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

Article


Sander, Kerstin, Galante, E., Gendron, Thibault, Yiannaki, Elena, Patel, Niral, Kalber, Tammy L., Badar, Adam, Robson, Mathew, Johnson, Sean P., Bauer, Florian, Mairinger, Severin, Stanek, Johann, Wanek, Thomas, Kuntner, Claudia, Kottke, Tim, Weizel, Lilia, Dickens, David, Erlandsson, Kjell, Hutton, Brian F., Lythgoe, Mark F., Stark, Holger, Langer, Oliver, Koepp, Matthias and Årstad, Erik 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.
AuthorsSander, Kerstin, Galante, E., Gendron, Thibault, Yiannaki, Elena, Patel, Niral, Kalber, Tammy L., Badar, Adam, Robson, Mathew, Johnson, Sean P., Bauer, Florian, Mairinger, Severin, Stanek, Johann, Wanek, Thomas, Kuntner, Claudia, Kottke, Tim, Weizel, Lilia, Dickens, David, Erlandsson, Kjell, Hutton, Brian F., Lythgoe, Mark F., Stark, Holger, Langer, Oliver, Koepp, Matthias and Årstad, Erik
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
PublisherACS Publications
Digital Object Identifier (DOI)doi: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 information© 2015 American Chemical Society
Permalink -

https://repository.uel.ac.uk/item/8556v

  • 12
    total views
  • 0
    total downloads
  • 4
    views this month
  • 0
    downloads this month

Related outputs

Novel nucleotide–calixarene conjugates via phosphoester linkage
Consoli, Grazia M.L., Granata, Giuseppe, Galante, E., Cunsolo, Francesca and Geraci, Corrada 2006. Novel nucleotide–calixarene conjugates via phosphoester linkage. Tetrahedron Letters. 47 (19), pp. 3245-3249.
Hydroxycinnamic acid clustered by a calixarene platform: radical scavenging and antioxidant activity
Consoli, Grazia M.L., Galante, E., Daquino, Carmelo, Granata, Giuseppe, Cunsolo, Francesca and Geraci, Corrada 2006. Hydroxycinnamic acid clustered by a calixarene platform: radical scavenging and antioxidant activity. Tetrahedron Letters. 47 (37), pp. 6611-6614.
Synthesis of water-soluble nucleotide-calixarene conjugates and preliminary investigation of their in vitro DNA replication inhibitory activity
Consoli, Grazia M.L., Granata, Giuseppe, Galante, E., Di Silvestro, Isabella, Salafia, Laura and Geraci, Corrada 2007. Synthesis of water-soluble nucleotide-calixarene conjugates and preliminary investigation of their in vitro DNA replication inhibitory activity. Tetrahedron. 63 (44), pp. 10758-10763.
Calix[4]arene Decorated with Four Tn Antigen Glycomimetic Units and P3CS Immunoadjuvant: Synthesis, Characterization, and Anticancer Immunological Evaluation
Geraci, Corrada, Consoli, Grazia M. L., Galante, E., Bousquet, Ennio, Pappalardo, Maria and Spadaro, Angelo 2008. Calix[4]arene Decorated with Four Tn Antigen Glycomimetic Units and P3CS Immunoadjuvant: Synthesis, Characterization, and Anticancer Immunological Evaluation. Bioconjugate Chemistry. 19 (3), pp. 751-758.
A sinapic acid–calix[4]arene hybrid selectively binds Pb2+ over Hg2+ and Cd2+
Sgarlata, Carmelo, Zito, Valeria, Arena, Giuseppe, Consoli, Grazia Maria Letizia, Galante, E. and Geraci, Corrada 2009. A sinapic acid–calix[4]arene hybrid selectively binds Pb2+ over Hg2+ and Cd2+. Polyhedron. 28 (2), pp. 343-348.
Glycoclusters presenting lactose on calix[4]arene cores display trypanocidal activity
Galante, E., Geraci, Corrada, Sciuto, Sebastiano, Campo, Vanessa L., Carvalho, Ivone, Sesti-Costa, Renata, Guedes, Paulo M.M., Silva, João S., Hill, Lionel, Nepogodiev, Sergey A. and Field, Robert A. 2011. Glycoclusters presenting lactose on calix[4]arene cores display trypanocidal activity. Tetrahedron. 67 (33), pp. 5902-5912.
A One-Pot Three-Component Radiochemical Reaction for Rapid Assembly of125I-Labeled Molecular Probes
Yan, Ran, Sander, Kerstin, Galante, E., Rajkumar, Vineeth, Badar, Adam, Robson, Mathew, El-Emir, Ethaar, Lythgoe, Mark F., Pedley, R. Barbara and Årstad, Erik 2012. A One-Pot Three-Component Radiochemical Reaction for Rapid Assembly of125I-Labeled Molecular Probes. Journal of the American Chemical Society. 135 (2), pp. 703-709.
Chelator-Accelerated One-Pot ‘Click’ Labeling of Small Molecule Tracers with 2-[18F]Fluoroethyl Azide
Galante, E., Schoultz, Bent, Koepp, Matthias and Årstad, Erik 2013. Chelator-Accelerated One-Pot ‘Click’ Labeling of Small Molecule Tracers with 2-[18F]Fluoroethyl Azide. Molecules. 18 (5), pp. 5335-5347.
First Self-Adjuvant Multicomponent Potential Vaccine Candidates by Tethering of Four or Eight MUC1 Antigenic Immunodominant PDTRP Units on a Calixarene Platform: Synthesis and Biological Evaluation
Geraci, Corrada, Consoli, Grazia M. L., Granata, Giuseppe, Galante, E., Palmigiano, Angelo, Pappalardo, Maria, Di Puma, Salvatore D. and Spadaro, Angelo 2013. First Self-Adjuvant Multicomponent Potential Vaccine Candidates by Tethering of Four or Eight MUC1 Antigenic Immunodominant PDTRP Units on a Calixarene Platform: Synthesis and Biological Evaluation. Bioconjugate Chemistry. 24 (10), pp. 1710-1720.
Development of Purine-Derived18F-Labeled Pro-drug Tracers for Imaging of MRP1 Activity with PET
Galante, E., Okamura, Toshimitsu, Sande, Kerstin, Kikuchi, Tatsuya, Okada, Maki, Zhang, Ming-Rong, Robson, Mathew, Badar, Adam, Lythgoe, Mark, Koepp, Matthias and Årstad, Erik 2014. Development of Purine-Derived18F-Labeled Pro-drug Tracers for Imaging of MRP1 Activity with PET. Journal of Medicinal Chemistry. 57 (3), pp. 1023-1032.
Preferential Targeting of Disseminated Liver Tumors Using a Recombinant Adeno-Associated Viral Vector
Della Peruta, Marco, Badar, Adam, Rosales, Cecilia, Chokshi, Shilpa, Kia, Azadeh, Nathwani, Devhrut, Galante, E., Yan, Ran, Arstad, Erik, Davidoff, Andrew M., Williams, Roger, Lythgoe, Mark F. and Nathwani, Amit C. 2015. Preferential Targeting of Disseminated Liver Tumors Using a Recombinant Adeno-Associated Viral Vector. Human Gene Therapy. 26 (2), pp. 94-103.