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201. In vitro and in vivo Human Metabolism of (S)-[18F]Fluspidine – A Radioligand for Imaging σ1 Receptors With Positron Emission Tomography (PET).

Author

Ludwig, Friedrich-Alexander, Fischer, Steffen, Houska, Richard, Hoepping, Alexander, Deuther-Conrad, Winnie, Schepmann, Dirk, Patt, Marianne, Meyer, Philipp M., Hesse, Swen, Becker, Georg-Alexander, Zientek, Franziska Ruth, Steinbach, Jörg, Wünsch, Bernhard, Sabri, Osama, and Brust, Peter

Subjects
POSITRON emission tomography, TRANSLOCATOR proteins, LIQUID chromatography-mass spectrometry
Abstract

(S)-[18F]fluspidine ((S)-[18F] 1) has recently been explored for positron emission tomography (PET) imaging of sigma-1 receptors in humans. In the current report, we have used plasma samples of healthy volunteers to investigate the radiometabolites of (S)-[18F] 1 and elucidate their structures with LC-MS/MS. For the latter purpose additional in vitro studies were conducted by incubation of (S)-[18F] 1 and (S)- 1 with human liver microsomes (HLM). In vitro metabolites were characterized by interpretation of MS/MS fragmentation patterns from collision-induced dissociation or by use of reference compounds. Thereby, structures of corresponding radio-HPLC-detected radiometabolites, both in vitro and in vivo (human), could be identified. By incubation with HLM, mainly debenzylation and hydroxylation occurred, beside further mono- and di-oxygenations. The product hydroxylated at the fluoroethyl side chain was glucuronidated. Plasma samples (10, 20, 30 min p.i., n = 5-6), obtained from human subjects receiving 250–300 MBq (S)-[18F] 1 showed 97.2, 95.4, and 91.0% of unchanged radioligand, respectively. In urine samples (90 min p.i.) the fraction of unchanged radioligand was only 2.6% and three major radiometabolites were detected. The one with the highest percentage, also found in plasma, matched the glucuronide formed in vitro. Only a small amount of debenzylated metabolite was detected. In conclusion, our metabolic study, in particular the high fractions of unchanged radioligand in plasma, confirms the suitability of (S)-[18F] 1 as PET radioligand for sigma-1 receptor imaging. [ABSTRACT FROM AUTHOR]

Published
2019
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204. German Society of Nuclear Medicine procedure guideline on beta-amyloid brain PET imaging

Author

Barthel, Henryk, Meyer, Philipp T., Drzezga, Alexander, Bartenstein, Peter, Boecker, Henning, Brust, Peter, Buchert, Ralph, Coenen, Heinz. H., la Fougere, Christian, Gruender, Gerhard, Gruenwald, Frank, Krause, Bernd J., Kuwert, Torsten, Schreckenberger, Matthias, Tatsch, Klaus, Langen, Karl-Josef, Sabri, Osama, Barthel, Henryk, Meyer, Philipp T., Drzezga, Alexander, Bartenstein, Peter, Boecker, Henning, Brust, Peter, Buchert, Ralph, Coenen, Heinz. H., la Fougere, Christian, Gruender, Gerhard, Gruenwald, Frank, Krause, Bernd J., Kuwert, Torsten, Schreckenberger, Matthias, Tatsch, Klaus, Langen, Karl-Josef, and Sabri, Osama

Abstract

Recently, a number of positron emission tomography (PET) radiotracers have been approved for clinical use. These tracers target cerebral beta-amyloid (AP) plaques, a hallmark of Alzheimer's disease. Increasing use of this method implies the need for respective standards. This German Society of Nuclear Medicine guideline describes adequate procedures for A beta plaque PET imaging. It not only discusses the tracers used for that purpose, but also lists measures for correct patient preparation, image data generation, processing, analysis and interpretation. With that, this S1 category (according to the German Association of the Scientific Medical Societies standard) guideline aims at contributing to quality assurance of nuclear imaging in Germany.

