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- Theodor-Boveri-Institut für Biowissenschaften (4)
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Gentzsch, Christian ; Chen, Xinyu ; Spatz, Philipp ; Košak, Urban ; Knez, Damijan ; Nose, Naoko ; Gobec, Stanislav ; Higuchi, Takahiro ; Decker, Michael
Purpose
A neuropathological hallmark of Alzheimer's disease (AD) is the presence of amyloid-β (Aβ) plaques in the brain, which are observed in a significant number of cognitively normal, older adults as well. In AD, butyrylcholinesterase (BChE) becomes associated with A\(_{β}\) aggregates, making it a promising target for imaging probes to support diagnosis of AD. In this study, we present the synthesis, radiochemistry, in vitro and preliminary ex and in vivo investigations of a selective, reversible BChE inhibitor as PET-tracer for evaluation as an AD diagnostic.
Procedures
Radiolabeling of the inhibitor was achieved by fluorination of a respective tosylated precursor using K[\(^{18}\)F]. IC\(_{50}\) values of the fluorinated compound were obtained in a colorimetric assay using recombinant, human (h) BChE. Dissociation constants were determined by measuring hBChE activity in the presence of different concentrations of inhibitor.
Results
Radiofluorination of the tosylate precursor gave the desired radiotracer in an average radiochemical yield of 20 ± 3 %. Identity and > 95.5 % radiochemical purity were confirmed by HPLC and TLC autoradiography. The inhibitory potency determined in Ellman's assay gave an IC\(_{50}\) value of 118.3 ± 19.6 nM. Dissociation constants measured in kinetic experiments revealed lower affinity of the inhibitor for binding to the acylated enzyme (K2 = 68.0 nM) in comparison to the free enzyme (K\(_{1}\) = 32.9 nM).
Conclusions
The reversibly acting, selective radiotracer is synthetically easily accessible and retains promising activity and binding potential on hBChE. Radiosynthesis with \(^{18}\)F labeling of tosylates was feasible in a reasonable time frame and good radiochemical yield.
Selcho, Mareike ; Millán, Carola ; Palacios-Muñoz, Angelina ; Ruf, Franziska ; Ubillo, Lilian ; Chen, Jiangtian ; Bergmann, Gregor ; Ito, Chihiro ; Silva, Valeria ; Wegener, Christian ; Ewer, John
Animal circadian clocks consist of central and peripheral pacemakers, which are coordinated to produce daily rhythms in physiology and behaviour. Despite its importance for optimal performance and health, the mechanism of clock coordination is poorly understood. Here we dissect the pathway through which the circadian clock of Drosophila imposes daily rhythmicity to the pattern of adult emergence. Rhythmicity depends on the coupling between the brain clock and a peripheral clock in the prothoracic gland (PG), which produces the steroid hormone, ecdysone. Time information from the central clock is transmitted via the neuropeptide, sNPF, to non-clock neurons that produce the neuropeptide, PTTH. These secretory neurons then forward time information to the PG clock. We also show that the central clock exerts a dominant role on the peripheral clock. This use of two coupled clocks could serve as a paradigm to understand how daily steroid hormone rhythms are generated in animals.
Gentzsch, Christian ; Hoffmann, Matthias ; Ohshima, Yasuhiro ; Nose, Naoko ; Chen, Xinyu ; Higuchi, Takahiro ; Decker, Michael
The enzyme butyrylcholinesterase (BChE) represents a promising target for imaging probes to potentially enable early diagnosis of neurodegenerative diseases like Alzheimer's disease (AD) and to monitor disease progression in some forms of cancer. In this study, we present the design, facile synthesis, in vitro and preliminary ex vivo and in vivo evaluation of a morpholine‐based, selective inhibitor of human BChE as a positron emission tomography (PET) tracer with a pseudo‐irreversible binding mode. We demonstrate a novel protecting group strategy for 18F radiolabeling of carbamate precursors and show that the inhibitory potency as well as kinetic properties of our unlabeled reference compound were retained in comparison to the parent compound. In particular, the prolonged duration of enzyme inhibition of such a morpholinocarbamate motivated us to design a PET tracer, possibly enabling a precise mapping of BChE distribution.
Neuropeptides have gained broad attraction in insect neuroscience and physiology, as new genetic tools are increasingly uncovering their wide-ranging pleiotropic functions with high cellular resolution. Allatostatin A (AstA) peptides constitute one of the best studied insect neuropeptide families. In insects and other panarthropods, AstA peptides qualify as brain-gut peptides and have regained attention with the discovery of their role in regulating feeding, growth, activity/sleep and learning. AstA receptor homologs are found throughout the protostomia and group with vertebrate somatostatin/galanin/kisspeptin receptors. In this review, we summarise the current knowledge on the evolution and the pleiotropic and cell-specific non-allatostatic functions of AstA. We speculate about the core functions of AstA signalling, and derive open questions and challengesfor future research on AstA and invertebrate neuropeptides in general.
