Quantification of brain phosphodiesterase 4 in rat with (R)-[ 11C]Rolipram-PET

Masahiro Fujita, Sami S. Zoghbi, Matthew S. Crescenzo, Jinsoo Hong, John L. Musachio, Jian Qiang Lu, Jeih San Liow, Nicholas Seneca, Dnyanesh N. Tipre, Vanessa L. Cropley, Masao Imaizumi, Antony D. Gee, Jurgen Seidel, Michael V. Green, Victor W. Pike, Robert B. Innis

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

Objective: Phosphodiesterase 4 (PDE4) catabolizes the second messenger 3′, 5′-cyclic adenosine monophosphate and may play a critical role in brain diseases. Our aim was to quantify PDE4 in rats with positron emission tomography (PET). Methods: High (n = 6) and low specific activity (SA) (n = 2) higher affinity ((R)-[11C]rolipram) and high SA lower affinity ((S)-[11C]rolipram) (n = 2) enantiomers were intravenously administered to Sprague-Dawley rats. Brain data were acquired using the ATLAS PET scanner and reconstructed using the 3D-ordered subset expectation maximization algorithm. Arterial samples were taken to measure unmetabolized [11C]rolipram. Total distribution volumes (VT′) were calculated using a 1-tissue compartment (1C) and an unconstrained 2-tissue compartment (2C) model. Results: High SA R experiments showed later and greater brain uptake, and slower washout than low SA R and S experiments. In all regions and in all experiments, the 2C model gave significantly better fitting than the 1C model. The poor fitting by the latter caused underestimation of V T′ by 19-31%. The 2C model identified VT′ reasonably well with coefficients of variation less than 10%. V T′ values by this model were 16.4-29.2 mL/cm3 in high SA R, 2.9-3.5 in low SA R, and 3.1-3.7 in S experiments. Conclusions: Specific binding of (R)-[11C]rolipram was accurately measured in living rats. In high SA R experiments, ∼86% of VT′ was specific binding. Distribution and changes of PDE4 in animal models can now be studied by measuring VT′ of high SA (R)-[11C] rolipram.

Original languageEnglish (US)
Pages (from-to)1201-1210
Number of pages10
JournalNeuroImage
Volume26
Issue number4
DOIs
StatePublished - Jul 15 2005

Keywords

  • Compartment analysis
  • Cyclic AMP
  • Pharmacokinetics
  • Plasma metabolites
  • Small animal PET

ASJC Scopus subject areas

  • Neurology
  • Cognitive Neuroscience

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