Published
2016

205. Changes in Binding of [123I]CLINDE, a High-Affinity Translocator Protein 18 kDa (TSPO) Selective Radioligand in a Rat Model of Traumatic Brain Injury

Author

Donat, Cornelius K, Gaber, Khaled, Meixensberger, Jürgen, Brust, Peter, Pinborg, Lars H, Hansen, Henrik H, Mikkelsen, Jens D, Donat, Cornelius K, Gaber, Khaled, Meixensberger, Jürgen, Brust, Peter, Pinborg, Lars H, Hansen, Henrik H, and Mikkelsen, Jens D

Abstract

After traumatic brain injury (TBI), secondary injuries develop, including neuroinflammatory processes that contribute to long-lasting impairments. These secondary injuries represent potential targets for treatment and diagnostics. The translocator protein 18 kDa (TSPO) is expressed in activated microglia cells and upregulated in response to brain injury and therefore a potential biomarker of the neuroinflammatory processes. Second-generation radioligands of TSPO, such as [(123)I]CLINDE, have a higher signal-to-noise ratio as the prototype ligand PK11195. [(123)I]CLINDE has been employed in human studies using single-photon emission computed tomography to image the neuroinflammatory response after stroke. In this study, we used the same tracer in a rat model of TBI to determine changes in TSPO expression. Adult Sprague-Dawley rats were subjected to moderate controlled cortical impact injury and sacrificed at 6, 24, 72 h and 28 days post surgery. TSPO expression was assessed in brain sections employing [(123)I]CLINDE in vitro autoradiography. From 24 h to 28 days post surgery, injured animals exhibited a marked and time-dependent increase in [(123)I]CLINDE binding in the ipsilateral motor, somatosensory and parietal cortex, as well as in the hippocampus and thalamus. Interestingly, binding was also significantly elevated in the contralateral M1 motor cortex following TBI. Craniotomy without TBI caused a less marked increase in [(123)I]CLINDE binding, restricted to the ipsilateral hemisphere. Radioligand binding was consistent with an increase in TSPO mRNA expression and CD11b immunoreactivity at the contusion site. This study demonstrates the applicability of [(123)I]CLINDE for detailed regional and quantitative assessment of glial activity in experimental models of TBI.

Published
2016

207. Comparison of in Silico, Electrochemical, in Vitro and in Vivo Metabolism of a Homologous Series of (Radio)fluorinated σ1Receptor Ligands Designed for Positron Emission Tomography

Author

Wiese, Christian, primary, Große Maestrup, Eva, additional, Galla, Fabian, additional, Schepmann, Dirk, additional, Hiller, Achim, additional, Fischer, Steffen, additional, Ludwig, Friedrich-Alexander, additional, Deuther-Conrad, Winnie, additional, Donat, Cornelius K., additional, Brust, Peter, additional, Büter, Lars, additional, Karst, Uwe, additional, and Wünsch, Bernhard, additional

Published
2016
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208. LC-MS Supported Studies on the in Vitro Metabolism of both Enantiomers of Flubatine and the in Vivo Metabolism of (+)-[18F]Flubatine—A Positron Emission Tomography Radioligand for Imaging α4β2 Nicotinic Acetylcholine Receptors

Author

Ludwig, Friedrich-Alexander, primary, Smits, René, additional, Fischer, Steffen, additional, Donat, Cornelius, additional, Hoepping, Alexander, additional, Brust, Peter, additional, and Steinbach, Jörg, additional

Published
2016
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209. Evaluation of the Enantiomer Specific Biokinetics and Radiation Doses of [18F]Fluspidine—A New Tracer in Clinical Translation for Imaging of σ1 Receptors

Author

Kranz, Mathias, primary, Sattler, Bernhard, additional, Wüst, Nathanael, additional, Deuther-Conrad, Winnie, additional, Patt, Marianne, additional, Meyer, Philipp, additional, Fischer, Steffen, additional, Donat, Cornelius, additional, Wünsch, Bernhard, additional, Hesse, Swen, additional, Steinbach, Jörg, additional, Brust, Peter, additional, and Sabri, Osama, additional

Published
2016
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210. Development of a High-Affinity PET Radioligand for Imaging Cannabinoid Subtype 2 Receptor

Author

Moldovan, Rareş-Petru, primary, Teodoro, Rodrigo, additional, Gao, Yongjun, additional, Deuther-Conrad, Winnie, additional, Kranz, Mathias, additional, Wang, Yuchuan, additional, Kuwabara, Hiroto, additional, Nakano, Masayoshi, additional, Valentine, Heather, additional, Fischer, Steffen, additional, Pomper, Martin G., additional, Wong, Dean F., additional, Dannals, Robert F., additional, Brust, Peter, additional, and Horti, Andrew G., additional

Published
2016
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211. Varying Chirality Across Nicotinic Acetylcholine Receptor Subtypes: Selective Binding of Quinuclidine Triazole Compounds

Author

Sarasamkan, Jiradanai, primary, Scheunemann, Matthias, additional, Apaijai, Nattayaporn, additional, Palee, Siripong, additional, Parichatikanond, Warisara, additional, Arunrungvichian, Kuntarat, additional, Fischer, Steffen, additional, Chattipakorn, Siriporn, additional, Deuther-Conrad, Winnie, additional, Schüürmann, Gerrit, additional, Brust, Peter, additional, and Vajragupta, Opa, additional

Published
2016
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212. Beta-Amyloid-PET-Bildgebung des Gehirns

Author

Meyer, Philipp, primary, Drzezga, Alexander, primary, Bartenstein, Peter, primary, Boecker, Henning, primary, Brust, Peter, primary, Buchert, Ralph, primary, Coenen, Heinz, primary, Fougère, Christian la, primary, Gründer, Gerhard, primary, Grünwald, Frank, primary, Krause, Bernd, primary, Kuwert, Torsten, primary, Schreckenberger, Matthias, primary, Tatsch, Klaus, primary, Langen, Karl-Josef, primary, Sabri, Osama, primary, and Barthel, Henryk, additional

Published
2016
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214. A novel thermoregulatory role for PDE 10A in mouse and human adipocytes

Author

Hankir, Mohammed K, primary, Kranz, Mathias, additional, Gnad, Thorsten, additional, Weiner, Juliane, additional, Wagner, Sally, additional, Deuther‐Conrad, Winnie, additional, Bronisch, Felix, additional, Steinhoff, Karen, additional, Luthardt, Julia, additional, Klöting, Nora, additional, Hesse, Swen, additional, Seibyl, John P, additional, Sabri, Osama, additional, Heiker, John T, additional, Blüher, Matthias, additional, Pfeifer, Alexander, additional, Brust, Peter, additional, and Fenske, Wiebke K, additional

Published
2016
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216. Development of a New Radiofluorinated Quinoline Analog for PET Imaging of Phosphodiesterase 5 (PDE5) in Brain

Author

Liu, Jianrong, primary, Wenzel, Barbara, additional, Dukic-Stefanovic, Sladjana, additional, Teodoro, Rodrigo, additional, Ludwig, Friedrich-Alexander, additional, Deuther-Conrad, Winnie, additional, Schröder, Susann, additional, Chezal, Jean-Michel, additional, Moreau, Emmanuel, additional, Brust, Peter, additional, and Maisonial-Besset, Aurélie, additional

Published
2016
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217. Development of a Novel Nonpeptidic 18F-Labeled Radiotracer for in Vivo Imaging of Oxytocin Receptors with Positron Emission Tomography

Author

Wenzel, Barbara, primary, Mollitor, Jan, additional, Deuther-Conrad, Winnie, additional, Dukic-Stefanovic, Sladjana, additional, Kranz, Mathias, additional, Vraka, Chrysoula, additional, Teodoro, Rodrigo, additional, Günther, Robert, additional, Donat, Cornelius K., additional, Ludwig, Friedrich-Alexander, additional, Fischer, Steffen, additional, Smits, Rene, additional, Wadsak, Wolfgang, additional, Mitterhauser, Markus, additional, Steinbach, Jörg, additional, Hoepping, Alexander, additional, and Brust, Peter, additional

Published
2016
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218. Use of 3-[18F]fluoropropanesulfonyl chloride as prosthetic agent for the radiolabelling of amines: Investigation of precursor molecules, labelling conditions and enzymatic stability of the corresponding sulfonamides

Author

Maisonial-Besset, Aurélie, Löser, Reik, Fischer, Steffen, Hiller, Achim, Köckerling, Martin, Funke, Uta, Maisonial, Aurélie, Brust, Peter, Steinbach, Jörg, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Synthèse et étude de systèmes à intêret biologique (SEESIB), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), and Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
hydrolytic metabolism, 010402 general chemistry, 01 natural sciences, Chloride, Full Research Paper, lcsh:QD241-441, chemistry.chemical_compound, lcsh:Organic chemistry, Nucleophile, Labelling, sulfonamides, medicine, Organic chemistry, Molecule, [CHIM]Chemical Sciences, radiochemistry, lcsh:Science, ComputingMilieux_MISCELLANEOUS, Sulfonyl, chemistry.chemical_classification, Thiocyanate, 010405 organic chemistry, Organic Chemistry, Radiosynthesis, 0104 chemical sciences, Chemistry, chemistry, fluorine-18, prosthetic groups, lcsh:Q, Fluoride, [CHIM.RADIO]Chemical Sciences/Radiochemistry, medicine.drug
Abstract

3-[18F]Fluoropropanesulfonyl chloride, a recently proposed prosthetic agent for fluorine-18 labelling, was prepared in a two-step radiosynthesis via 3-[18F]fluoropropyl thiocyanate as an intermediate. Two benzenesulfonate-based radiolabelling precursors were prepared by various routes. Comparing the reactivities of 3-thiocyanatopropyl nosylate and the corresponding tosylate towards [18F]fluoride the former proved to be superior accounting for labelling yields of up to 85%. Conditions for a reliable transformation of 3-[18F]fluoropropyl thiocyanate to the corresponding sulfonyl chloride with the potential for automation have been identified. The reaction of 3-[18F]fluoropropanesulfonyl chloride with eight different aliphatic and aromatic amines was investigated and the identity of the resulting 18F-labelled sulfonamides was confirmed chromatographically by comparison with their nonradioactive counterparts. Even for weakly nucleophilic amines such as 4-nitroaniline the desired radiolabelled sulfonamides were accessible in satisfactory yields owing to systematic variation of the reaction conditions. With respect to the application of the 18F-fluoropropansulfonyl group to the labelling of compounds relevant as imaging agents for positron emission tomography (PET), the stability of N-(4-fluorophenyl)-3-fluoropropanesulfonamide against degradation catalysed by carboxylesterase was investigated and compared to that of the analogous fluoroacetamide.

Published
2013

219. Investigation of an 18F-labelled Imidazopyridotriazine for Molecular Imaging of Cyclic Nucleotide Phosphodiesterase 2A.

Author

Schröder, Susann, Wenzel, Barbara, Deuther-Conrad, Winnie, Teodoro, Rodrigo, Kranz, Mathias, Scheunemann, Matthias, Egerland, Ute, Höfgen, Norbert, Briel, Detlef, Steinbach, Jörg, and Brust, Peter

Abstract

Specific radioligands for in vivo visualization and quantification of cyclic nucleotide phosphodiesterase 2A (PDE2A) by positron emission tomography (PET) are increasingly gaining interest in brain research. Herein we describe the synthesis, the 18F-labelling as well as the biological evaluation of our latest PDE2A (radio-)ligand 9-(5-Butoxy-2-fluorophenyl)-2-(2-([18F])fluoroethoxy)- 7-methylimidazo[5,1-c]pyrido[2,3-e][1,2,4]triazine (([18F])TA5). It is the most potent PDE2A ligand out of our series of imidazopyridotriazine-based derivatives so far (IC50 hPDE2A = 3.0 nM; IC50 hPDE10A > 1000 nM). Radiolabelling was performed in a one-step procedure starting from the corresponding tosylate precursor. In vitro autoradiography on rat and pig brain slices displayed a homogenous and non-specific binding of the radioligand. Investigation of stability in vivo by reversed-phase HPLC (RP-HPLC) and micellar liquid chromatography (MLC) analyses of plasma and brain samples obtained from mice revealed a high fraction of one main radiometabolite. Hence, we concluded that [18F]TA5 is not appropriate for molecular imaging of PDE2A neither in vitro nor in vivo. Our ongoing work is focusing on further structurally modified compounds with enhanced metabolic stability. [ABSTRACT FROM AUTHOR]

Published
2018
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220. Bridging from Brain to Tumor Imaging: (S)-(--)- and (R)-(+)-[18F]Fluspidine for Investigation of Sigma-1 Receptors in Tumor-Bearing Mice.

Author

Kranz, Mathias, Bergmann, Ralf, Kniess, Torsten, Belter, Birgit, Neuber, Christin, Cai, Zhengxin, Deng, Gang, Fischer, Steffen, Zhou, Jiangbing, Huang, Yiyun, Brust, Peter, Deuther-Conrad, Winnie, and Pietzsch, Jens

Abstract

Abstract Sigma-1 receptors (Sig1R) are highly expressed in various human cancer cells and hence imaging of this target with positron emission tomography (PET) can contribute to a better understanding of tumor pathophysiology and support the development of antineoplastic drugs. Two Sig1R-specific radiolabeled enantiomers (S)-(−)- and (R)-(+)-[18F]fluspidine were investigated in several tumor cell lines including melanoma, squamous cell/epidermoid carcinoma, prostate carcinoma, and glioblastoma. Dynamic PET scans were performed in mice to investigate the suitability of both radiotracers for tumor imaging. The Sig1R expression in the respective tumors was confirmed by Western blot. Rather low radiotracer uptake was found in heterotopically (subcutaneously) implanted tumors. Therefore, a brain tumor model (U87-MG) with orthotopic implantation was chosen to investigate the suitability of the two Sig1R radiotracers for brain tumor imaging. High tumor uptake as well as a favorable tumor-to-background ratio was found. These results suggest that Sig1R PET imaging of brain tumors with [18F]fluspidine could be possible. Further studies with this tumor model will be performed to confirm specific binding and the integrity of the blood-brain barrier (BBB). [ABSTRACT FROM AUTHOR]

Published
2018
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221. Exploring the Metabolism of (+)-[18F]Flubatine In Vitro and In Vivo: LC-MS/MS Aided Identification of Radiometabolites in a Clinical PET Study.

Author

Ludwig, Friedrich-Alexander, Fischer, Steffen, Smits, René, Deuther-Conrad, Winnie, Hoepping, Alexander, Tiepolt, Solveig, Patt, Marianne, Sabri, Osama, and Brust, Peter

Subjects
ENANTIOMERS, RADIOLIGAND assay, NICOTINIC acetylcholine receptors, POSITRON emission tomography, GLUCURONIDES, LIVER microsomes
Abstract

Both (+)-[18F]flubatine and its enantiomer (−)-[18F]flubatine are radioligands for the neuroimaging of α4β2 nicotinic acetylcholine receptors (nAChRs) by positron emission tomography (PET). In a clinical study in patients with early Alzheimer’s disease, (+)-[18F]flubatine ((+)-[18F]1) was examined regarding its metabolic fate, in particular by identification of degradation products detected in plasma and urine. The investigations included an in vivo study of (+)-flubatine ((+)-1) in pigs and structural elucidation of formed metabolites by LC-MS/MS. Incubations of (+)-1 and (+)-[18F]1 with human liver microsomes were performed to generate in vitro metabolites, as well as radiometabolites, which enabled an assignment of their structures by comparison of LC-MS/MS and radio-HPLC data. Plasma and urine samples taken after administration of (+)-[18F]1 in humans were examined by radio-HPLC and, on the basis of results obtained in vitro and in vivo, formed radiometabolites were identified. In pigs, (+)-1 was monohydroxylated at different sites of the azabicyclic ring system of the molecule. Additionally, one intermediate metabolite underwent glucuronidation, as also demonstrated in vitro. In humans, a fraction of 95.9 ± 1.9% (n = 10) of unchanged tracer remained in plasma, 30 min after injection. However, despite the low metabolic degradation, both radiometabolites formed in humans could be characterized as (i) a product of C-hydroxylation at the azabicyclic ring system, and (ii) a glucuronide conjugate of the precedingly-formed N8-hydroxylated (+)-[18F]1. [ABSTRACT FROM AUTHOR]

Published
2018
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222. Radiosynthesis and Radiotracer Properties of a 7-(2-[18F]Fluoroethoxy)-6-methoxypyrrolidinylquinazoline for Imaging of Phosphodiesterase 10A with PET

Author

Maisonial-Besset, Aurélie, Funke, Uta, Deuther-Conrad, Winnie, Schwan, Gregor, Maisonial, Aurélie, Scheunemann, Matthias, Fischer, Steffen, Hiller, Achim, Briel, Detlef, Brust, Peter, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Institute of Radiopharmacy, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Synthèse et étude de systèmes à intêret biologique (SEESIB), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), and Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Pathology, medicine.medical_specialty, Biodistribution, positron emission tomography, lcsh:Medicine, lcsh:RS1-441, Pharmaceutical Science, PDE10A, quinazoline, fluorine-18, PET, Article, lcsh:Pharmacy and materia medica, 03 medical and health sciences, 0302 clinical medicine, In vivo, Drug Discovery, Radioligand, Medicine, [CHIM]Chemical Sciences, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, business.industry, [CHIM.ORGA]Chemical Sciences/Organic chemistry, lcsh:R, Radiosynthesis, Phosphodiesterase, Ligand (biochemistry), Intracellular signal transduction, Biochemistry, Molecular Medicine, business, [CHIM.RADIO]Chemical Sciences/Radiochemistry, 030217 neurology & neurosurgery
Abstract

Phosphodiesterase 10A (PDE10A) is a key enzyme of intracellular signal transduction which is involved in the regulation of neurotransmission. The molecular imaging of PDE10A by PET is expected to allow a better understanding of physiological and pathological processes related to PDE10A expression and function in the brain. The aim of this study was to develop a new 18F-labeled PDE10A ligand based on a 6,7-dimethoxy-4-pyrrolidinylquinazoline and to evaluate its properties in biodistribution studies. Nucleophilic substitution of the 7-tosyloxy-analogue led to the 7-[18F]fluoroethoxy-derivative [18F]IV with radiochemical yields of 25% ± 9% (n = 9), high radiochemical purity of ≥99% and specific activities of 110–1,100 GBq/μmol. [18F]IV showed moderate PDE10A affinity (KD,PDE10A = 14 nM) and high metabolic stability in the brain of female CD-1 mice, wherein the radioligand entered rapidly with a peak uptake of 2.3% ID/g in striatum at 5 min p.i. However, ex vivo autoradiographic and in vivo blocking studies revealed no target specific accumulation and demonstrated [18F]IV to be inapplicable for imaging PDE10A with PET.

Published
2012

226. PET imaging evaluation of [18F]DBT-10, a novel radioligand specific to α7 nicotinic acetylcholine receptors, in nonhuman primates

Author

Hillmer, Ansel T., primary, Zheng, Ming-Qiang, additional, Li, Songye, additional, Scheunemann, Matthias, additional, Lin, Shu-fei, additional, Holden, Daniel, additional, Labaree, David, additional, Ropchan, Jim, additional, Teodoro, Rodrigo, additional, Deuther-Conrad, Winnie, additional, Carson, Richard E., additional, Brust, Peter, additional, and Huang, Yiyun, additional

Published
2015
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227. A Promising PET Tracer for Imaging of α7 Nicotinic Acetylcholine Receptors in the Brain: Design, Synthesis, and in Vivo Evaluation of a Dibenzothiophene-Based Radioligand

Author

Teodoro, Rodrigo, primary, Scheunemann, Matthias, additional, Deuther-Conrad, Winnie, additional, Wenzel, Barbara, additional, Fasoli, Francesca, additional, Gotti, Cecilia, additional, Kranz, Mathias, additional, Donat, Cornelius, additional, Patt, Marianne, additional, Hillmer, Ansel, additional, Zheng, Ming-Qiang, additional, Peters, Dan, additional, Steinbach, Jörg, additional, Sabri, Osama, additional, Huang, Yiyun, additional, and Brust, Peter, additional

Published
2015
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228. First-in-human PET quantification study of cerebral α4β2* nicotinic acetylcholine receptors using the novel specific radioligand (−)-[18F]Flubatine

Author

Sabri, Osama, primary, Becker, Georg-Alexander, additional, Meyer, Philipp M., additional, Hesse, Swen, additional, Wilke, Stephan, additional, Graef, Susanne, additional, Patt, Marianne, additional, Luthardt, Julia, additional, Wagenknecht, Gudrun, additional, Hoepping, Alexander, additional, Smits, René, additional, Franke, Annegret, additional, Sattler, Bernhard, additional, Habermann, Bernd, additional, Neuhaus, Petra, additional, Fischer, Steffen, additional, Tiepolt, Solveig, additional, Deuther-Conrad, Winnie, additional, Barthel, Henryk, additional, Schönknecht, Peter, additional, and Brust, Peter, additional

Published
2015
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229. 18F-Labeled 1,4-Dioxa-8-azaspiro[4.5]decane Derivative: Synthesis and Biological Evaluation of a σ1 Receptor Radioligand with Low Lipophilicity as Potent Tumor Imaging Agent

Author

Xie, Fang, primary, Bergmann, Ralf, additional, Kniess, Torsten, additional, Deuther-Conrad, Winnie, additional, Mamat, Constantin, additional, Neuber, Christin, additional, Liu, Boli, additional, Steinbach, Jörg, additional, Brust, Peter, additional, Pietzsch, Jens, additional, and Jia, Hongmei, additional

Published
2015
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231. Synthesis, 18F-Radiolabelling and Biological Characterization of Novel Fluoroalkylated Triazine Derivatives for in Vivo Imaging of Phosphodiesterase 2A in Brain via Positron Emission Tomography

Author

Schröder, Susann, primary, Wenzel, Barbara, additional, Deuther-Conrad, Winnie, additional, Teodoro, Rodrigo, additional, Egerland, Ute, additional, Kranz, Mathias, additional, Scheunemann, Matthias, additional, Höfgen, Norbert, additional, Steinbach, Jörg, additional, and Brust, Peter, additional

Published
2015
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232. Novel indole-based sigma-2 receptor ligands: synthesis, structure–affinity relationship and antiproliferative activity

Author

Xie, Fang, primary, Kniess, Torsten, additional, Neuber, Christin, additional, Deuther-Conrad, Winnie, additional, Mamat, Constantin, additional, Lieberman, Brian P., additional, Liu, Boli, additional, Mach, Robert H., additional, Brust, Peter, additional, Steinbach, Jörg, additional, Pietzsch, Jens, additional, and Jia, Hongmei, additional

Published
2015
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236. PET imaging of α nicotinic acetylcholine receptors: a comparative study of [F]ASEM and [F]DBT-10 in nonhuman primates, and further evaluation of [F]ASEM in humans.

Author

Hillmer, Ansel, Li, Songye, Zheng, Ming-Qiang, Scheunemann, Matthias, Lin, Shu-fei, Nabulsi, Nabeel, Holden, Daniel, Pracitto, Richard, Labaree, David, Ropchan, Jim, Teodoro, Rodrigo, Deuther-Conrad, Winnie, Esterlis, Irina, Cosgrove, Kelly, Brust, Peter, Carson, Richard, and Huang, Yiyun

Subjects
NEUROBEHAVIORAL disorders, POSITRON emission tomography, NICOTINIC acetylcholine receptors, VARENICLINE, THIOPHENE derivatives, PRIMATES as laboratory animals, DIAGNOSIS
Abstract

Purpose: The α nicotinic acetylcholine receptor (nAChR) is implicated in many neuropsychiatric disorders, making it an important target for positron emission tomography (PET) imaging. The first aim of this work was to compare two α nAChRs PET radioligands, [F]ASEM (3-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-6-([F]fluorodibenzo[ b,d]thiophene 5,5-dioxide) and [F]DBT-10 (7-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-2-([F]fluorodibenzo[ b,d]thiophene 5,5-dioxide), in nonhuman primates. The second aim was to assess further the quantification and test-retest variability of [F]ASEM in humans. Methods: PET scans with high specific activity [F]ASEM or [F]DBT-10 were acquired in three rhesus monkeys (one male, two female), and the kinetic properties of these radiotracers were compared. Additional [F]ASEM PET scans with blocking doses of nicotine, varenicline, and cold ASEM were acquired separately in two animals. Next, six human subjects (five male, one female) were imaged with [F]ASEM PET for 180 min, and arterial sampling was used to measure the parent input function. Different modeling approaches were compared to identify the optimal analysis method and scan duration for quantification of [F]ASEM distribution volume ( V ). In addition, retest scans were acquired in four subjects (three male, one female), and the test-retest variability of V was assessed. Results: In the rhesus monkey brain [F]ASEM and [F]DBT-10 exhibited highly similar kinetic profiles. Dose-dependent blockade of [F]ASEM binding was observed, while administration of either nicotine or varenicline did not change [F]ASEM V . [F]ASEM was selected for further validation because it has been used in humans. Accurate quantification of [F]ASEM V in humans was achieved using multilinear analysis with at least 90 min of data acquisition, resulting in V values ranging from 19.6 ± 2.5 mL/cm in cerebellum to 25.9 ± 2.9 mL/cm in thalamus. Test-retest variability of V was 11.7 ± 9.8%. Conclusions: These results confirm [F]ASEM as a suitable radiotracer for the imaging and quantification of α nAChRs in humans. [ABSTRACT FROM AUTHOR]

Published
2017
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238. Radiosynthesis and biological evaluation of the new PDE10A radioligand [18F]AQ28A.

Author

Wagner, Sally, Teodoro, Rodrigo, Deuther ‐ Conrad, Winnie, Kranz, Mathias, Scheunemann, Matthias, Fischer, Steffen, Wenzel, Barbara, Egerland, Ute, Hoefgen, Norbert, Steinbach, Jörg, and Brust, Peter

Subjects
CYCLIC nucleotide phosphodiesterases, NEURODEGENERATION, PATHOLOGICAL psychology -- Risk factors, POSITRON emission tomography, RADIOLIGAND assay
Abstract

Cyclic nucleotide phosphodiesterase 10A (PDE10A) regulates the level of the second messengers cAMP and cGMP in particular in brain regions assumed to be associated with neurodegenerative and psychiatric diseases. A better understanding of the pathophysiological role of the expression of PDE10A could be obtained by quantitative imaging of the enzyme by positron emission tomography (PET). Thus, in this study we developed, radiolabeled, and evaluated a new PDE10A radioligand, 8-bromo-1-(6-[18F]fluoropyridin-3-yl)-3,4-dimethylimidazo[1,5- a]quinoxaline ([18F] AQ28A). [18F] AQ28A was radiolabeled by both nucleophilic bromo-to-fluoro or nitro-to-fluoro exchange using K[18F]F-K2.2.2-carbonate complex with different yields. Using the superior nitro precursor, we developed an automated synthesis on a Tracerlab FX F-N module and obtained [18F] AQ28A with high radiochemical yields (33 ± 6%) and specific activities (96-145 GBq·μmol−1) for further evaluation. Initially, we investigated the binding of [18F] AQ28A to the brain of different species by autoradiography and observed the highest density of binding sites in striatum, the brain region with the highest PDE10A expression. Subsequent dynamic PET studies in mice revealed a region-specific accumulation of [18F] AQ28A in this region, which could be blocked by preinjection of the selective PDE10A ligand MP-10. In conclusion, the data suggest [18F] AQ28A is a suitable candidate for imaging of PDE10A in rodent brain by PET. [ABSTRACT FROM AUTHOR]

Published
2017
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240. Internal Dose Assessment of (–)-18F-Flubatine, Comparing Animal Model Datasets of Mice and Piglets with First-in-Human Results

Author

Sattler, Bernhard, primary, Kranz, Mathias, additional, Starke, Alexander, additional, Wilke, Stephan, additional, Donat, Cornelius K., additional, Deuther-Conrad, Winnie, additional, Patt, Marianne, additional, Schildan, Andreas, additional, Patt, Jörg, additional, Smits, René, additional, Hoepping, Alexander, additional, Schoenknecht, Peter, additional, Steinbach, Jörg, additional, Brust, Peter, additional, and Sabri, Osama, additional

Published
2014
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242. Distinctive In Vivo Kinetics of the New σ1 Receptor Ligands (R)-(+)- and (S)-(–)-18F-Fluspidine in Porcine Brain

Author

Brust, Peter, primary, Deuther-Conrad, Winnie, additional, Becker, Georg, additional, Patt, Marianne, additional, Donat, Cornelius K., additional, Stittsworth, Shannon, additional, Fischer, Steffen, additional, Hiller, Achim, additional, Wenzel, Barbara, additional, Dukic-Stefanovic, Sladjana, additional, Hesse, Swen, additional, Steinbach, Jörg, additional, Wünsch, Bernhard, additional, Lever, Susan Z., additional, and Sabri, Osama, additional

Published
2014
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243. Evaluation of metabolism, plasma protein binding and other biological parameters after administration of (−)-[18F]Flubatine in humans

Author

Patt, Marianne, primary, Becker, Georg A., additional, Grossmann, Udo, additional, Habermann, Bernd, additional, Schildan, Andreas, additional, Wilke, Stephan, additional, Deuther-Conrad, Winnie, additional, Graef, Susanne, additional, Fischer, Steffen, additional, Smits, René, additional, Hoepping, Alexander, additional, Wagenknecht, Gudrun, additional, Steinbach, Jörg, additional, Gertz, Hermann-Josef, additional, Hesse, Swen, additional, Schönknecht, Peter, additional, Brust, Peter, additional, and Sabri, Osama, additional

Published
2014
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246. Fluorine-Containing 6,7-Dialkoxybiaryl-Based Inhibitors for Phosphodiesterase 10 A: Synthesis and in vitro Evaluation of Inhibitory Potency, Selectivity, and Metabolism

Author

Schwan, Gregor, primary, Barbar Asskar, Ghadir, additional, Höfgen, Norbert, additional, Kubicova, Lenka, additional, Funke, Uta, additional, Egerland, Ute, additional, Zahn, Michael, additional, Nieber, Karen, additional, Scheunemann, Matthias, additional, Sträter, Norbert, additional, Brust, Peter, additional, and Briel, Detlef, additional

Published
2014
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249. Resistance of brain glucose metabolism to thiopental-induced CNS depression in newborn piglets

Author

Walter, Bernd, Eiselt, Michael, Cumming, Paul, Xiong, Guoming, Hinz, Rainer, Uthe, Susanne, Brust, Peter, Bauer, Reinhard, Walter, Bernd, Eiselt, Michael, Cumming, Paul, Xiong, Guoming, Hinz, Rainer, Uthe, Susanne, Brust, Peter, and Bauer, Reinhard

Abstract

The transition from mild sedation to deep anaesthesia is marked by the phenomenon of burst suppression (BS). FDG-PET studies show that the cerebral metabolic rate for glucose (CMRglc) declines dramatically with onset of BS in the adult brain. Global CMRglc increases substantially in the post-natal period and achieves its maximum in preadolescence. However, the impact of post-natal brain development on the vulnerability of CMRglc to the onset of BS has not been documented. Therefore, cerebral blood flow and metabolism were measured using a variant of the Kety–Schmidt method, in conjunction with quantitative regional estimation of brain glucose uptake by FDG-PET in groups of neonate and juvenile pigs, under a condition of light sedation or after induction of deep anaesthesia with thiopental. Quantification of simultaneous ECoG recordings was used to establish the correlation between anaesthesia-related changes in brain electrical activity and the observed cerebrometabolic changes. In the condition of light sedation the magnitude of CMRglc was approximately 20% higher in the older pigs, with the greatest developmental increase evident in the cerebral cortex and basal ganglia (P < 0.05). Onset of BS was associated with 20–40% declines in CMRglc. Subtraction of the mean parametric maps for CMRglc showed the absolute reductions in CMRglc evoked by thiopental anaesthesia to be two-fold greater in the pre-adolescent pigs than in the neonates (P < 0.05). Thus, the lesser suppression of brain energy demand of neonate brain during deep anaesthesia represents a reduced part of thiopental suppressing brain metabolism in neonates.

Published
2013

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