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Meeting ReportGeneral Clinical Specialties

PET imaging of phosphodiesterase 4 in brain and peripheral organs of McCune-Albright syndrome

Lora Weidner, Michael Collins, Alison Boyce, Yuichi Wakabayashi, Louise Stolz, Lori Guthrie, Denise Rallis-Frutos, Sami Zoghbi, Victor Pike, Masahiro Fujita and Robert Innis
Journal of Nuclear Medicine May 2019, 60 (supplement 1) 506;
Lora Weidner
5Molecular Imaging Branch National Institute of Mental Health Bethesda MD United States
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Michael Collins
1Bethesda MD United States
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Alison Boyce
6National Institutes of Health Bethesda MD United States
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Yuichi Wakabayashi
5Molecular Imaging Branch National Institute of Mental Health Bethesda MD United States
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Louise Stolz
5Molecular Imaging Branch National Institute of Mental Health Bethesda MD United States
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Lori Guthrie
3National Institute of Dental and Craniofacial Research Bethesda MD United States
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Denise Rallis-Frutos
5Molecular Imaging Branch National Institute of Mental Health Bethesda MD United States
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Sami Zoghbi
7NIH Bethesda MD United States
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Victor Pike
4National Institute of Mental Health Bethesda MD United States
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Masahiro Fujita
8NIMH Bethesda MD United States
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Robert Innis
2National Institute Mental Health Bethesda MD United States
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Abstract

506

Objectives: McCune-Albright syndrome (MAS) is a mosaic disorder arising from mutations of the GNAS gene, which encodes the 3′, 5′-cyclic adenosine monophosphate (cAMP) pathway-associated G-protein, Gsα. This mutation results in dysregulation of the cAMP signaling cascade, leading to upregulation of phosphodiesterase type 4 (PDE4), an enzyme that catalyzes the hydrolysis of cAMP. Positron emission tomography (PET) imaging of PDE4 using [11C](R)-rolipram has been successfully used to study the in vivo activity of the cAMP cascade. Rolipram is a reversible inhibitor of PDE4, and binding of [11C](R)-rolipram provides a measure of the activity of this enzyme in brain. Due to a feedback mechanism, in vivo binding of [11C](R)-rolipram reflects the activity of the cAMP cascade; essentially, increased cAMP stimulates protein kinase A (PKA), which phosphorylates PDE4 that, in turn, increases rolipram binding. Clinical manifestations of MAS, such as fibrous dysplasia, in a given individual are determined by the timing of the GNAS mutation during embryogenesis, the tissues involved, and the role of Gsα in affected tissues. Animal models of fibrous dysplasia have shown increases in PDE4 activity, however this correlation has not been shown in humans with fibrous dysplasia. Therefore, it is unknown whether fibrous dysplasia, and other symptoms of MAS, is related to increased PDE4 activity in humans. We hypothesize that subjects with MAS would show greater rolipram binding than healthy controls in areas known to affected by the disorder.

Methods: [11C](R)-rolipram whole body PET scans were performed in two patients with MAS and six healthy controls. Uptake of [11C](R)-rolipram was measured in organs such as the heart, kidneys, and liver, as well as in the brain.

Results: Binding of [11C](R)-rolipram in the body correlated with known locations of fibrous dysplasia in patients with MAS, with no uptake in the bones of healthy controls (Figure 1). SUV brain TACs showed a two-fold difference in uptake in MAS patient #2 (SUVmax = 4) as compared to MAS patient #1 and healthy controls (SUVmax = 2). While we could not correct for differences in brain exposure without arterial blood samples, this study is ongoing and we will be obtaining dedicated brain scans. VT/fP values for healthy control brain regions were similar to those previously reported (whole brain, 14.1 ± 2.4; frontal cortex, 15.22 ± 2.7; cerebellum, 11.63 ± 2.4).

Conclusions: Our results are consistent with animal studies showing that increased cAMP leads to activation of PKA, which in turn increases the phosphorylation of PDE4 (which has increased activity and ten-fold higher affinity for rolipram). This study revealed that rolipram binding does reflect increased cAMP pathway activation. To determine if the increased binding is specific, we will perform whole-body blocking scans with the PDE4 inhibitor roflumilast. Differences in rolipram binding in the brain will be determined by radiometabolite-corrected arterial sampling.

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Journal of Nuclear Medicine
Vol. 60, Issue supplement 1
May 1, 2019
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PET imaging of phosphodiesterase 4 in brain and peripheral organs of McCune-Albright syndrome
Lora Weidner, Michael Collins, Alison Boyce, Yuichi Wakabayashi, Louise Stolz, Lori Guthrie, Denise Rallis-Frutos, Sami Zoghbi, Victor Pike, Masahiro Fujita, Robert Innis
Journal of Nuclear Medicine May 2019, 60 (supplement 1) 506;

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PET imaging of phosphodiesterase 4 in brain and peripheral organs of McCune-Albright syndrome
Lora Weidner, Michael Collins, Alison Boyce, Yuichi Wakabayashi, Louise Stolz, Lori Guthrie, Denise Rallis-Frutos, Sami Zoghbi, Victor Pike, Masahiro Fujita, Robert Innis
Journal of Nuclear Medicine May 2019, 60 (supplement 1) 506;
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