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

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• 作者：Kerstin Sander ; Eva Galante ; Thibault Gendron ; Elena Yiannaki ; Niral Patel ; Tammy L. Kalber ; Adam Badar ; Mathew Robson ; Sean P. Johnson ; Florian Bauer ; Severin Mairinger ; Johann Stanek ; Thomas Wanek ; Claudia Kuntner ; Tim Kottke ; Lilia Weizel ; David Dickens ; Kjell Erlandsson ; Brian F. Hutton ; Mark F. Lythgoe ; Holger Stark ; Oliver Langer ; Matthias Koepp ; Erik 脜rstad
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：August 13, 2015
• 年：2015
• 卷：58
• 期：15
• 页码：6058-6080
• 全文大小：927K
• ISSN：1520-4804

文摘

Increased activity of efflux transporters, e.g., P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), at the blood鈥揵rain 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.