18 research outputs found

    Lithium Complexes of Neutral Bis-NHC Ligands

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    The employment of lithium hexamethyldisilazide for the deprotonation of methylene-bridged bis­(imidazolium) salts led to the formation of lithium carbene adducts. Depending on the crystallization method and the substituents of the ligands, monomeric, dimeric, or polymeric solid-state structures were obtained. These lithium carbene complexes represent the first examples of lithium complexes bearing neutral bis­(N-heterocyclic carbene) ligands

    Synthesis and Reactivity of Platinum(II) <i>cis</i>-Dialkyl, <i>cis</i>-Alkyl Chloro, and <i>cis-</i>Alkyl Hydrido Bis‑<i>N</i>‑heterocyclic Carbene Chelate Complexes

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    Platinum­(II) <i>cis-</i>dimethyl and <i>cis-</i>dineopentyl complexes bearing the alkyl-substituted bis-NHC ligands L<sup><i>t</i>‑Bu</sup>, L<sup>Me</sup>, and L<sup><i>i</i>‑Pr</sup> (L<sup><i>t</i>‑Bu</sup> = 1,1′-di-<i>tert</i>-butyl-3,3′-methylenedi­imid­azolin-2,2′-diylidene, L<sup>Me</sup> = 1,1′-dimethyl-3,3′-methylenedi­imid­azolin-2,2′-diylidene, L<sup><i>i</i>‑Pr</sup> = 1,1′-diisopropyl-3,3′-methylenedi­imid­azolin-2,2′-diylidene) as well as novel <i>cis-</i>alkyl chloro and <i>cis-</i>alkyl hydrido compounds were synthesized. The reactivity of the dimethyl complexes toward dichloromethane and methanol was investigated. Reductive elimination of alkanes from <i>cis-</i>alkyl hydrido complexes requires much higher temperatures than in related bisphosphine systems, which limits their applicability for the generation of reactive, bent platinum(0) d<sup>10</sup>-ML<sub>2</sub> fragments for bond-activation chemistry. The platinum­(II) complexes were characterized by NMR and IR spectroscopy, mass spectrometry, elemental analysis, and X-ray diffraction in most cases

    Development and Preclinical Evaluation of a Copper-64-Labeled Antibody Targeting Glycine-Alanine Dipeptides for PET Imaging of C9orf72‑Associated Amyotrophic Lateral Sclerosis/Frontotemporal Dementia

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    Aggregating poly(glycine-alanine) (poly-GA) is derived from the unconventional translation of the pathogenic intronic hexanucleotide repeat expansion in the C9orf72 gene, which is the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Poly-GA accumulates predominantly in neuronal cytoplasmic inclusions unique to C9orf72 ALS/FTD patients. Poly-GA is, therefore, a promising target for PET/CT imaging of FTD/ALS to monitor disease progression and therapeutic interventions. A novel 64Cu-labeled anti-GA antibody (mAb1A12) targeting the poly-GA protein was developed and evaluated in a transgenic mouse model. It was obtained with high radiochemical purity (RCP), radiochemical yield (RCY), and specific activity, and showed high stability in vitro and ex vivo and specifically bound to poly-GA. The affinity of NODAGA-mAb1A12 for poly-GA was not affected by this modification. [64Cu]Cu-NODAGA-mAb1A12 was injected into transgenic mice expressing GFP-(GA)175 in excitatory neurons driven by Camk2a-Cre and in control littermates. PET/CT imaging was performed at 2, 20, and 40 h post-injection (p.i.) and revealed a higher accumulation in the cortex in transgenic mice than in wild-type mice, as reflected by higher standardized uptake value ratios (SUVR) using the cerebellum as the reference region. The organs were isolated for biodistribution and ex vivo autoradiography. Autoradiography revealed a higher cortex-to-cerebellum ratio in the transgenic mice than in the controls. Results from autoradiography were validated by immunohistochemistry and poly-GA immunoassays. Moreover, we confirmed antibody uptake in the CNS in a pharmacokinetic study of the perfused tissues. In summary, [64Cu]Cu-NODAGA-mAb1A12 demonstrated favorable in vitro characteristics and an increased relative binding in poly-GA transgenic mice compared to wild-type mice in vivo. Our results with this first-in-class radiotracer suggested that targeting poly-GA is a promising approach for PET/CT imaging in FTD/ALS