Dornelas, Maria ; Antão, Laura H. ; Moyes, Faye ; Bates, Amanda E. ; Magurran, Anne E. ; Adam, Dušan ; Akhmetzhanova, Asem A. ; Appeltans, Ward ; Arcos, José Manuel ; Arnold, Haley ; Ayyappan, Narayanan ; Badihi, Gal ; Baird, Andrew H. ; Barbosa, Miguel ; Barreto, Tiago Egydio ; Bässler, Claus ; Bellgrove, Alecia ; Belmaker, Jonathan ; Benedetti-Cecchi, Lisandro ; Bett, Brian J. ; Bjorkman, Anne D. ; Błażewicz, Magdalena ; Blowes, Shane A. ; Bloch, Christopher P. Bloch ; Bonebrake, Timothy C. ; Boyd, Susan ; Bradford, Matt ; Brooks, Andrew J. ; Brown, James H. ; Bruelheide, Helge ; Budy, Phaedra ; Carvalho, Fernando ; Castañeda-Moya, Edward ; Chen, Chaolun Allen ; Chamblee, John F. ; Chase, Tory J. ; Siegwart Collier, Laura ; Collinge, Sharon K. ; Condit, Richard ; Cooper, Elisabeth J. ; Cornelissen, J. Hans C. ; Cotano, Unai ; Crow, Shannan Kyle ; Damasceno, Gabriella ; Davies, Claire H. ; Davis, Robert A. ; Day, Frank P. ; Degraer, Steven ; Doherty, Tim S. ; Dunn, Timothy E. ; Durigan, Giselda ; Duffy, J. Emmett ; Edelist, Dor ; Edgar, Graham J. ; Elahi, Robin ; Elmendorf, Sarah C. ; Enemar, Anders ; Ernest, S. K. Morgan ; Escribano, Rubén ; Estiarte, Marc ; Evans, Brian S. ; Fan, Tung-Yung ; Turini Farah, Fabiano ; Loureiro Fernandes, Luiz ; Farneda, Fábio Z. ; Fidelis, Alessandra ; Fitt, Robert ; Fosaa, Anna Maria ; Franco, Geraldo Antonio Daher Correa ; Frank, Grace E. ; Fraser, William R. ; García, Hernando ; Cazzolla Gatti, Roberto ; Givan, Or ; Gorgone-Barbosa, Elizabeth ; Gould, William A. ; Gries, Corinna ; Grossman, Gary D. ; Gutierréz, Julio R. ; Hale, Stephen ; Harmon, Mark E. ; Harte, John ; Haskins, Gary ; Henshaw, Donald L. ; Hermanutz, Luise ; Hidalgo, Pamela ; Higuchi, Pedro ; Hoey, Andrew ; Van Hoey, Gert ; Hofgaard, Annika ; Holeck, Kristen ; Hollister, Robert D. ; Holmes, Richard ; Hoogenboom, Mia ; Hsieh, Chih-hao ; Hubbell, Stephen P. ; Huettmann, Falk ; Huffard, Christine L. ; Hurlbert, Allen H. ; Ivanauskas, Natália Macedo ; Janík, David ; Jandt, Ute ; Jażdżewska, Anna ; Johannessen, Tore ; Johnstone, Jill ; Jones, Julia ; Jones, Faith A. M. ; Kang, Jungwon ; Kartawijaya, Tasrif ; Keeley, Erin C. ; Kelt, Douglas A. ; Kinnear, Rebecca ; Klanderud, Kari ; Knutsen, Halvor ; Koenig, Christopher C. ; Kortz, Alessandra R. ; Král, Kamil ; Kuhnz, Linda A. ; Kuo, Chao-Yang ; Kushner, David J. ; Laguionie-Marchais, Claire ; Lancaster, Lesley T. ; Lee, Cheol Min ; Lefcheck, Jonathan S. ; Lévesque, Esther ; Lightfoot, David ; Lloret, Francisco ; Lloyd, John D. ; López-Baucells, Adrià ; Louzao, Maite ; Madin, Joshua S. ; Magnússon, Borgþór ; Malamud, Shahar ; Matthews, Iain ; McFarland, Kent P. ; McGill, Brian ; McKnight, Diane ; McLarney, William O. ; Meador, Jason ; Meserve, Peter L. ; Metcalfe, Daniel J. ; Meyer, Christoph F. J. ; Michelsen, Anders ; Milchakova, Nataliya ; Moens, Tom ; Moland, Even ; Moore, Jon ; Moreira, Carolina Mathias ; Müller, Jörg ; Murphy, Grace ; Myers-Smith, Isla H. ; Myster, Randall W. ; Naumov, Andrew ; Neat, Francis ; Nelson, James A. ; Nelson, Michael Paul ; Newton, Stephen F. ; Norden, Natalia ; Oliver, Jeffrey C. ; Olsen, Esben M. ; Onipchenko, Vladimir G. ; Pabis, Krzysztof ; Pabst, Robert J. ; Paquette, Alain ; Pardede, Sinta ; Paterson, David M. ; Pélissier, Raphaël ; Peñuelas, Josep ; Pérez-Matus, Alejandro ; Pizarro, Oscar ; Pomati, Francesco ; Post, Eric ; Prins, Herbert