More than 400 membrane transporters have been identified in humans, to date. Many of these transporters affect in vivo drug distribution, therapeutic efficacy and adverse drug reactions. Moreover, clinical pharmacokinetic drug-drug interactions have suggested that transporters often co-operate with drug metabolising enzymes to influence drug absorption and elimination. Organic anion transporting polypeptides (OATP's) and organic ion transporters (OAT's) are two of the transporter classes that are known to influence drug distribution and/or side-effects (Giacomini et al. 2010). An important aim of preclinical drug evaluation is to identify potential safety issues that need to be studied in the clinic. There are several methods already available to study transporters in cells e.g. membrane- and cell-based assay systems, intact organ/in vivo models etc. However, there is currently no significant capability to use molecular imaging to study OATP's and OAT's, as useful tracers have not yet been developed. A Positron Emission Tomography (PET) tracer would be an important in vivo research tool, as it would make it possible to perform non-invasive studies to qualitatively and quantitatively elucidate whether particular receptors/sub-classes of receptor are present in the tissue of interest. Moreover, a PET tracer could be used as a pharmacokinetic or pharmacodynamic endpoint marker in animal or human studies. This could provide important information on the effects of transporter inhibition on drug pharmacokinetics, or the binding affinity of an experimental transporter inhibitor.
The main goal of this PhD project is to develop a radiotracer for PET Imaging studies to study membrane transporters in vivo.
Project Team: Professor Matteo Zanda
Funding: SINAPSE (AstraZeneca)
Giacomini et al. Nature Reviews Drug Discovery, vol. 9, no. 3, pp. 215-236.