Kinetics of (R)-[11C] rolipram and (S)-[11C] rolipram In the Dog Heart: Investigation of Four Compartment Models

The PET tracers (R)-[
¹¹
C]rolipram and (S)-[
¹¹
C]rolipram have been proposed to measure phosphodiesterase-4 (PDE4) density as an indirect index of cAMP-mediated cell signaling, which is altered in many cardiac pathologies. The aim of this study was to determine which of the following models (if any) describe the kinetics of these tracers in normal dog hearts: a one-compartment model, a two-compartment model, and dual-input models comprising one or two compartments for rolipram and one compartment for labeled metabolites. Dynamic PET data were acquired from 6 healthy dogs with (R)-[
¹¹
C]rolipram (10 studies) and (S)-[
¹¹
C]rolipram (6 studies). Parameter estimates were obtained for 648 ROI's and median values determined. Distribution volumes were estimated from the parameter estimates. The one-compartment model did not fit the data acquired with either tracer adequately. Both the two-compartment model and the model comprising one compartment for the unchanged tracer and a parallel compartment to account for labeled metabolites provided good fits to the data obtained with (S)-[
¹¹
C]rolipram (R-square: 0.99-1). The two-compartment model, with or without a parallel compartment to account for metabolites, described the kinetics of (R)-[
¹¹
C]rolipram very well (R-square: 0.98-0.99). Estimates of the distribution volumes obtained with models that provided good fits to the data were very reproducible (CV: 10%-21%), suggesting that reliable measurement of PDE4 density in the heart may be possible.