PET Measurements of cAMP-Mediated Phosphodiesterase-4 with (R)-[11C]Rolipram

Kenk, Miran; Thomas, Adam; Lortie, Mireille; deKemp, Rob; DaSilva, Jean N.

doi:10.2174/1874471011104010044

Cited by 10 publications

(16 citation statements)

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“…Further studies are needed to verify whether these results may be of benefit in human nutrition, for example to help patients with stress disorders. Kenk et al (305) demonstrated via positron emission tomography imaging of cAMP, a strong region-specific signal in the brain, as well as an impaired cAMP-mediated signalling in obese pigs, giving some insight into pathological progression with potential for directing therapy in humans. Kenk et al (305) demonstrated via positron emission tomography imaging of cAMP, a strong region-specific signal in the brain, as well as an impaired cAMP-mediated signalling in obese pigs, giving some insight into pathological progression with potential for directing therapy in humans.…”

Section: Differences Between Pigs and Humans Or Pig Studies With No mentioning

confidence: 99%

Critical review evaluating the pig as a model for human nutritional physiology

et al. 2016

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The present review examines the pig as a model for physiological studies in human subjects related to nutrient sensing, appetite regulation, gut barrier function, intestinal microbiota and nutritional neuroscience. The nutrient-sensing mechanisms regarding acids (sour), carbohydrates (sweet), glutamic acid (umami) and fatty acids are conserved between humans and pigs. In contrast, pigs show limited perception of high-intensity sweeteners and NaCl and sense a wider array of amino acids than humans. Differences on bitter taste may reflect the adaptation to ecosystems. In relation to appetite regulation, plasma concentrations of cholecystokinin and glucagon-like peptide-1 are similar in pigs and humans, while peptide YY in pigs is ten to twenty times higher and ghrelin two to five times lower than in humans. Pigs are an excellent model for human studies for vagal nerve function related to the hormonal regulation of food intake. Similarly, the study of gut barrier functions reveals conserved defence mechanisms between the two species particularly in functional permeability. However, human data are scant for some of the defence systems and nutritional programming. The pig model has been valuable for studying the changes in human microbiota following nutritional interventions. In particular, the use of human flora-associated pigs is a useful model for infants, but the long-term stability of the implanted human microbiota in pigs remains to be investigated. The similarity of the pig and human brain anatomy and development is paradigmatic. Brain explorations and therapies described in pig, when compared with available human data, highlight their value in nutritional neuroscience, particularly regarding functional neuroimaging techniques.

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Section: Differences Between Pigs and Humans Or Pig Studies With No mentioning

confidence: 99%

Critical review evaluating the pig as a model for human nutritional physiology

et al. 2016

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“…Furthermore, up to our knowledge the only reported PDE PET radioligand that has been evaluated in human subjects is the radiolabeled PDE4 inhibitor [ 11 C]rolipram [36]. Kenk and coworkers have recently reviewed the studies that have been reported so far with [ 11 C]rolipram [37]. However, in view of the fact that PDE4 can also be found in heart, lung and skeletal muscle, PDE4 inhibitors were also evaluated as potential new antiinflammatory drugs [13].…”

Section: Pde4 Pet Radioligandsmentioning

confidence: 99%

“…Since PDE4 enzyme is ubiquitous expressed in brain and no reference region is possible to use for PET purposes, several research studies have been reported exploring the possibility to use the (S)-isomer to define the nonspecific binding component for the (R)analogue [51,53]. Therefore, the difference between those values could be used to calculate the PDE4specific binding of (R)-[ 11 C]rolipram [37]. Therefore, the difference between those values could be used to calculate the PDE4specific binding of (R)-[ 11 C]rolipram [37].…”

Section: Pde4 Pet Radioligandsmentioning

confidence: 99%

Recent Advances in Positron Emission Tomography (PET) Radiotracers for Imaging Phosphodiesterases

Andrés¹,

Angelis²,

Alcázar³

et al. 2012

CTMC

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Phosphodiesterases (PDEs) are a family of enzymes that metabolically inactivate the second messengers 3',5'- cyclic adenosine monophosphate (cAMP) and/or 3',5'-cyclic guanosine monophosphate (cGMP). These two messengers regulate the extracellular signal from the plasma membrane G protein-coupled receptors (GPCRs) to the intracellular effector proteins, hence modulating a wide variety of biological processes both in the central nervous system (CNS) and peripheral tissues. Although there are many radiotracers available for positron emission tomography (PET) studies of different receptors, there are just a few tracers available for imaging studies of second messenger systems. The first reported PDE PET ligands were the 11C-labeled versions of the PDE4 inhibitors rolipram and Ro 20-1724, and, to date, PET imaging studies in human subjects have only been reported with [11C]rolipram. As a consequence of the growing interest in identifying selective PDE inhibitors as potential new therapeutic agents, new PET radiotracers for imaging specific PDEs have been described in literature as well. This article highlights these efforts on the design and evaluation of novel PET radioligands for in vivo imaging of PDEs.

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“…Numerous other 11 C- and 18 F-labeled PDE10A inhibitors have been evaluated in preclinical rodent models, and although several candidate tracers have proceeded to studies in nonhuman primates and human subjects, the search for a PET tracer with ideal pharmacological properties is ongoing. 22–31 …”

Section: Introductionmentioning

confidence: 99%

Synthesis of Fluorine-Containing Phosphodiesterase 10A (PDE10A) Inhibitors and the In Vivo Evaluation of F-18 Labeled PDE10A PET Tracers in Rodent and Nonhuman Primate

Zhang

Jin

et al. 2015

J. Med. Chem.

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A series of fluorine-containing PDE10A inhibitors were designed and synthesized to improve the metabolic stability of [11C]MP-10. Twenty of the 22 new analogues had high potency and selectivity for PDE10A: 18a–j, 19d–j, 20a–b, and 21b had IC50 values <5 nM for PDE10A. Seven F-18 labeled compounds [18F]18a–e, [18F]18g, and [18F]20a were radiosynthesized by 18F-introduction onto the quinoline rather than the pyrazole moiety of the MP-10 pharmacophore and performed in vivo evaluation. Biodistribution studies in rats showed ~2-fold higher activity in the PDE10A-enriched striatum than nontarget brain regions; this ratio increased from 5 to 30 min postinjection, particularly for [18F]18a–d and [18F]20a. Micro-PET studies of [18F]18d and [18F]20a in nonhuman primates provided clear visualization of striatum with suitable equilibrium kinetics and favorable metabolic stability. These results suggest this strategy may identify a 18F-labeled PET tracer for quantifying the levels of PDE10A in patients with CNS disorders including Huntington’s disease and schizophrenia.

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PET Measurements of cAMP-Mediated Phosphodiesterase-4 with (R)-[11C]Rolipram

Cited by 10 publications

References 0 publications

Critical review evaluating the pig as a model for human nutritional physiology

Critical review evaluating the pig as a model for human nutritional physiology

Recent Advances in Positron Emission Tomography (PET) Radiotracers for Imaging Phosphodiesterases

Synthesis of Fluorine-Containing Phosphodiesterase 10A (PDE10A) Inhibitors and the In Vivo Evaluation of F-18 Labeled PDE10A PET Tracers in Rodent and Nonhuman Primate

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