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

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 (V_T′) 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 V_T′ 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 V_T′ was specific binding. Distribution and changes of PDE4 in animal models can now be studied by measuring V_T′ of high SA (R)-[¹¹C] rolipram.