Kinetic analysis in human brain of [11C](R)-rolipram, a positron emission tomographic radioligand to image phosphodiesterase 4: a retest study and use of an image-derived input function

Abstract

[(11)C](R)-rolipram provides a measure of the density of phosphodiesterase 4 (PDE4) in brain, an enzyme that metabolizes cAMP. The aims of this study were to perform kinetic modeling of [(11)C](R)-rolipram in healthy humans using an arterial input function and to replace this arterial input in humans with an image-derived input function.

Methods: Twelve humans had two injections of [(11)C](R)-rolipram. An image-derived input function was obtained from the carotid arteries and four blood samples. The samples were used for partial volume correction and for estimating the parent concentration using HPLC analysis.

Results: An unconstrained two-compartment model and Logan analysis measured distribution volume V(T), with good identifiability but with moderately high retest variability (15%). Similar results were obtained using the image input (ratio image/arterial V(T)=1.00±0.06).

Conclusions: Binding of [(11)C](R)-rolipram to PDE4 can be quantified in human brain using kinetic modeling and an arterial input function. Image input function from carotid arteries provides an equally accurate and reproducible method to quantify PDE4.

Figure 1

Example of manually defined carotid and background regions of interest identified in the early summed PET frames.

Figure 2

Concentration of [¹¹C](R)-rolipram (●) and total radioactivity (○) in plasma (A) and percentage of unchanged [¹¹C](R)-rolipram in total plasma radioactivity (parent plus radiometabolites) (B). Symbols show mean ± SD from 24 scans in 12 subjects.

Figure 2

Concentration of [¹¹C](R)-rolipram (●) and total radioactivity (○) in plasma (A) and percentage of unchanged [¹¹C](R)-rolipram in total plasma radioactivity (parent plus radiometabolites) (B). Symbols show mean ± SD from 24 scans in 12 subjects.

Figure 3

The concentrations of radioactivity in lateral temporal cortex from a typical healthy subject were fitted with a one- and an unconstrained two-tissue compartment model. The two-tissue compartment model () more closely followed the measured values than did the one-compartment model ().The values of V_T were 0.668 mL/cm³ from the one-tissue compartment model and 0.756 mL/cm³ from the two-tissue compartment model. Weighting using Noise Equivalent Counts is influenced by radioactive decay, and that explains the slight deviation of the two-tissue compartment model to the measured data at late time-points. Brain data for this region were also quantified with the Logan method using either the arterial input function or the image input function. The values of V_T (derived from the slope of the lines) were similar for both inputs: 0.781 mL/cm³ for arterial and 0.783 mL/cm³ for image.

Figure 4

V_T/f_P was calculated for caudate using an unconstrained two-tissue compartment model. Scans were analyzed using brain data from time 0 to the specified time on x-axis. V_T/f_P was expressed as a percentage of terminal value – i.e., V_T/f_P calculated from the entire 120-min data set. Error bars are identifiability (standard errors %) of V_T/f_P. Imaging for the initial 80 min provided V_T/f_P within 10% (dashed lines) of that obtained with the full length data and also provided good identifiability of < 12%. Note that V_T and V_T/f_P have the identical dependency on the length of data.

Figure 5

[¹¹C](R)-rolipram parent concentration over time obtained from the image input function () and from the arterial input function (○) of a representative healthy subject. The parent fraction has been estimated by fitting a monoexponential function through the parent/whole blood ratio measured in the four blood samples used to calculate the image-derived input function.