H. T. ; Priscu, John C. ; Provoost, Pieter ; Prudic, Kathleen L. ; Pulliainen, Erkki ; Ramesh, B. R. ; Ramos, Olivia Mendivil ; Rassweiler, Andrew ; Rebelo, Jose Eduardo ; Reed, Daniel C. ; Reich, Peter B. ; Remillard, Suzanne M. ; Richardson, Anthony J. ; Richardson, J. Paul ; van Rijn, Itai ; Rocha, Ricardo ; Rivera-Monroy, Victor H. ; Rixen, Christian ; Robinson, Kevin P. ; Rodrigues, Ricardo Ribeiro ; de Cerqueira Rossa-Feres, Denise ; Rudstam, Lars ; Ruhl, Henry ; Ruz, Catalina S. ; Sampaio, Erica M. ; Rybicki, Nancy ; Rypel, Andrew ; Sal, Sofia ; Salgado, Beatriz ; Santos, Flavio A. M. ; Savassi-Coutinho, Ana Paula ; Scanga, Sara ; Schmidt, Jochen ; Schooley, Robert ; Setiawan, Fakhrizal ; Shao, Kwang-Tsao ; Shaver, Gaius R. ; Sherman, Sally ; Sherry, Thomas W. ; Siciński, Jacek ; Sievers, Caya ; da Silva, Ana Carolina ; da Silva, Fernando Rodrigues ; Silveira, Fabio L. ; Slingsby, Jasper ; Smart, Tracey ; Snell, Sara J. ; Soudzilovskaia, Nadejda A. ; Souza, Gabriel B. G. ; Souza, Flaviana Maluf ; Souza, Vinícius Castro ; Stallings, Christopher D. ; Stanforth, Rowan ; Stanley, Emily H. ; Sterza, José Mauro ; Stevens, Maarten ; Stuart-Smith, Rick ; Suarez, Yzel Rondon ; Supp, Sarah ; Tamashiro, Jorge Yoshio ; Tarigan, Sukmaraharja ; Thiede, Gary P. ; Thorn, Simon ; Tolvanen, Anne ; Toniato, Maria Teresa Zugliani ; Totland, Ørjan ; Twilley, Robert R. ; Vaitkus, Gediminas ; Valdivia, Nelson ; Vallejo, Martha Isabel ; Valone, Thomas J. ; Van Colen, Carl ; Vanaverbeke, Jan ; Venturoli, Fabio ; Verheye, Hans M. ; Vianna, Marcelo ; Vieira, Rui P. ; Vrška, Tomáš ; Vu, Con Quang ; Vu, Lien Van ; Waide, Robert B. ; Waldock, Conor ; Watts, Dave ; Webb, Sara ; Wesołowski, Tomasz ; White, Ethan P. ; Widdicombe, Claire E. ; Wilgers, Dustin ; Williams, Richard ; Williams, Stefan B. ; Williamson, Mark ; Willig, Michael R. ; Willis, Trevor J. ; Wipf, Sonja ; Woods, Kerry D. ; Woehler, Eric J. ; Zawada, Kyle ; Zettler, Michael L.
Motivation
The BioTIME database contains raw data on species identities and abundances in ecological assemblages through time. These data enable users to calculate temporal trends in biodiversity within and amongst assemblages using a broad range of metrics. BioTIME is being developed as a community-led open-source database of biodiversity time series. Our goal is to accelerate and facilitate quantitative analysis of temporal patterns of biodiversity in the Anthropocene.
Main types of variables included
The database contains 8,777,413 species abundance records, from assemblages consistently sampled for a minimum of 2 years, which need not necessarily be consecutive. In addition, the database contains metadata relating to sampling methodology and contextual information about each record.
Spatial location and grain
BioTIME is a global database of 547,161 unique sampling locations spanning the marine, freshwater and terrestrial realms. Grain size varies across datasets from 0.0000000158 km2 (158 cm2) to 100 km2 (1,000,000,000,000 cm2).
Time period and grain
BioTIME records span from 1874 to 2016. The minimal temporal grain across all datasets in BioTIME is a year.
Major taxa and level of measurement
BioTIME includes data from 44,440 species across the plant and animal kingdoms, ranging from plants, plankton and terrestrial invertebrates to small and large vertebrates.
Software format
.csv and .SQL.