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

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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.

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Acknowledgement

This work was supported by the Intramural Research Program of NIH (NIMH; project no. Z01-MH002795-04).

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Authors and Affiliations

  1. PET Radiopharmaceutical Sciences, Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Building 10, Room B3 C351, MSC 1003, 10 Center Drive, Bethesda, MD, 20892-1003, USA

    H. Umesha Shetty, Sami S. Zoghbi, Jeih-San Liow, Masanori Ichise, Jinsoo Hong, John L. Musachio, Robert B. Innis & Victor W. Pike

  2. Department of Clinical Neuroscience, Psychiatry Section, Karolinska Hospital, Stockholm, Sweden

    Christer Halldin

  3. Department of Nuclear Medicine, Warren Grant Magnuson Clinical Center, National Institutes of Health, Bethesda, MD, USA

    Jurgen Seidel

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  1. H. Umesha Shetty
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Correspondence to H. Umesha Shetty.

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Shetty, H.U., Zoghbi, S.S., Liow, JS. et al. Identification and regional distribution in rat brain of radiometabolites of the dopamine transporter PET radioligand [11C]PE2I. Eur J Nucl Med Mol Imaging 34, 667–678 (2007). https://doi.org/10.1007/s00259-006-0277-1

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