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

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 ( 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/cm 3 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.