Ibogaine labeling with 99mTc-tricarbonyl: Synthesis and transport at the mouse blood-brain barrier

The 99mTc-tricarbonyl core may be used as an ideal tool for gamma-labeling ligands in noninvasive SPECT imaging. However, most 99mTc-tricarbonyl-labeled agents have difficulty crossing the blood-brain barrier (BBB). We radiolabeled the neuroactive indole ibogaine with 99mTc-tricarbonyl and measured its transport into the mouse brain by in situ brain perfusion. We measured the interactions of [99mTc(CO)3-ibogaine]+ and 99mTc-tricarbonyl with the main BBB efflux transporters P-gp and BCRP in vitro and in vivo. Ibogaine was radiolabeled (yield: over 95%). [99mTc(CO)3-ibogaine]+ entered the brain (Kin) poorly (0.18 µL/g/s), at about the same rate as 99mTc-tricarbonyl (0.16 µL/g/s) and [99mTc-sestamibi]+ (0.10 µL/g/s). The CNS tracer [99mTc-HMPAO]0 entered the brain ∼70-times higher than [99mTc(CO)3-ibogaine]+. In vitro studies revealed that neither [99mTc(CO)3-ibogaine]+ nor 99mTc-tricarbonyl ion were substrates for P-gp or BCRP. But lowering the membrane dipole potential barrier with phloretin enhanced the brain transport of [99mTc(OH2)3(CO)3]+ ∼3-fold. Thus, ibogaine directly labeled with 99mTc-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.