- Development of Fluorine-18 Labeled Metabolically Activated Tracers for Imaging of Drug Efflux Transporters with Positron Emission Tomography
-
Increased activity of efflux transporters, e.g., P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), at the blood-brain barrier is a pathological hallmark of many neurological diseases, and the resulting multiple drug resistance represents a major clinical challenge. Noninvasive imaging of transporter activity can help to clarify the underlying mechanisms of drug resistance and facilitate diagnosis, patient stratification, and treatment monitoring. We have developed a metabolically activated radiotracer for functional imaging of P-gp/BCRP activity with positron emission tomography (PET). In preclinical studies, the tracer showed excellent initial brain uptake and clean conversion to the desired metabolite, although at a sluggish rate. Blocking with P-gp/BCRP modulators led to increased levels of brain radioactivity; however, dynamic PET did not show differential clearance rates between treatment and control groups. Our results provide proof-of-concept for development of prodrug tracers for imaging of P-gp/BCRP function in vivo but also highlight some challenges associated with this strategy.
- Sander, Kerstin,Galante, Eva,Gendron, Thibault,Yiannaki, Elena,Patel, Niral,Kalber, Tammy L.,Badar, Adam,Robson, Mathew,Johnson, Sean P.,Bauer, Florian,Mairinger, Severin,Stanek, Johann,Wanek, Thomas,Kuntner, Claudia,Kottke, Tim,Weizel, Lilia,Dickens, David,Erlandsson, Kjell,Hutton, Brian F.,Lythgoe, Mark F.,Stark, Holger,Langer, Oliver,Koepp, Matthias,?rstad, Erik
-
p. 6058 - 6080
(2015/08/24)
-