Ibogaine labeling with 99mTc-tricarbonyl: synthesis and transport at the mouse blood-brain barrier.
Nicolas Tournier, Pascal André, Sandy Blondeel, Nathalie Rizzo-Padoin, Amaury Du Moulinet D'Hardemarre, Xavier Declèves, Jean-Michel Scherrmann, Salvatore Cisternino
Journal of Pharmaceutical Sciences December 1, 2009 DOI: 10.1002/jps.21771 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Mice |
| Intervention | in situ brain perfusion |
| Topics | Ibogaine |
| Keywords | Brain imaging Neuroimaging Molecular imaging Imaging agents Radiotracers Diagnostic imaging Bbb transport Brain penetration Cns penetration Blood-brain barrier permeability Ibogaine research Neuroactive compounds Psychoactive compounds Cns drugs Neuromodulators Iboga alkaloids Medicinal chemistry Compound design Drug development Preclinical drug discovery Drug transport Drug uptake Efflux mechanisms Lipophilicity Membrane interactions Pharmacokinetics Drug design |
| Citations | 14 |
| Key findings | Ibogaine radiolabeled with 99mTc-tricarbonyl showed poor brain uptake, about 70 times lower than the CNS tracer 99mTc-HMPAO, due to lipophilicity and membrane dipole potential interactions rather than efflux transporter activity. |
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.