title: Synthesis and preclinical evaluation of novel PET probes for P-glycoprotein function and expression.
abstract: P-glycoprotein (P-gp) is an ATP-dependent efflux pump protecting the body against xenobiotics. A P-gp substrate (7) and an inhibitor (6) were labeled with (11)C, resulting in potential tracers of P-gp function and expression.
  
  
  METHODS
  6 and 7 were labeled using (11)CH(3)I. (11)C-verapamil was prepared as published previously, using (11)C-methyl triflate. MicroPET scans (with arterial sampling) and biodistribution studies were performed in rats pretreated with saline, cyclosporin A (CsA, 50 mg/kg), or cold 6 (15 mg/kg).
  
  
  RESULTS
  The radiochemical yields of (11)C-6 and (11)C-7 were approximately 30% with a total synthesis time of 45 min. Cerebral distribution volumes (DV) of (11)C-6 (2.35 +/- 0.11) and (11)C-7 (1.86 +/- 0.15) in saline-treated rats were higher than of (11)C-verapamil (0.64 +/- 0.12). DVs of (11)C-7 and (11)C-verapamil were significantly increased by CsA (to 5.26 +/- 0.14 and 5.85 +/- 0.32, respectively). The DV of (11)C-6 was reduced by cold 6 (to 1.65 +/- 0.03). Its uptake was also reduced (up to 67%) in several peripheral organs that express P-gp.
  
  
  CONCLUSIONS
  (11)C-7 is a novel tracer of P-gp function with higher baseline uptake than (11)C-verapamil. Upregulation of P-gp function in response to treatment (which is hard to detect with (11)C-verapamil) may be detectable using (11)C-7 and PET. Because (11)C-6 shows specific binding in target organs, this compound is the first PET tracer allowing measurement of P-gp expression.
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713GZ Groningen, The Netherlands. a.van.waarde@ngmb.umcg.nl
authors.forename: Aren
authors.initials: A
authors.lastname: van Waarde
authors.forename: Nisha K
authors.initials: NK
authors.lastname: Ramakrishnan
authors.forename: Anna A
authors.initials: AA
authors.lastname: Rybczynska
authors.forename: Philip H
authors.initials: PH
authors.lastname: Elsinga
authors.forename: Francesco
authors.initials: F
authors.lastname: Berardi
authors.forename: Johan R
authors.initials: JR
authors.lastname: de Jong
authors.forename: Chantal
authors.initials: C
authors.lastname: Kwizera
authors.forename: Roberto
authors.initials: R
authors.lastname: Perrone
authors.forename: Mariangela
authors.initials: M
authors.lastname: Cantore
authors.forename: Jurgen W A
authors.initials: JW
authors.lastname: Sijbesma
authors.forename: Rudi A
authors.initials: RA
authors.lastname: Dierckx
authors.forename: Nicola A
authors.initials: NA
authors.lastname: Colabufo
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D002250:Carbon Radioisotopes; D004353:Drug Evaluation, Preclinical; D005786:Gene Expression Regulation; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D007700:Kinetics; D008297:Male; D049268:Positron-Emission Tomography; D011849:Radioactive Tracers; D011851:Radioactivity; D051381:Rats; D017208:Rats, Wistar; D013194:Staining and Labeling; D014018:Tissue Distribution
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002250:Carbon Radioisotopes; D007546:Isoquinolines; D011849:Radioactive Tracers; C039109:isoquinoline