Development of Fluorine-18 Labeled Metabolically Activated Tracers for Imaging of Drug Efflux Transporters with Positron Emission Tomography

Article


Sander, K., Galante, E., Gendron, T., Yiannaki, E., Patel, N., Kalber, T. L., Badar, A., Robson, M., Johnson, S. P., Bauer, F., Mairinger, S., Stanek, J., Wanek, T., Kuntner, C., Kottke, T., Weizel, L., Dickens, D., Erlandsson, K., Hutton, B. F., Lythgoe, M. F., Stark, H., Langer, O., Koepp, M. and Årstad, E. 2015. Development of Fluorine-18 Labeled Metabolically Activated Tracers for Imaging of Drug Efflux Transporters with Positron Emission Tomography. Journal of Medicinal Chemistry. 58 (15), pp. 6058-6080. https://doi.org/10.1021/acs.jmedchem.5b00652
AuthorsSander, K., Galante, E., Gendron, T., Yiannaki, E., Patel, N., Kalber, T. L., Badar, A., Robson, M., Johnson, S. P., Bauer, F., Mairinger, S., Stanek, J., Wanek, T., Kuntner, C., Kottke, T., Weizel, L., Dickens, D., Erlandsson, K., Hutton, B. F., Lythgoe, M. F., Stark, H., Langer, O., Koepp, M. and Årstad, E.
Abstract

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.

JournalJournal of Medicinal Chemistry
Journal citation58 (15), pp. 6058-6080
ISSN0022-2623
Year2015
PublisherAmerican Chemical Society (ACS)
Digital Object Identifier (DOI)https://doi.org/10.1021/acs.jmedchem.5b00652
Web address (URL)https://doi.org/10.1021/acs.jmedchem.5b00652
Publication dates
Print10 Jul 2015
Publication process dates
Deposited18 Aug 2017
Accepted01 Jul 2015
Copyright holder© 2015, American Chemical Society
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