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PET Measurement of the In Vivo Affinity of ¹¹C-(R)-Rolipram and the Density of Its Target, Phosphodiesterase-4, in the Brains of Conscious and Anesthetized Rats

¹ Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland; ² Developmental Research Laboratories, Shionogi & Co., Ltd., Toyonaka, Osaka, Japan; and ³ Division of Health Sciences, Osaka University Graduate School of Medicine, Suita, Osaka, Japan

Correspondence: For correspondence or reprints contact: Masahiro Fujita, Molecular Imaging Branch, National Institute of Mental Health, Building 31, Room B2B37, 31 Center Dr., MSC-2035, Bethesda, MD 20892-2035. E-mail: FujitaM{at}intra.nimh.nih.gov

A variety of phosphodiesterases hydrolyze and terminate the effects of the intracellular second messenger 3',5'-cyclic adenosine monophosphate (cAMP). Phosphodiesterase subtype 4 (PDE4) is particularly abundant in the brain and has been imaged with ¹¹C-(R)-rolipram, a selective inhibitor of PDE4. We sought to measure in vivo both the binding site density (B_max) and the radioligand affinity (1/K_D) of ¹¹C-(R)-rolipram in the rat brain. We also studied 2 critical factors in small-animal PET scans: the influence of anesthesia and the difference in binding under in vivo and in vitro conditions. Methods: In vivo, B_max and K_D were measured in PET saturation experiments by the administration of ¹¹C-(R)-rolipram and various doses of carrier (R)-rolipram in conscious and isoflurane-anesthetized rats. The metabolite-corrected arterial input function was measured in each scan. To image conscious rats, the head of the rat was fixed in a holder and the animals were trained to comply with this apparatus. Bound and free (R)-rolipram levels were calculated under transient equilibrium conditions (i.e., at the time of peak specific binding). Results: The B_max and K_D of conscious rats were significantly greater than those of anesthetized rats, by 29% and 59%, respectively. In addition, the in vitro K_D was 3–7 times greater than was the in vivo K_D, although the B_max was similar in both conditions. Conclusion: The in vivo B_max and K_D of (R)-rolipram were successfully measured in both conscious and anesthetized rats. K_D was affected to a greater extent than was B_max by the 2 conditions. That is, K_D was increased in the conscious rat, compared with in the anesthetized rat, and K_D was increased in vitro, compared with in vivo. The current study shows that the rat, a readily available species for research, can be used to measure in vivo both affinity and density of radioligand targets, which can later be directly assessed with standard in vitro techniques.

Key Words: small-animal PET • isoflurane • compartmental analysis • transient equilibrium • cAMP

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