title: Pharmacokinetic investigation of sildenafil using positron emission tomography and determination of its effect on cerebrospinal fluid cGMP levels.
abstract: Sildenafil (Viagra) is a selective inhibitor of phosphodiesterase type 5 (PDE5), which degrades cyclic guanosine monophosphate to the linear nucleotide. Sildenafil is acutely used in erectile dysfunction and chronically in pulmonary hypertension. Evidence in the last decade shows that sildenafil may have potential as a therapeutic option for Alzheimer's disease or other neurodegenerative disorders. The purpose of this work was to explore whether sildenafil crosses the blood-brain barrier. Pharmacokinetic properties of sildenafil in rodents were investigated using (11) C-radiolabeling followed by in vivo positron emission tomography (PET) and ex vivo tissue dissection and gamma counting. PET results in rats suggest penetration into the central nervous system. Ex vivo data in perfused animals suggest that trapping of [(11) C]sildenafil within the cerebral vascular endothelium limits accumulation in the central nervous system parenchyma. Peroral sildenafil administration to Macaca fascicularis and subsequent chemical analysis of plasma and cerebrospinal fluid (CSF) using liquid chromatography coupled with tandem mass spectrometry showed that drug content in the CSF was high enough to achieve PDE5 inhibition, which was also demonstrated by the significant increases in CSF cyclic guanosine monophosphate levels. Central actions of sildenafil include both relaxation of the cerebral vasculature and inhibition of PDE5 in neurons and glia. This central action of sildenafil may underlie its efficacy in neuroprotection models, and may justify the continued search for a PDE5 ligand suitable for PET imaging. Sildenafil interacts with phosphodiesterase type 5 (PDE5) expressed in the endothelium and/or smooth muscle cells of brain vessels and also crosses the blood-brain barrier to interact with PDE5 expressed in brain cells. At therapeutic doses, the concentration of sildenafil in the cerebrospinal fluid (CSF) is high enough to inhibit PDE5 in the neural cells (neurons and glia). In turn, the concentration of cGMP likely increases in parenchymal cells and, as shown in this report, in the CSF. Read the Editorial Highlight for this article on page 220. Cover Image for this issue: doi: 10.1111/jnc.13302.
authors.affiliation: Radiochemistry Platform, CIC biomaGUNE, San Sebastian, Spain.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Gómez-Vallejo
authors.affiliation: Small Molecule Discovery Platform, Molecular Therapeutics Program, Centre for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Ugarte
authors.affiliation: Neurobiology of Alzheimer's disease, Neurosciences Division, Centre for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: Carolina
authors.initials: C
authors.lastname: García-Barroso
authors.affiliation: Neurobiology of Alzheimer's disease, Neurosciences Division, Centre for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.|Anatomy Department, School of Medicine, University of Navarra, Pamplona, Spain.
authors.forename: Mar
authors.initials: M
authors.lastname: Cuadrado-Tejedor
authors.affiliation: Nuclear Imaging Platform, CIC biomaGUNE, San Sebastian, Spain.
authors.forename: Boguslaw
authors.initials: B
authors.lastname: Szczupak
authors.affiliation: Neurosciences Division, Centre for Applied Medical Research, CIMA, University of Navarra, Pamplona, Spain.|Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED), Pamplona, Spain.|Instituto de Investigaciones Sanitarias de Navarra (IdiSNA), Pamplona, Spain.
authors.forename: Iria G
authors.initials: IG
authors.lastname: Dopeso-Reyes
authors.affiliation: Neurosciences Division, Centre for Applied Medical Research, CIMA, University of Navarra, Pamplona, Spain.|Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED), Pamplona, Spain.|Instituto de Investigaciones Sanitarias de Navarra (IdiSNA), Pamplona, Spain.
authors.forename: José L
authors.initials: JL
authors.lastname: Lanciego
authors.affiliation: Neurobiology of Alzheimer's disease, Neurosciences Division, Centre for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: García-Osta
authors.affiliation: Radiochemistry and Nuclear Imaging Group, CIC biomaGUNE, San Sebastian, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Llop
authors.affiliation: Small Molecule Discovery Platform, Molecular Therapeutics Program, Centre for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: Julen
authors.initials: J
authors.lastname: Oyarzabal
authors.affiliation: Neurobiology of Alzheimer's disease, Neurosciences Division, Centre for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Franco
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects; D002853:Chromatography, Liquid; D006152:Cyclic GMP / Q000097:blood / Q000134:cerebrospinal fluid*; D007668:Kidney / Q000000981:diagnostic imaging / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D058986:Phosphodiesterase 5 Inhibitors / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography; D051381:Rats; D017207:Rats, Sprague-Dawley; D000068677:Sildenafil Citrate / Q000493:pharmacokinetics*; D053719:Tandem Mass Spectrometry; D013737:Testis / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D014018:Tissue Distribution / Q000187:drug effects; D015898:Tomography Scanners, X-Ray Computed
chemical_list: D058986:Phosphodiesterase 5 Inhibitors; D000068677:Sildenafil Citrate; D006152:Cyclic GMP
keywords: Alzheimer; Positron emission tomography; biodistribution; cGMP; cerebrospinal fluid (CSF); neurodegeneration; nootropic