Imaging of ABC transporters with positron emission tomography - new insights from the development of new radiotracers / submitted by Thomas Wanek
Verfasser / VerfasserinWanek, Thomas
Begutachter / BegutachterinLanger, Oliver
UmfangX, 153 Bl. : Ill., graph. Darst.
HochschulschriftWien, Med. Univ., Diss., 2013
Zsfassung in dt. Sprache
Bibl. ReferenzOeBB
Schlagwörter (DE)Bildgebende Verfahren / Positronen-Emissions-Tomographie / Nuklearmedizin / Efflux-Pumpen
Schlagwörter (EN)Multidrug resistance / PET / Imaging / P-glycoprotein
URNurn:nbn:at:at-ubmuw:1-2953 Persistent Identifier (URN)
 Das Werk ist frei verfügbar
Imaging of ABC transporters with positron emission tomography - new insights from the development of new radiotracers [17.85 mb]
Zusammenfassung (Englisch)

Adenosine triphosphate-binding cassette (ABC) transporters, such as P-glycoprotein (Pgp), breast cancer resistance protein (BCRP) and multidrug resistance-associated protein 1 (MRP1), form through their ability to transport a multitude of chemically unrelated compounds across cellular membranes a powerful physiological defense system which protects the body from exposure to xenobiotics. Historically, ABC transporters have been implicated in multidrug resistance (MDR) in cancer, but more recent evidence suggests that changes in ABC transporter function and expression at the blood-brain barrier (BBB) occur in several neurological disorders, such as epilepsy, Alzheimer's and Parkinson's disease. To better understand the role of ABC transporters in disease a tool is needed to assess their function and expression in-vivo. The nuclear imaging technique positron emission tomography (PET), which enables measurement of tissue concentration levels of radiolabeled compounds, has great potential for studying ABC transporters in-vivo, provided the availability of suitable radiotracers and imaging protocols. In this thesis the interaction of new radiotracers with Pgp and BCRP was investigated in order to assess their suitability for PET imaging. The radiolabeled Pgp inhibitors [11C]tariquidar and [11C]elacridar had been initially developed to visualize Pgp density at the BBB but had failed to provide useful, quantifiable brain PET signals. In this thesis, the suitability of [11C]tariquidar and [11C]elacridar to visualize Pgp density in tumors was investigated. An experimental murine tumor model comprising a wild-type and a Pgp overexpressing variant was developed and binding characteristics of [11C]tariquidar and [11C]elacridar as well as two other newly developed PET tracers ([11C]MC113 and [11C]HM30181) were systematically evaluated. These studies showed, that contrary to the BBB, radiolabeled Pgp inhibitors were able to assess Pgp density in tumors, which may find application in clinical PET imaging.

Additionally, following observations made during this thesis, the capability of [11C]tariquidar to image BCRP function at the murine BBB was evaluated, which resulted in a novel BCRP PET imaging protocol. Some results of this thesis are currently under investigation in clinical studies, which may enhance our current understanding of ABC transporters in humans.