33 results on '"Hopewell, Robert"'
Search Results
2. Author Correction: [11C]Martinostat PET analysis reveals reduced HDAC I availability in Alzheimer’s disease
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Pascoal, Tharick A., Chamoun, Mira, Lax, Elad, Wey, Hsiao-Ying, Shin, Monica, Ng, Kok Pin, Kang, Min Su, Mathotaarachchi, Sulantha, Benedet, Andrea L., Therriault, Joseph, Lussier, Firoza Z., Schroeder, Frederick A., DuBois, Jonathan M., Hightower, Baileigh G., Gilbert, Tonya M., Zürcher, Nicole R., Wang, Changning, Hopewell, Robert, Chakravarty, Mallar, Savard, Melissa, Thomas, Emilie, Mohaddes, Sara, Farzin, Sarah, Salaciak, Alyssa, Tullo, Stephanie, Cuello, A. Claudio, Soucy, Jean-Paul, Massarweh, Gassan, Hwang, Heungsun, Kobayashi, Eliane, Hyman, Bradley T., Dickerson, Bradford C., Guiot, Marie-Christine, Szyf, Moshe, Gauthier, Serge, Hooker, Jacob M., and Rosa-Neto, Pedro
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- 2022
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3. [11C]Martinostat PET analysis reveals reduced HDAC I availability in Alzheimer’s disease
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Pascoal, Tharick A., Chamoun, Mira, Lax, Elad, Wey, Hsiao-Ying, Shin, Monica, Ng, Kok Pin, Kang, Min Su, Mathotaarachchi, Sulantha, Benedet, Andrea L., Therriault, Joseph, Lussier, Firoza Z., Schroeder, Frederick A., DuBois, Jonathan M., Hightower, Baileigh G., Gilbert, Tonya M., Zürcher, Nicole R., Wang, Changning, Hopewell, Robert, Chakravarty, Mallar, Savard, Melissa, Thomas, Emilie, Mohaddes, Sara, Farzin, Sarah, Salaciak, Alyssa, Tullo, Stephanie, Cuello, A. Claudio, Soucy, Jean-Paul, Massarweh, Gassan, Hwang, Heungsun, Kobayashi, Eliane, Hyman, Bradley T., Dickerson, Bradford C., Guiot, Marie-Christine, Szyf, Moshe, Gauthier, Serge, Hooker, Jacob M., and Rosa-Neto, Pedro
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- 2022
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4. CSF tau368/total-tau ratio reflects cognitive performance and neocortical tau better compared to p-tau181 and p-tau217 in cognitively impaired individuals
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Simrén, Joel, Brum, Wagner S., Ashton, Nicholas J., Benedet, Andrea L., Karikari, Thomas K., Kvartsberg, Hlin, Sjons, Emma, Lussier, Firoza Z., Chamoun, Mira, Stevenson, Jenna, Hopewell, Robert, Pallen, Vanessa, Ye, Keqiang, Pascoal, Tharick A., Zetterberg, Henrik, Rosa-Neto, Pedro, and Blennow, Kaj
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- 2022
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5. Characterization of scintillating fibers for use as positron detector in positron emission tomography
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Turgeon, Vincent, Kertzscher, Gustavo, Carroll, Liam, Hopewell, Robert, Massarweh, Gassan, and Enger, Shirin A.
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- 2019
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6. Development of “[11C]kits” for a fast, efficient and reliable production of carbon-11 labeled radiopharmaceuticals for Positron Emission Tomography
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Jolly, Dean, Hopewell, Robert, Kovacevic, Miriam, Li, Qian Ying, Soucy, Jean-Paul, and Kostikov, Alexey
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- 2017
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7. Distribution of [11C]-JNJ-42491293 in the marmoset brain: a positron emission tomography study.
