Identification and regional distribution in rat brain of radiometabolites of the dopamine transporter PET radioligand [11C]PE2I

  • H. Umesha Shetty
  • Sami S. Zoghbi
  • Jeih-San Liow
  • Masanori Ichise
  • Jinsoo Hong
  • John L. Musachio
  • Christer Halldin
  • Jurgen Seidel
  • Robert B. Innis
  • Victor W. Pike
Original article

DOI: 10.1007/s00259-006-0277-1

Cite this article as:
Shetty, H.U., Zoghbi, S.S., Liow, JS. et al. Eur J Nucl Med Mol Imaging (2007) 34: 667. doi:10.1007/s00259-006-0277-1

Abstract

Purpose

We aimed to determine the composition of radioactivity in rat brain after intravenous administration of the dopamine transporter radioligand, [11C]PE2I.

Methods

PET time-activity curves (TACs) and regional brain distribution ex vivo were measured using no-carrier-added [11C]PE2I. Carrier-added [11C]PE2I was administered to identify metabolites with high-performance liquid radiochromatography (RC) or RC with mass spectrometry (LC-MS and MS-MS). The stability of [11C]PE2I was assessed in rat brain homogenates.

Results

After peak brain uptake of no-carrier-added [11C]PE2I, there was differential washout rate from striata and cerebellum. Thirty minutes after injection, [11C]PE2I represented 10.9 ± 2.9% of the radioactivity in plasma, 67.1 ± 11.0% in cerebellum, and 92.5 ± 3.2% in striata, and was accompanied by two less lipophilic radiometabolites. [11C]PE2I was stable in rat brain homogenate for at least 1 h at 37°C. LC-MS identified hydroxylated PE2I (1) (m/z 442) and carboxyl-desmethyl-PE2I (2) (m/z 456) in brain. MS-MS of 1 gave an m/z 442→424 transition due to H2O elimination, so verifying the presence of a benzyl alcohol group. Metabolite 2 was the benzoic acid derivative. Ratios of ex vivo measurements of [11C]PE2I, [11C]1, and [11C]2 in striata to their cognates in cerebellum were 6.1 ± 3.4, 3.7 ± 2.2 and 1.33 ± 0.38, respectively, showing binding selectivity of metabolite [11C]1 to striata.

Conclusion

Radiometabolites [11C]1 and [11C]2 were characterized as the 4-hydroxymethyl and 4-carboxyl analogs of [11C]PE2I, respectively. The presence of the pharmacologically active [11C]1 and the inactive [11C]2 is a serious impediment to successful biomathematical analysis.

Keywords

Dopamine transporter Brain PET [11C]PE2I Metabolites 

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • H. Umesha Shetty
    • 1
  • Sami S. Zoghbi
    • 1
  • Jeih-San Liow
    • 1
  • Masanori Ichise
    • 1
  • Jinsoo Hong
    • 1
  • John L. Musachio
    • 1
  • Christer Halldin
    • 2
  • Jurgen Seidel
    • 3
  • Robert B. Innis
    • 1
  • Victor W. Pike
    • 1
  1. 1.PET Radiopharmaceutical Sciences, Molecular Imaging BranchNational Institute of Mental Health, National Institutes of HealthBethesdaUSA
  2. 2.Department of Clinical Neuroscience, Psychiatry SectionKarolinska HospitalStockholmSweden
  3. 3.Department of Nuclear MedicineWarren Grant Magnuson Clinical Center, National Institutes of HealthBethesdaUSA

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