Development of Fluorine-18 Labeled Metabolically Activated Tracers for Imaging of Drug Efflux Transporters with Positron Emission Tomography
| Autor: | Thomas Wanek, Florian Bauer, Brian Hutton, SP Johnson, David Dickens, Erik Årstad, Oliver Langer, Holger Stark, Tammy L. Kalber, Kjell Erlandsson, Johann Stanek, Lilia Weizel, Mark F. Lythgoe, Mathew Robson, Niral Patel, Elena Yiannaki, Eva Galante, Claudia Kuntner, Kerstin Sander, Matthias J. Koepp, Severin Mairinger, Adam Badar, Thibault Gendron, Tim Kottke |
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| Rok vydání: | 2015 |
| Předmět: |
Fluorine Radioisotopes
Abcg2 Metabolite Pharmacology Blood–brain barrier chemistry.chemical_compound Mice In vivo Drug Discovery medicine Animals Tissue Distribution biology medicine.diagnostic_test Chemistry Membrane Transport Proteins Transporter Prodrug 3. Good health Functional imaging medicine.anatomical_structure Positron emission tomography Blood-Brain Barrier Positron-Emission Tomography biology.protein Molecular Medicine Female |
| Zdroj: | Journal of medicinal chemistry. 58(15) |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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