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Analysis of (R)- and (S)-[11C]rolipram Kinetics in Canine Myocardium for the Evaluation of Phosphodiesterase-4 with PET

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Abstract

Purpose

(R)-[11C]rolipram and (S)-[11C]rolipram have been proposed to investigate phosphodiesterase-4 and, indirectly, cAMP-mediated signaling with PET. This study assessed binding of these tracers to phosphodiesterase-4 in canine myocardium.

Procedures

Seven dogs underwent (R)-[11C]rolipram and (S)-[11C]rolipram dynamic PET imaging at baseline and with co-injection of saturating doses of (R)-rolipram. Dual-input compartment models were applied to estimate the volumes of distribution (V T).

Results

The model comprising one compartment for unmetabolized tracer and one compartment for labeled metabolites provided excellent fits to data acquired with (S)-[11C]rolipram at baseline and with both enantiomers during co-injection scans. Use of two compartments for unmetabolized (R)-[11C]rolipram at baseline was warranted according to Akaike and Schwarz criteria. V T estimates obtained with these models were robust (CV ≤ 8.2%) and reproducible (CV ≤ 15%).

Conclusion

An important fraction (~65%) of the V T of (R)-[11C]rolipram at baseline reflects specific binding. Thus, the latter may be a useful index of phosphodiesterase-4 levels in canine myocardium.

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Acknowledgments

The authors thank Dr. Roger Gunn for helpful discussions. The authors also thank the University of Ottawa Heart Institute Animal Care Veterinary Service for assistance with experimental animals, the University of Ottawa Heart Institute Cardiac PET radiochemistry staff for the synthesis of (R)-[11C]rolipram and (S)-[11C]rolipram, as well as James Thackeray, Michael Greene, and Maryam Parsanejad for their assistance during imaging sessions. This work was supported in part by a grant from the Canadian Institutes of Health Research (MOP 62765) and in part by the Heart and Stroke Foundation of Ontario (HSFO) Program Grant on Molecular Function and Imaging (PRG6242). R. S. Beanlands is a Career Investigator supported by the Heart and Stroke Foundation of Ontario.

Conflict of Interest

The authors declare that they have no conflict of interest.

Author information

Correspondence to Mireille Lortie.

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Lortie, M., DaSilva, J.N., Kenk, M. et al. Analysis of (R)- and (S)-[11C]rolipram Kinetics in Canine Myocardium for the Evaluation of Phosphodiesterase-4 with PET. Mol Imaging Biol 14, 225–236 (2012). https://doi.org/10.1007/s11307-011-0482-6

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Key words

  • (R)-[11C]rolipram
  • PDE4
  • Cyclic AMP
  • Kinetic modeling
  • Cardiac imaging
  • PET