Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 58, Issue 15, Pages 6058-6080Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.5b00652
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Funding
- European Community's Seventh Framework Programme (FP7) [201380]
- EPSRC [EP/L006472/1] Funding Source: UKRI
- Cancer Research UK [16463] Funding Source: researchfish
- Engineering and Physical Sciences Research Council [EP/L006472/1] Funding Source: researchfish
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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- /BCRP function in vivo but also highlight some challenges associated with this strategy.
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