Influence of Multidrug Resistance-Associated Proteins on the Excretion of the ABCC1 Imaging Probe 6-Bromo-7-[ 11 C]Methylpurine in Mice

Mol Imaging Biol. 2019 Apr;21(2):306-316. doi: 10.1007/s11307-018-1230-y.

Abstract

Purpose: Multidrug resistance-associated proteins (MRPs) mediate the hepatobiliary and renal excretion of many drugs and drug conjugates. The positron emission tomography (PET) tracer 6-bromo-7-[11C]methylpurine is rapidly converted in tissues by glutathione-S-transferases into its glutathione conjugate, and has been used to measure the activity of Abcc1 in the brain and the lungs of mice. Aim of this work was to investigate if the activity of MRPs in excretory organs can be measured with 6-bromo-7-[11C]methylpurine.

Procedures: We performed PET scans with 6-bromo-7-[11C]methylpurine in groups of wild-type, Abcc4(-/-) and Abcc1(-/-) mice, with and without pre-treatment with the prototypical MRP inhibitor MK571.

Results: 6-Bromo-7-[11C]methylpurine-derived radioactivity predominantly underwent renal excretion. In blood, MK571 treatment led to a significant increase in the AUC and a decrease in the elimination rate constant of radioactivity (kelimination,blood). In the kidneys, there were significant decreases in the rate constant for radioactivity uptake from the blood (kuptake,kidney), kelimination,kidney, and the rate constant for tubular secretion of radioactivity (kurine). Experiments in Abcc4(-/-) mice indicated that Abcc4 contributed to renal excretion of 6-bromo-7-[11C]methylpurine-derived radioactivity.

Conclusions: Our data suggest that 6-bromo-7-[11C]methylpurine may be useful to assess the activity of MRPs in the kidneys as well as in other organs (brain, lungs), although further work is needed to identify the MRP subtypes involved in the disposition of 6-bromo-7-[11C]methylpurine-derived radioactivity.

Keywords: 6-Bromo-7-[11C]methylpurine; ABC transporters; Glutathione-S-transferases (GST); Multidrug resistance-associated proteins; PET; Renal excretion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carbon Radioisotopes / chemistry*
  • Glutathione / metabolism
  • Mice, Inbred C57BL
  • Molecular Probes / chemistry*
  • Multidrug Resistance-Associated Proteins / metabolism*
  • Positron-Emission Tomography*
  • Propionates / pharmacokinetics
  • Purines / chemistry*
  • Quinolines / pharmacokinetics
  • Time Factors
  • Tissue Distribution

Substances

  • 6-bromo-7-methylpurine
  • Carbon Radioisotopes
  • Carbon-11
  • Molecular Probes
  • Multidrug Resistance-Associated Proteins
  • Propionates
  • Purines
  • Quinolines
  • verlukast
  • Glutathione
  • multidrug resistance-associated protein 1