    Cross-Sectional Comparison of Small Animal [<sup>18</sup>F]-Florbetaben Amyloid-PET between Transgenic AD Mouse Models

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    <div><p>We aimed to compare [<sup>18</sup>F]-florbetaben PET imaging in four transgenic mouse strains modelling Alzheimer’s disease (AD), with the main focus on APPswe/PS2 mice and C57Bl/6 mice serving as controls (WT). A consistent PET protocol (N = 82 PET scans) was used, with cortical standardized uptake value ratio (SUVR) relative to cerebellum as the endpoint. We correlated methoxy-X04 staining of β-amyloid with PET results, and undertook <i>ex vivo</i> autoradiography for further validation of a partial volume effect correction (PVEC) of PET data. The SUVR in APPswe/PS2 increased from 0.95±0.04 at five months (N = 5) and 1.04±0.03 (p<0.05) at eight months (N = 7) to 1.07±0.04 (p<0.005) at ten months (N = 6), 1.28±0.06 (p<0.001) at 16 months (N = 6) and 1.39±0.09 (p<0.001) at 19 months (N = 6). SUVR was 0.95±0.03 in WT mice of all ages (N = 22). In APPswe/PS1G384A mice, the SUVR was 0.93/0.98 at five months (N = 2) and 1.11 at 16 months (N = 1). In APPswe/PS1dE9 mice, the SUVR declined from 0.96/0.96 at 12 months (N = 2) to 0.91/0.92 at 24 months (N = 2), due to β-amyloid plaques in cerebellum. PVEC reduced the discrepancy between SUVR-PET and autoradiography from −22% to +2% and increased the differences between young and aged transgenic animals. SUVR and plaque load correlated highly between strains for uncorrected (R = 0.94, p<0.001) and PVE-corrected (R = 0.95, p<0.001) data. We find that APPswe/PS2 mice may be optimal for longitudinal amyloid-PET monitoring in planned interventions studies.</p></div

    Multi-modal analysis of the four AD mouse strains studies in this cross-sectional [<sup>18</sup>F]-florbetaben PET study.

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    <p>Upper images represent group averaged sagittal PET slices, normalised to the cerebellum and overlayed on an MRI mouse atlas [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0116678#pone.0116678.ref039" target="_blank">39</a>]. Dots indicate corresponding assessments of SUVR<sub>CTX/CBL</sub> in individual mice. Dashed lines express the estimated time dependent progression in PS2APP (red; five months: N = 5; eight months: N = 7; 10 months: N = 6; 12 months: N = 2; 16 months: N = 6, 19 months: N = 6), G384A (green; five months: N = 2; 16 months: N = 1) and APP/PS1dE9 (purple; 12 months: N = 2; 24 months: N = 2) mice, fitted with a polynomial function (for the purposes of illustration). Longitudinal progression in APPswe mice is indicated by a continuous blue line. Lower images depict representative <i>ex vivo</i> autoradiography results; autoradiography of APP/PS1dE9 mice and young G384A mice was performed <i>in vitro</i>. WT level expresses the mean SUVR<sub>CTX/CBL</sub> of pooled WT mice (N = 22).</p

    Amyloid-PET and <i>ex vivo</i> autoradiography in PS2APP mice before and after PVEC.

