Small-animal PET evaluation of [¹¹C]MC113 as a PET tracer for P-glycoprotein

Background

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 specifically 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].

Methods

Female wild-type (n = 3) and Mdr1a/b^−/− (n = 2) mice (Taconic Inc., USA) underwent paired PET scans with [¹¹C]MC113 using a microPET Focus220 scanner (Siemens, Medical Solutions, USA). A baseline scan (150 min), during which the P-gp inhibitor tariquidar (15 mg/kg) was administered i.v. at 60 min after radiotracer injection, was followed by a second 60-min scan at 2 h after administration of tariquidar. Whole-brain time-activity curves were calculated using the image analysis software Amide.

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 wild-type mice and that inhibitor administration increased brain activity uptake in wild-type mice. However, the observed effects were smaller for [¹¹C]MC113 than for [¹¹C]elacridar.

Conclusions

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. The higher brain activity uptake of [¹¹C]MC113 might be an advantage over [¹¹C]elacridar for PET imaging of P-gp.