NIMH DIRP Molecular Imaging Branch - Section on PET Imaging

Background. Phosphodiesterase4 (PDE4) metabolizes cAMP and thereby stops the activity of this important second messenger. [¹¹C]-(R)-rolipram inhibits PDE4 and thereby increases the concentration of cAMP. We have used [¹¹C]-()-rolipram binding in brain to measure the density and activity of PDE4. In this study in a rat, we examined a negative feedback mechanism by which cAMP-activated protein kinase (PKA) modulates the enzymatic activity and affinity of [¹¹C]-()-rolipram binding. Injection of dibutyryl-cAMP into one striatum activated PKA and increased the binding of [¹¹C]-(R)-rolipram, as predicted. We also found that local injection of an inhibitor of PKA had the opposite effect. These studies showed that the binding of [¹¹C]-(R)-rolipram in brain reflects not only the density of PDE4 but also the activity level of this enzyme. (PDF File)

Legend. The proposed mechanism of action of antidepressant medications is to upregulate the cyclic adenosine monophosphate (cAMP) signaling cascade. Phosphodiesterase4 (PDE4) is an enzyme that metabolizes cAMP and may play a mechanistic role in antidepressant efficacy. For example, chronic antidepressant treatment of animals increases PDE4, and a PDE4 inhibitor (rolipram) was found to have antidepressant effects in both animals and humans. We evaluated the PET radioligand [¹¹C](R)-rolipram in rodents and found that in vivo radioligand binding can monitor the phosphorylation (activation) status of PDE4 (Itoh et al., 2010; (PDF File)). Masahiro Fujita, MD, PhD (nuclear medicine physician and Staff Scientist) recently studied the safety, kinetics, and test/retest reproducibility of [¹¹C](R)-rolipram in healthy subjects (Zanotti Fregonara et al., 2011; (PDF File)). Dr. Fujita is imaging patients with major depressive disorder before and after antidepressant treatment. Our PET results confirm for the first time in the living human brain the "cAMP theory of depression," which posits that low cAMP signaling predisposes to depression and that antidepressants of various types increase cAMP signaling. That is, [¹¹C](R)-rolipram binding in brain of patients with major depressive disorder at baseline (i.e., taking no medications) was decreased 18% compared to controls (P = 0.002) (Fujita et al., 2012. (PDF File)). Preliminary analysis of the repeat PET after about two months treatment with SSRI show a comparable upregulation (i.e., normalization) of [¹¹C](R)-rolipram binding (in progress).

References.
1.) M. Fujita, S.S. Zoghbi, M.S. Crescenzo, J. Hong, J.L. Musachio, J.Q. Lu, J.-S. Liow, N.Seneca, D.N. Tipre, V.L. Cropley, M. Imaizumi, A.D. Gee, J. Seidel, M.V. Green, V.W. Pike, and R.B. Innis. Quantification of brain phosphodiesterase 4 in rat with (R)-[¹¹C]rolipram-PET. NeuroImage. 26: 1201-1210, 2005. (PDF File)

2)T. Itoh, K. Abe, J. Hong, O. Inoue, V.W. Pike, R.B. Innis, and M. Fujita. Effects of cAMP dependent protein kinase activator and inhibitor on in vivo PET rolipram binding to phosphodiesterase 4 in conscious rats. Synapse, 64: 172-176, 2010. (PDF File)

3) P. Zanotti Fregonara, S.S. Zoghbi, J.-S. Liow, E. Luong, R. Boellaard, R.L. Gladding, V.W. Pike, R.B. Innis, and M. Fujita. 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. NeuroImage, 283: 1903-1909, 2011. (PDF File)