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Kang, Min Su, Hamadjida, Adjia, Bédard, Dominique, Nuara, Stephen G., Gourdon, Jim C., Frey, Stephen, Aliaga, Arturo, Ross, Karen, Hopewell, Robert, Bdair, Hussein, Mathieu, Axel, Tardif, Christine Lucas, Soucy, Jean-Paul, Massarweh, Gassan, Rosa-Neto, Pedro, and Huot, Philippe
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POSITRON emission tomography ,MARMOSETS ,CALLITHRIX jacchus ,MAGNETIC resonance imaging ,AUTORADIOGRAPHY - Abstract
JNJ-42491293 is a metabotropic glutamate 2 (mGlu
2 ) positive allosteric modulator (PAM) that was radiolabelled with [11 C]- to serve as a positron emission tomography (PET) ligand. Indeed, in vitro, the molecule displays high selectivity at mGlu2 receptors. However, PET experiments performed in rats, macaques and humans, have suggested that [11 C]-JNJ-42491293 could interact with an unidentified, non-mGlu2 receptor binding site. The brain distribution of [11 C]-JNJ-42491293 has not been determined in the brain of the common marmoset, a small non-human primate increasingly used in neuroscience research. Here, we investigated the distribution of [11 C]-JNJ-42491293 in the marmoset brain. Three marmosets underwent brain magnetic resonance imaging (MRI) and 90-min dynamic PET scans with [11 C]-JNJ-42491293 in combination with vehicle or the mGlu2 PAM AZD8529 (0.1, 1 and 10 mg/kg). In the scans in which [11 C]-JNJ-42491293 was co-administered with vehicle, the brain areas with the highest standardised uptake values (SUVs) were the midbrain, cerebellum and thalamus, while the lowest SUVs were found in the pons. The addition of AZD8529 (0.1, 1 and 10 mg/kg) to [11 C]-JNJ-42491293 did not modify the SUVs obtained with [11 C]-JNJ-42491293 alone, and ex vivo blocking autoradiography with PAM AZD8529 (10, 100, 300 µM) on marmoset brain sections showed increased signals in the blocking conditions compared to vehicle, suggesting that no competition occurred between the 2 ligands. The results we obtained here do not suggest that [11 C]-JNJ-42491293 interacts selectively, or even at all, with mGlu2 receptors in the marmoset, in agreement with findings previously reported in macaque and human. [ABSTRACT FROM AUTHOR]- Published
- 2023
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8. [18F]MK6240 and [18F]PI2620 autoradiography on postmortem human brain tissue in AD.
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Aliaga, Antonio, Therriault, Joseph, Socualaya, Kely Quispialaya, Aliaga, Arturo Aliaga, Hopewell, Robert, Tissot, Cécile, Rahmouni, Nesrine, Macedo, Arthur C., Massarweh, Gassan, Pascoal, Tharick A., Soucy, Jean‐Paul, Rosa‐Neto, Pedro, and Zimmer, Eduardo R
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- 2023
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9. In vivo quantification of neurofibrillary tangles with [18F]MK-6240
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Pascoal, Tharick A., Shin, Monica, Kang, Min Su, Chamoun, Mira, Chartrand, Daniel, Mathotaarachchi, Sulantha, Bennacef, Idriss, Therriault, Joseph, Ng, Kok Pin, Hopewell, Robert, Bouhachi, Reda, Hsiao, Hung-Hsin, Benedet, Andrea L., Soucy, Jean-Paul, Massarweh, Gassan, Gauthier, Serge, and Rosa-Neto, Pedro
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- 2018
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10. [11C]Martinostat PET analysis reveals reduced HDAC I availability in Alzheimer's disease.
