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.