Abstract
Background The radiolabelled inhibitor of the multidrug efflux transporter P-glycoprotein (P-gp) [C]elacridar was developed as a positron emission tomography (PET) tracer to assess expression levels of P-gp at the blood-brain barrier (BBB) [1]. [C]Elacridar was shown to interact specifically with P-gp at the rodent BBB, but its brain PET signal was very low, which was possibly caused by transport of [C]elacridar by P-gp [1]. In an attempt to gain a better understanding of the required properties of an effective P-gp PET tracer we evaluated C-labelled MC113, a structural analogue of elacridar, which was characterised as an unambiguous non-transported P-gp inhibitor and which possesses lower molecular weight, lower lipophilicity and higher potency for P-gp inhibition than elacridar (EC50 for inhibition of [ H]vinblastine transport in Caco-2 cell monolayers: 0.6 μM vs. 2.0 μM for elacridar) [2].
Highlights
The radiolabelled inhibitor of the multidrug efflux transporter P-glycoprotein (P-gp) [11C]elacridar was developed as a positron emission tomography (PET) tracer to assess expression levels of P-gp at the blood-brain barrier (BBB) [1]. [11C]Elacridar was shown to interact with P-gp at the rodent BBB, but its brain PET signal was very low, which was possibly caused by transport of [11C]elacridar by P-gp [1]
Results [11C]MC113 was evaluated using an identical set-up which we had previously used for [11C]elacridar and which employed a combination of chemical and genetic knockout of P-gp [1]. [11C]MC113 had a 3 times higher peak brain activity uptake than [11C]elacridar, but otherwise behaved identically to [11C]elacridar, in that brain activity uptake was higher in Mdr1a/b−/− than in wildtype mice and that inhibitor administration increased brain activity uptake in wild-type mice
Our data suggest that [11C]MC113 interacts with P-gp at the murine blood-brain barrier, but as for [11C]elacridar its in vivo behaviour points to transport by P-gp
Summary
The radiolabelled inhibitor of the multidrug efflux transporter P-glycoprotein (P-gp) [11C]elacridar was developed as a positron emission tomography (PET) tracer to assess expression levels of P-gp at the blood-brain barrier (BBB) [1]. [11C]Elacridar was shown to interact with P-gp at the rodent BBB, but its brain PET signal was very low, which was possibly caused by transport of [11C]elacridar by P-gp [1]. The radiolabelled inhibitor of the multidrug efflux transporter P-glycoprotein (P-gp) [11C]elacridar was developed as a positron emission tomography (PET) tracer to assess expression levels of P-gp at the blood-brain barrier (BBB) [1]. [11C]Elacridar was shown to interact with P-gp at the rodent BBB, but its brain PET signal was very low, which was possibly caused by transport of [11C]elacridar by P-gp [1]. In an attempt to gain a better understanding of the required properties of an effective P-gp PET tracer we evaluated 11C-labelled MC113, a structural analogue of elacridar, which was characterised as an unambiguous non-transported P-gp inhibitor and which possesses lower molecular weight, lower lipophilicity and higher potency for P-gp inhibition than elacridar (EC50 for inhibition of [3H]vinblastine transport in Caco-2 cell monolayers: 0.6 μM vs 2.0 μM for elacridar) [2]
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