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Pascoal, Tharick A., Chamoun, Mira, Lax, Elad, Wey, Hsiao-Ying, Shin, Monica, Ng, Kok Pin, Kang, Min Su, Mathotaarachchi, Sulantha, Benedet, Andrea L., Therriault, Joseph, Lussier, Firoza Z., Schroeder, Frederick A., DuBois, Jonathan M., Hightower, Baileigh G., Gilbert, Tonya M., Zürcher, Nicole R., Wang, Changning, Hopewell, Robert, Chakravarty, Mallar, and Savard, Melissa
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ALZHEIMER'S disease ,TAU proteins ,POSITRON emission tomography ,HISTONES ,HISTONE deacetylase ,CEREBRAL atrophy ,PATIENT-ventilator dyssynchrony ,FORENSIC pathology - Abstract
Alzheimer's disease (AD) is characterized by the brain accumulation of amyloid-β and tau proteins. A growing body of literature suggests that epigenetic dysregulations play a role in the interplay of hallmark proteinopathies with neurodegeneration and cognitive impairment. Here, we aim to characterize an epigenetic dysregulation associated with the brain deposition of amyloid-β and tau proteins. Using positron emission tomography (PET) tracers selective for amyloid-β, tau, and class I histone deacetylase (HDAC I isoforms 1–3), we find that HDAC I levels are reduced in patients with AD. HDAC I PET reduction is associated with elevated amyloid-β PET and tau PET concentrations. Notably, HDAC I reduction mediates the deleterious effects of amyloid-β and tau on brain atrophy and cognitive impairment. HDAC I PET reduction is associated with 2-year longitudinal neurodegeneration and cognitive decline. We also find HDAC I reduction in the postmortem brain tissue of patients with AD and in a transgenic rat model expressing human amyloid-β plus tau pathology in the same brain regions identified in vivo using PET. These observations highlight HDAC I reduction as an element associated with AD pathophysiology. The link between amyloid and tau proteins with Alzheimer's disease progression remains unclear. Here, the authors propose HDACs I downregulation as an element linking the deleterious effects of brain proteinopathies with disease progression. [ABSTRACT FROM AUTHOR]
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- 2022
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11. High‐yielding, automated radiosynthesis of [11C]martinostat using [11C]methyl triflate.
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Hopewell, Robert, Jolly, Dean, Li, Qian Ying, Ross, Karen, Tsai, I‐Huang, Lacatus‐Samoila, Monica, Soucy, Jean‐Paul, Kobayashi, Eliane, Rosa‐Neto, Pedro, and Massarweh, Gassan
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METHYL triflate , *SOLID phase extraction , *HIGH performance liquid chromatography , *METHYL iodide , *CENTRAL nervous system , *NEUROBEHAVIORAL disorders , *MARINE toxins , *ETHANOL - Abstract
Histone deacetylases (HDACs) mediate epigenetic mechanisms implicated in a broad range of central nervous system dysfunction, including neurodegenerative diseases and neuropsychiatric disorders. [11C]Martinostat allows in vivo quantification of class I/IIb HDACs and may be useful for the quantification of drug–occupancy relationship, facilitating drug development for disease modifying therapies. The present study reports a radiosynthesis of [11C]martinostat using [11C]methyl triflate in ethanol, as opposed to the originally described synthesis using [11C]methyl iodide and DMSO. [11C]Methyl triflate is trapped in a solution of 2 mg of precursor 1 dissolved in anhydrous ethanol (400 μl), reacted at ambient temperature for 5 min and purified by high‐performance liquid chromatography; 1.5–1.8 GBq (41–48 mCi; n = 3) of formulated [11C]martinostat was obtained from solid‐phase extraction using a hydrophilic–lipophilic cartridge in a radiochemical yield of 11.4% ± 1.1% (nondecay corrected to trapped [11C]MeI), with a molar activity of 369 ± 53 GBq/μmol (9.97 ± 1.3 Ci/μmol) at the end of synthesis (40 min) and validated for human use. This methodology was used at our production site to produce [11C]martinostat in sufficient quantities of activity to scan humans, including losses incurred from decay during pre‐release quality control testing. [ABSTRACT FROM AUTHOR]
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- 2022
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12. Situating tau pathology and neuroinflammation along the principal gradients of brain organisation in Alzheimer's disease.
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Ottoy, Julie, Kang, Min Su, Yeh, Yi‐Hsuan, de Wael, Reinder Vos, Park, Bo‐yong, Isen, Jonah, Agopian, Mary, Bezgin, Gleb, Lussier, Firoza Z, Mathotaarachchi, Sulantha, Stevenson, Jenna, Chamoun, Mira, Rahmouni, Nesrine, Hopewell, Robert, Massarweh, Gassan, Soucy, Jean‐Paul, Gauthier, Serge, Bernhardt, Boris, Black, Sandra E., and Rosa‐Neto, Pedro
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- 2022
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13. Azapeptides and their therapeutic potential
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Proulx, Caroline, Sabatino, David, Hopewell, Robert, Spiegel, Jochen, García Ramos, Yésica, and Lubell, William D.
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- 2011
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14. Preliminary Evaluations of [11C]Verubulin: Implications for Microtubule Imaging With PET.
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Lindberg, Anton, Mossine, Andrew V., