Objectives

This workpackage aims at developing new radiotracers for in-vivo imaging of cerebral multidrug transporters with PET and SPET. These radiotracers will be based on known transporter inhibitors and substrates. They will be useful tools to study in-vivo the distribution and function of multidrug transporters in animals (WP02 and 04) and humans (WP04 to 07).

 

Workpackage description

Background
Currently available radiotracers for the imaging of P-glycoprotein (P-gp) are based on substrates, such as verapamil and loperamide. By virtue of their high transporter affinity these compounds possess very low brain uptake in-vivo. A promising alternative to the use of substrates is the use of radiolabelled inhibitors that bind selectively and with nanomolar affinity to multidrug transporters without being transported. Such radiotracers will give a signal increase rather than a reduction in brain regions that over-express multidrug transporters. Another strategy is the use of weak transporter substrates that are able to penetrate the blood-brain barrier. The combined use of radiolabelled transporter inhibitors with substrates will be very rich in information, as inhibitors will allow assessment of transporter distribution and substrates will allow assessment of transporter function.

Participating consortium partners

VUmc, ARC, TIHO, UniLiv, DRC

Main tasks

Task 1 and 5:
Precursor chemistry and radiosynthesis of 11C-labelled PET tracers for the visualisation of cerebral multidrug transporters.

Task 4, and 6-8:
Radiopharmacological evaluation of new radiotracers (binding assays, biodistribution studies, autoradiography, and assessment of metabolites).

Task 7, 8:
Development of longer-lived radiotracers for PET (18F) and SPET (123I) imaging.