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)-[(11)C]rolipram) and high SA lower affinity ((S)-[(11)C]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 [(11)C]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)-[(11)C]rolipram was accurately measured in living rats. In high SA R experiments, approximately 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)-[(11)C]rolipram.
Fujita
Masahiro
M
Molecular Imaging Branch, National Institute of Mental Health, Building 1, Room B3-10, 1 Center Drive, MSC-0135, Bethesda, MD 20892-0135, USA. FujitaM@intra.nimh.nih.gov
Zoghbi
Sami S
SS
Crescenzo
Matthew S
MS
Hong
Jinsoo
J
Musachio
John L
JL
Lu
Jian-Qiang
JQ
Liow
Jeih-San
JS
Seneca
Nicholas
N
Tipre
Dnyanesh N
DN
Cropley
Vanessa L
VL
Imaizumi
Masao
M
Gee
Antony D
AD
Seidel
Jurgen
J
Green
Michael V
MV
Pike
Victor W
VW
Innis
Robert B
RB
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000032:analysis*; D000465:Algorithms; D000818:Animals; D001345:Autoradiography; D001798:Blood Proteins / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging* / Q000201:enzymology*; D002851:Chromatography, High Pressure Liquid; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D007090:Image Interpretation, Computer-Assisted; D007553:Isotope Labeling; D016018:Least-Squares Analysis; D008297:Male; D017711:Nonlinear Dynamics; D010726:Phosphodiesterase Inhibitors / Q000097:blood / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography; D011485:Protein Binding; D019275:Radiopharmaceuticals / Q000097:blood / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020889:Rolipram / Q000097:blood / Q000493:pharmacokinetics
D001798:Blood Proteins; D010726:Phosphodiesterase Inhibitors; D019275:Radiopharmaceuticals; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram