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  1. Article ; Online: Heterogeneous cardiac sympathetic innervation gradients promote arrhythmogenesis in murine dilated cardiomyopathy

    Al-Hassan J. Dajani / Michael B. Liu / Michael A. Olaopa / Lucian Cao / Carla Valenzuela-Ripoll / Timothy J. Davis / Megan D. Poston / Elizabeth H. Smith / Jaime Contreras / Marissa Pennino / Christopher M. Waldmann / Donald B. Hoover / Jason T. Lee / Patrick Y. Jay / Ali Javaheri / Roger Slavik / Zhilin Qu / Olujimi A. Ajijola

    JCI Insight, Vol 8, Iss

    2023  Volume 22

    Abstract: Ventricular arrhythmias (VAs) in heart failure are enhanced by sympathoexcitation. However, radiotracer studies of catecholamine uptake in failing human hearts demonstrate a proclivity for VAs in patients with reduced cardiac sympathetic innervation. We ... ...

    Abstract Ventricular arrhythmias (VAs) in heart failure are enhanced by sympathoexcitation. However, radiotracer studies of catecholamine uptake in failing human hearts demonstrate a proclivity for VAs in patients with reduced cardiac sympathetic innervation. We hypothesized that this counterintuitive finding is explained by heterogeneous loss of sympathetic nerves in the failing heart. In a murine model of dilated cardiomyopathy (DCM), delayed PET imaging of sympathetic nerve density using the catecholamine analog [11C]meta-Hydroxyephedrine demonstrated global hypoinnervation in ventricular myocardium. Although reduced, sympathetic innervation in 2 distinct DCM models invariably exhibited transmural (epicardial to endocardial) gradients, with the endocardium being devoid of sympathetic nerve fibers versus controls. Further, the severity of transmural innervation gradients was correlated with VAs. Transmural innervation gradients were also identified in human left ventricular free wall samples from DCM versus controls. We investigated mechanisms underlying this relationship by in silico studies in 1D, 2D, and 3D models of failing and normal human hearts, finding that arrhythmogenesis increased as heterogeneity in sympathetic innervation worsened. Specifically, both DCM-induced myocyte electrical remodeling and spatially inhomogeneous innervation gradients synergistically worsened arrhythmogenesis. Thus, heterogeneous innervation gradients in DCM promoted arrhythmogenesis. Restoration of homogeneous sympathetic innervation in the failing heart may reduce VAs.
    Keywords Cardiology ; Medicine ; R
    Subject code 610
    Language English
    Publishing date 2023-11-01T00:00:00Z
    Publisher American Society for Clinical investigation
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article: PSMA ligands in prostate cancer – Probe optimization and theranostic applications

    Lütje, Susanne / Ken Herrmann / Matthias Eiber / Roger Slavik / Wolfgang Fendler

    Methods. 2017 Nov. 01, v. 130

    2017  

    Abstract: Due to its selective overexpression in prostate cancer (PCa), the prostate-specific membrane antigen (PSMA) has been recognized as a highly promising target for diagnostic and therapeutic applications. So far, various PSMA ligands have been developed for ...

    Abstract Due to its selective overexpression in prostate cancer (PCa), the prostate-specific membrane antigen (PSMA) has been recognized as a highly promising target for diagnostic and therapeutic applications. So far, various PSMA ligands have been developed for radiolabeling with radioisotopes such as 68Ga or 18F which can be used for specific visualization and diagnosis of PSMA-expressing PCa. In addition, PSMA ligands suitable for radiolabeling with 131I or 177Lu have become available to the clinics, allowing PSMA-based radioligand therapies. Here, we provide a comprehensive review of the most frequently used PSMA ligands, their structural modifications, and the impact of those on clinical applications.
    Keywords antigens ; ligands ; prostatic neoplasms ; radiolabeling ; radionuclides
    Language English
    Dates of publication 2017-1101
    Size p. 42-50.
    Publishing place Elsevier Inc.
    Document type Article
    ZDB-ID 1066584-5
    ISSN 1095-9130 ; 1046-2023
    ISSN (online) 1095-9130
    ISSN 1046-2023
    DOI 10.1016/j.ymeth.2017.06.026
    Database NAL-Catalogue (AGRICOLA)

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  3. Article ; Online: Synthesis and Preliminary Evaluation of a 2-Oxoquinoline Carboxylic Acid Derivative for PET Imaging the Cannabinoid Type 2 Receptor

    Linjing Mu / Roger Slavik / Adrienne Müller / Kasim Popaj / Stjepko Čermak / Markus Weber / Roger Schibli / Stefanie D. Krämer / Simon M. Ametamey

    Pharmaceuticals, Vol 7, Iss 3, Pp 339-

    2014  Volume 352

    Abstract: Cannabinoid receptor subtype 2 (CB2) has been shown to be up-regulated in activated microglia and therefore plays an important role in neuroinflammatory and neurodegenerative diseases such as multiple sclerosis, amyotrophic lateral sclerosis and ... ...

    Abstract Cannabinoid receptor subtype 2 (CB2) has been shown to be up-regulated in activated microglia and therefore plays an important role in neuroinflammatory and neurodegenerative diseases such as multiple sclerosis, amyotrophic lateral sclerosis and Alzheimer’s disease. The CB2 receptor is therefore considered as a very promising target for therapeutic approaches as well as for imaging. A promising 2-oxoquinoline derivative designated KP23 was synthesized and radiolabeled and its potential as a ligand for PET imaging the CB2 receptor was evaluated. [11C]KP23 was obtained in 10%–25% radiochemical yield (decay corrected) and 99% radiochemical purity. It showed high stability in phosphate buffer, rat and mouse plasma. In vitro autoradiography of rat and mouse spleen slices, as spleen expresses a high physiological expression of CB2 receptors, demonstrated that [11C]KP23 exhibits specific binding towards CB2. High spleen uptake of [11C]KP23 was observed in dynamic in vivo PET studies with Wistar rats. In conclusion, [11C]KP23 showed promising in vitro and in vivo characteristics. Further evaluation with diseased animal model which has higher CB2 expression levels in the brain is warranted.
    Keywords cannabinoid receptor type 2 ligand ; CB2 receptor ; neurodegeneration ; radiolabeling ; autoradiography ; small-animal PET ; Medicine ; R ; Pharmacy and materia medica ; RS1-441
    Subject code 570
    Language English
    Publishing date 2014-03-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Development and Evaluation of Novel PET Tracers for Imaging Cannabinoid Receptor Type 2 in Brain

    Roger Slavik / Daniel Bieri / Stjepko Čermak / Adrienne Müller / Stefanie D. Krämer / Markus Weber / Roger Schibli / Simon M. Ametamey / Linjing Mu

    CHIMIA, Vol 68, Iss

    2014  Volume 4

    Abstract: The cannabinoid receptor type 2 (CB2) has a very low expression level in brain tissue under basal conditions, but it is up-regulated in diverse pathological conditions. Two promising lead structures from the literature, N-((3S,5S,7S)-adamantan-1-yl)-8- ... ...

    Abstract The cannabinoid receptor type 2 (CB2) has a very low expression level in brain tissue under basal conditions, but it is up-regulated in diverse pathological conditions. Two promising lead structures from the literature, N-((3S,5S,7S)-adamantan-1-yl)-8-methoxy-4-oxo-1-pentyl-1,4-dihydroquinoline-3-carboxamide and 8-butoxy-N-(2-fluoro-2-phenylethyl)-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxamide – designated KD2 and KP23, respectively – were evaluated as potential PET ligands for imaging CB2. Both KD2 and KP23 were synthesized and labeled with carbon-11. In vitro autoradiographic studies on rodent spleen tissues showed that [11C]KD2 exhibits superior properties. A pilot study using [11C]KD2 on human post mortem ALS spinal cord slices indicated high CB2 expression level and specific binding, a very exciting finding if considering the future diagnostic application of CB2 ligands and their utility in therapy monitoring. In vivo blocking studies in rats with [11C]KD2 showed also high specific uptake in spleen tissue. Although the protein-bound fraction is relatively high, KD2 or KD2 derivatives could be very useful tools for the non-invasive investigation of CB2 levels under various neuroinflammatory conditions.
    Keywords Autoradiography ; Cannabinoid receptor type 2 ligand ; Neuroinflammation ; Positron emission tomography ; Radiolabeling ; Chemistry ; QD1-999
    Subject code 500
    Language German
    Publishing date 2014-04-01T00:00:00Z
    Publisher Swiss Chemical Society
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Preclinical evaluation of PSMA expression in response to androgen receptor blockade for theranostics in prostate cancer

    Katharina Lückerath / Liu Wei / Wolfgang P. Fendler / Susan Evans-Axelsson / Andreea D. Stuparu / Roger Slavik / Christine E. Mona / Jeremie Calais / Matthew Rettig / Robert E. Reiter / Ken Herrmann / Caius G. Radu / Johannes Czernin / Matthias Eiber

    EJNMMI Research, Vol 8, Iss 1, Pp 1-

    2018  Volume 9

    Abstract: Abstract Background Prostate-specific membrane antigen (PSMA)-directed radioligand therapy (RLT) is a promising yet not curative approach in castration-resistant (CR) prostate cancer (PC). Rational combination therapies may improve treatment efficacy. ... ...

    Abstract Abstract Background Prostate-specific membrane antigen (PSMA)-directed radioligand therapy (RLT) is a promising yet not curative approach in castration-resistant (CR) prostate cancer (PC). Rational combination therapies may improve treatment efficacy. Here, we explored the effect of androgen receptor blockade (ARB) on PSMA expression visualized by PET and its potential additive effect when combined with 177Lu-PSMA RLT in a mouse model of prostate cancer. Methods Mice bearing human CRPC (C4-2 cells) xenografts were treated with 10 mg/kg enzalutamide (ENZ), with 50 mg/kg bicalutamide (BIC), or vehicle (control) for 21 days. PSMA expression was evaluated by 68Ga-PSMA11 PET/CT and quantified by flow cytometry of tumor fine needle aspirations before treatment and on days 23, 29, 34, and 39 post-therapy induction. For the RLT combination approach, mice bearing C4-2 tumors were treated with 10 mg/kg ENZ or vehicle for 21 days before receiving either 15 MBq (84 GBq/μmol) 177Lu-PSMA617 or vehicle. DNA damage was assessed as phospho-γH2A.X foci in tumor biopsies. Reduction of tumor volume on CT and survival were used as study endpoints. Results Tumor growth was delayed by ARB while 68Ga-PSMA11 uptake increased up to 2.3-fold over time when compared to controls. ABR-induced upregulation of PSMA expression was confirmed by flow cytometry. Phospho-γH2A.X levels increased 1.8- and 3.4-fold at 48 h in response to single treatment ENZ or RLT and ENZ+RLT, respectively. Despite significantly greater DNA damage and persistent increase of PSMA expression at the time of RLT, no additional tumor growth retardation was observed in the ENZ+RLT group (vs. RLT only, p = 0.372 at day 81). Median survival did not improve significantly when ENZ was combined with RLT. Conclusion ARB-mediated increases in PSMA expression in PC xenografts were evident by 68Ga-PSMA11 PET imaging and flow cytometry. 177Lu-PSMA617 effectively decreased C4-2 tumor size. However, while pre-treatment with ARB increased DNA damage significantly, it did not result in ...
    Keywords PSMA ; Prostate cancer ; 68Ga-PSMA PET/CT ; Androgen receptor blockade ; Radioligand therapy ; Medical physics. Medical radiology. Nuclear medicine ; R895-920
    Language English
    Publishing date 2018-10-01T00:00:00Z
    Publisher SpringerOpen
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Synthesis and Biological Evaluation of a New Acyclic Pyrimidine Derivative as a Probe for Imaging Herpes Simplex Virus Type 1 Thymidine Kinase Gene Expression

    Simon M. Ametamey / Silvana Raić-Malić / Stjepko Čermak / Roger Slavik / Adrienne Müller / Thomas Betzel / Andrijana Meščić

    Molecules, Vol 18, Iss 7, Pp 8535-

    2013  Volume 8549

    Abstract: With the idea of finding a more selective radiotracer for imaging herpes simplex virus type 1 thymidine kinase (HSV1-tk) gene expression by means of positron emission tomography (PET), a novel [18F]fluorine radiolabeled pyrimidine with 4-hydroxy-3-( ... ...

    Abstract With the idea of finding a more selective radiotracer for imaging herpes simplex virus type 1 thymidine kinase (HSV1-tk) gene expression by means of positron emission tomography (PET), a novel [18F]fluorine radiolabeled pyrimidine with 4-hydroxy-3-(hydroxymethyl)butyl side chain at N-1 (HHB-5-[18F]FEP) was prepared and evaluated as a potential PET probe. Unlabeled reference compound, HHB-5-FEP, was synthesized via a five-step reaction sequence starting from 5-(2-acetoxyethyl)-4-methoxypyrimidin-2-one. The radiosynthesis of HHB-[18F]-FEP was accomplished by nucleophilic radiofluorination of a tosylate precursor using [18F]fluoride-cryptate complex in 45% ± 4 (n = 4) radiochemical yields and high purity (>99%). The biological evaluation indicated the feasibility of using HHB-5-[18F]FEP as a PET radiotracer for monitoring HSV1-tk expression in vivo.
    Keywords acyclic pyrimidine nucleoside analogues ; PCV-like side chain ; fluorination ; radiosynthesis ; positron emission tomography (PET) ; HSV1-TK ; Organic chemistry ; QD241-441
    Language English
    Publishing date 2013-07-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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