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    <p><b>(A)</b> Comparison of uncorrected [<sup>18</sup>F]-florbetaben PET images (upper row), corresponding <i>ex vivo</i> autoradiography (mid row) and PVE-corrected PET (lower row) of representative PS2APP mice at 8, 12 and 19 months of age. Sagittal PET images captured 1.6 mm left of the midline were scaled to cerebellum and overlain on a 3T MRI mouse template [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0116678#pone.0116678.ref013" target="_blank">13</a>]. PVEC was performed with a 10 region mask (four cerebral and six extracerebral VOIs). <b>(B)</b> Error-(%) (±SD) of uncorrected (black bar) and PVE-corrected (blue bar) data versus <i>ex vivo</i> autoradiography are shown for the whole group of PS2APP mice.</p

    Comparison of uncorrected (A) and PVE-corrected (B) SUVR<sub>CTX/CBL</sub> of the entire dataset.

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    <p>Dots indicate corresponding assessments of SUVR<sub>CTX/CBL</sub> in individual mice. Dashed lines express the estimated time dependent progression in PS2APP (red; five months: N = 5; eight months: N = 7; 10 months: N = 6; 12 months: N = 2; 16 months: N = 6, 19 months: N = 6), G384A (green; five months: N = 2; 16 months: N = 1) and APP/PS1dE9 (purple; 12 months: N = 2; 24 months: N = 2) mice, fitted with a polynomial function (for the purposes of illustration). Longitudinal progression in APPswe mice is indicated by a continuous blue line. P-values for one-way ANOVA (incl. post hoc Tukey) testing of PS2APP and APPswe mice versus youngest littermates were as indicated: * p < 0.05; ** p < 0.005; *** p < 0.001.</p

    Table_1_Clinical Routine FDG-PET Imaging of Suspected Progressive Supranuclear Palsy and Corticobasal Degeneration: A Gatekeeper for Subsequent Tau-PET Imaging?.DOCX

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    <p>Background: F-18-fluordeoxyglucose positron emission tomography (FDG-PET) is widely used for discriminative diagnosis of tau-positive atypical parkinsonian syndromes (T+APS). This approach now stands to be augmented with more specific tau tracers. Therefore, we retrospectively analyzed a large clinical routine dataset of FDG-PET images for evaluation of the strengths and limitations of stand-alone FDG-PET.</p><p>Methods: A total of 117 patients (age 68.4 ± 11.1 y) underwent an FDG-PET exam. Patients were followed clinically for a minimum of one year and their final clinical diagnosis was recorded. FDG-PET was rated visually (positive/negative) and categorized as high, moderate or low likelihood of T+APS and other neurodegenerative disorders. We then calculated positive and negative predictive values (PPV/NPV) of FDG-PET readings for the different subgroups relative to their final clinical diagnosis.</p><p>Results: Suspected diagnoses were confirmed by clinical follow-up (≥1 y) for 62 out of 117 (53%) patients. PPV was excellent when FDG-PET indicated a high likelihood of T+APS in combination with low to moderate likelihood of another neurodegenerative disorder. PPV was distinctly lower when FDG-PET indicated only a moderate likelihood of T+APS or when there was deemed equal likelihood of other neurodegenerative disorder. NPV of FDG-PET with a low likelihood for T+APS was high.</p><p>Conclusions: FDG-PET has high value in clinical routine evaluation of suspected T+APS, gaining satisfactory differential diagnosis in two thirds of the patients. One third of patients would potentially profit from further evaluation by more specific radioligands, with FDG-PET serving gatekeeper function for the more expensive methods.</p

    α<sub>v</sub>ß<sub>3</sub>-integrin/CD31 fluorescent double stainings.

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    <p>A— α<sub>v</sub>ß<sub>3</sub>-integrin; B—CD31; C—overlay of A and B. Fluorescent double stainings demonstrated a significant coexpression (C) of α<sub>v</sub>ß<sub>3</sub>-integrin and the endothelial receptor CD31 and therefore confirmed the predominantly endothelial expression of α<sub>v</sub>ß<sub>3</sub>-integrin in the investigated tumor model. No relevant tumor cell α<sub>v</sub>ß<sub>3</sub>-integrin expression was detected.</p
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