title: Synthesis and preclinical evaluation of the radiolabeled P-glycoprotein inhibitor [(11)C]MC113.
abstract: OBJECTIVE
  With the aim to develop a PET tracer to visualize P-glycoprotein (Pgp) expression levels in different organs, the Pgp inhibitor MC113 was labeled with (11)C and evaluated using small-animal PET.
  
  
  METHODS
  [(11)C]MC113 was synthesized by reaction of O-desmethyl MC113 with [(11)C]methyl triflate. Small-animal PET was performed with [(11)C]MC113 in FVB wild-type and Mdr1a/b((-/-)) mice (n=3 per group) and in a mouse model of high (EMT6Ar1.0) and low (EMT6) Pgp expressing tumor grafts (n=5). In the tumor model, PET scans were performed before and after administration of the reference Pgp inhibitor tariquidar (15mg/kg).
  
  
  RESULTS
  Brain uptake of [(11)C]MC113, expressed as area under the time-activity curve from time 0 to 60min (AUC(0-60)), was moderately but not significantly increased in Mdr1a/b((-/-)) compared with wild-type mice (mean±SD AUC(0-60), Mdr1a/b((-/-)): 88±7min, wild-type: 62±6min, P=0.100, Mann Whitney test). In the tumor model, AUC(0-60) values were not significantly different between EMT6Ar1.0 and EMT6 tumors. Neither in brain nor in tumors was activity concentration significantly changed in response to tariquidar administration. Half-maximum effect concentrations (IC(50)) for inhibition of Pgp-mediated rhodamine 123 efflux from CCRFvcr1000 cells were 375±60nM for MC113 versus 8.5±2.5nM for tariquidar.
  
  
  CONCLUSIONS
  [(11)C]MC113 showed higher brain uptake in mice than previously described Pgp PET tracers, suggesting that [(11)C]MC113 was only to a low extent effluxed by Pgp. However, [(11)C]MC113 was found unsuitable to visualize Pgp expression levels presumably due to insufficiently high Pgp binding affinity of MC113 in relation to Pgp densities in brain and tumors.
authors.affiliation: Health & Environment Department, Biomedical Systems, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria.
authors.forename: Severin
authors.initials: S
authors.lastname: Mairinger
authors.forename: Thomas
authors.initials: T
authors.lastname: Wanek
authors.forename: Claudia
authors.initials: C
authors.lastname: Kuntner
authors.forename: Yaprak
authors.initials: Y
authors.lastname: Doenmez
authors.forename: Sabine
authors.initials: S
authors.lastname: Strommer
authors.forename: Johann
authors.initials: J
authors.lastname: Stanek
authors.forename: Elena
authors.initials: E
authors.lastname: Capparelli
authors.forename: Peter
authors.initials: P
authors.lastname: Chiba
authors.forename: Markus
authors.initials: M
authors.lastname: Müller
authors.forename: Nicola A
authors.initials: NA
authors.lastname: Colabufo
authors.forename: Oliver
authors.initials: O
authors.lastname: Langer
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D002250:Carbon Radioisotopes; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D005240:Feasibility Studies; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055786:Gene Knockout Techniques; D007553:Isotope Labeling; D051379:Mice; D049268:Positron-Emission Tomography; D011854:Radiochemistry; D020112:Rhodamine 123 / Q000378:metabolism; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*
chemical_list: C569748:4'-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-ylmethyl)biphenyl-4-ol; C579243:6,7-dimethoxy-2-(4-methoxybiphenyl-4-yl-methyl)-1,2,3,4-tetrahydroisoquinoline; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001713:Biphenyl Compounds; D002250:Carbon Radioisotopes; D044005:Tetrahydroisoquinolines; D020112:Rhodamine 123