title: Ibogaine labeling with 99mTc-tricarbonyl: synthesis and transport at the mouse blood-brain barrier.
abstract: The (99m)Tc-tricarbonyl core may be used as an ideal tool for gamma-labeling ligands in noninvasive SPECT imaging. However, most (99m)Tc-tricarbonyl-labeled agents have difficulty crossing the blood-brain barrier (BBB). We radiolabeled the neuroactive indole ibogaine with (99m)Tc-tricarbonyl and measured its transport into the mouse brain by in situ brain perfusion. We measured the interactions of [(99m)Tc(CO)(3)-ibogaine](+) and (99m)Tc-tricarbonyl with the main BBB efflux transporters P-gp and BCRP in vitro and in vivo. Ibogaine was radiolabeled (yield: over 95%). [(99m)Tc(CO)(3)-ibogaine](+) entered the brain (K(in)) poorly (0.18 microL/g/s), at about the same rate as (99m)Tc-tricarbonyl (0.16 microL/g/s) and [(99m)Tc-sestamibi](+) (0.10 microL/g/s). The CNS tracer [(99m)Tc-HMPAO](0) entered the brain approximately 70-times higher than [(99m)Tc(CO)(3)-ibogaine](+). In vitro studies revealed that neither [(99m)Tc(CO)(3)-ibogaine](+) nor (99m)Tc-tricarbonyl ion were substrates for P-gp or BCRP. But lowering the membrane dipole potential barrier with phloretin enhanced the brain transport of [(99m)Tc(OH(2))(3)(CO)(3)](+) approximately 3-fold. Thus, ibogaine directly labeled with (99m)Tc-tricarbonyl is not suitable for CNS imaging because of its poor uptake. Brain transport is not restricted by efflux transporters but is reduced by its lipophilicity and interaction with the membrane-positive dipole potential.
authors.affiliation: INSERM U705, CNRS UMR 7157, Université Paris Descartes, Université Paris Diderot, Hôpital F. Widal, 200, rue du Fbg Saint Denis, 75010 Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Tournier
authors.forename: Pascal
authors.initials: P
authors.lastname: André
authors.forename: Sandy
authors.initials: S
authors.lastname: Blondeel
authors.forename: Nathalie
authors.initials: N
authors.lastname: Rizzo-Padoin
authors.forename: Amaury
authors.initials: A
authors.lastname: du Moulinet d'Hardemarre
authors.forename: Xavier
authors.initials: X
authors.lastname: Declèves
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Scherrmann
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cisternino
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000818:Animals; D001693:Biological Transport, Active; D001812:Blood-Brain Barrier; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D001923:Brain Chemistry / Q000235:genetics; D002478:Cells, Cultured; D002855:Chromatography, Thin Layer; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007050:Ibogaine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D007211:Indoles / Q000737:chemistry; D007553:Isotope Labeling; D008297:Male; D051379:Mice; D015609:Organotechnetium Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D013667:Technetium
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C501412:Abcg2 protein, mouse; D007211:Indoles; D015609:Organotechnetium Compounds; D019275:Radiopharmaceuticals; C546956:technetium 99m tricarbonyl ibogaine; D007050:Ibogaine; D013667:Technetium