Identification and regional distribution in rat brain of radiometabolites of the dopamine transporter PET radioligand [11C]PE2I.
OBJECTIVE
We aimed to determine the composition of radioactivity in rat brain after intravenous administration of the dopamine transporter radioligand, [(11)C]PE2I.


METHODS
PET time-activity curves (TACs) and regional brain distribution ex vivo were measured using no-carrier-added [(11)C]PE2I. Carrier-added [(11)C]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 [(11)C]PE2I was assessed in rat brain homogenates.


RESULTS
After peak brain uptake of no-carrier-added [(11)C]PE2I, there was differential washout rate from striata and cerebellum. Thirty minutes after injection, [(11)C]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. [(11)C]PE2I was stable in rat brain homogenate for at least 1 h at 37 degrees 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 H(2)O elimination, so verifying the presence of a benzyl alcohol group. Metabolite 2 was the benzoic acid derivative. Ratios of ex vivo measurements of [(11)C]PE2I, [(11)C]1, and [(11)C]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 [(11)C]1 to striata.


CONCLUSIONS
Radiometabolites [(11)C]1 and [(11)C]2 were characterized as the 4-hydroxymethyl and 4-carboxyl analogs of [(11)C]PE2I, respectively. The presence of the pharmacologically active [(11)C]1 and the inactive [(11)C]2 is a serious impediment to successful biomathematical analysis.
Shetty
H Umesha
HU
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. shettyu@mail.nih.gov.
Zoghbi
Sami S
SS
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.
Liow
Jeih-San
JS
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.
Ichise
Masanori
M
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.
Hong
Jinsoo
J
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.
Musachio
John L
JL
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.
Halldin
Christer
C
Department of Clinical Neuroscience, Psychiatry Section, Karolinska Hospital, Stockholm, Sweden.
Seidel
Jurgen
J
Department of Nuclear Medicine, Warren Grant Magnuson Clinical Center, National Institutes of Health, Bethesda, MD, USA.
Innis
Robert B
RB
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.
Pike
Victor W
VW
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.
D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging* / Q000473:pathology; D002853:Chromatography, Liquid; D008297:Male; D013058:Mass Spectrometry; D008956:Models, Chemical; D008962:Models, Theoretical; D009662:Nortropanes / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography / Q000295:instrumentation* / Q000379:methods*; D011859:Radiography; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012680:Sensitivity and Specificity; D013997:Time Factors; D014018:Tissue Distribution
C113010:N-(3-iodoprop-2-enyl)-2-beta-carbomethoxy-3-(4-methylphenyl)nortropane; D009662:Nortropanes; D019275:Radiopharmaceuticals