. The ability to acquire PET and fMRI simultaneously, allows us to combine the specificity of PET with the dynamics and downstream effects of fMRI.

With simultaneous PET/fMRI, both occupancy and functional effects of a drug can be determined and used to predict its potency in vivo. There are several areas that open up to exploration with these tools: We can learn about neurovascular coupling to specific receptor occupancy, and compare dynamic timecourses that are measured at the same time without any ambiguities (e.g. changes in physiology) that come from sequential studies. Timecourses of occupancy and fMRI signal have been observed to be matched in certain cases (antagonists), where a classical receptor occupancy model is valid. However, with other ligands (agonists), timecourses can diverge, which allows us to image mechanisms in which drug binding does not equate to function, such as receptor desensitization or internalization. Specifically, we have shown that at the D2/D3 dopamine system, we can classify agonists and antagonists according to their fMRI response, suggesting that we can characterize drug function and efficacy to inform about the in vivo potency of a drug. Models of neurovascular coupling to occupancy can shed light on the mechanism behind the imaging signals and enable us to develop novel biomarkers to assess therapeutic responses. Being able to assess such quantities is going to be important to understand in vivo drug efficacy, changes in affinity and other drug parameters, all of which are crucial to assess therapeutic outcome and varying disease states in an era that is increasingly targeting personalized medicine.