Debora Petroni1, Antonietta Bartoli2, Simona Rapposelli3, Maria Digiacomo4, Silvia Burchielli5, Giulia Nesi4, Annalina Lapucci4, Silvia Pardini6, Sabrina Fucci5, Marco Macchia4, Piero A Salvadori6, Luca Menichetti6. 1. Institute of Clinical Physiology, Consiglio Nazionale delle Ricerche (CNR), Via Moruzzi, 1, I-56124, Pisa, Italy. debora.petroni@ifc.cnr.it. 2. Molecular Imaging Centre, University of Turin, Via Nizza, 52, I-10125, Ivrea, Italy. 3. Department of Pharmacy, University of Pisa, Via Bonanno 6, I-56126, Pisa, Italy. simona.rapposelli@farm.unipi.it. 4. Department of Pharmacy, University of Pisa, Via Bonanno 6, I-56126, Pisa, Italy. 5. Fondazione Toscana G. Monasterio, Via Moruzzi, 1, I-56124, Pisa, Italy. 6. Institute of Clinical Physiology, Consiglio Nazionale delle Ricerche (CNR), Via Moruzzi, 1, I-56124, Pisa, Italy.
Abstract
PURPOSE: The plasma membrane P-glycoprotein (Pgp) is an efflux transporter involved in multidrug resistance and in the onset of neurodegenerative disease. Its function and most mechanisms of action are still under investigation. We developed a C-11-labeled 2-arylethylphenylamine-([11C]AEPH) derivative for positron emission tomography (PET), as a novel probe to better understand the activity and the function of Pgp in vivo. PROCEDURES: The synthetic procedure and the quality control of the selected lead compound, [11C]AEPH-1, were set up and optimized. The biodistribution and the dynamic extraction in target organs of [11C]AEPH-1 were studied in vivo by PET in healthy rats at baseline and after pre-treatment with a Pgp inhibitor (tariquidar). RESULTS: In vivo dynamic imaging was consistent with the results of ex vivo extraction on explanted organs. An adequate stability for in vivo studies, as well as a high activity of [11C]AEPH-1 in intestine and barrier tissues, has been demonstrated. Results of the blockade study showed a decrease of uptake after the pre-treatment, indicating a behavior attributable to a Pgp ligand. CONCLUSIONS: The suitable pharmacokinetics and the specificity tested in the pre-treated animals have indicated the potentiality of this AEPH derivative to act as Pgp ligand, providing new opportunities for further studies on expression and function of this important efflux transporter in the fields of neurology and oncology.
PURPOSE: The plasma membrane P-glycoprotein (Pgp) is an efflux transporter involved in multidrug resistance and in the onset of neurodegenerative disease. Its function and most mechanisms of action are still under investigation. We developed a C-11-labeled 2-arylethylphenylamine-([11C]AEPH) derivative for positron emission tomography (PET), as a novel probe to better understand the activity and the function of Pgp in vivo. PROCEDURES: The synthetic procedure and the quality control of the selected lead compound, [11C]AEPH-1, were set up and optimized. The biodistribution and the dynamic extraction in target organs of [11C]AEPH-1 were studied in vivo by PET in healthy rats at baseline and after pre-treatment with a Pgp inhibitor (tariquidar). RESULTS: In vivo dynamic imaging was consistent with the results of ex vivo extraction on explanted organs. An adequate stability for in vivo studies, as well as a high activity of [11C]AEPH-1 in intestine and barrier tissues, has been demonstrated. Results of the blockade study showed a decrease of uptake after the pre-treatment, indicating a behavior attributable to a Pgp ligand. CONCLUSIONS: The suitable pharmacokinetics and the specificity tested in the pre-treated animals have indicated the potentiality of this AEPH derivative to act as Pgp ligand, providing new opportunities for further studies on expression and function of this important efflux transporter in the fields of neurology and oncology.
Authors: Joost Bart; Antoon T M Willemsen; Harry J M Groen; Winette T A van der Graaf; Theodora D Wegman; Willem Vaalburg; Elisabeth G E de Vries; N Harry Hendrikse Journal: Neuroimage Date: 2003-11 Impact factor: 6.556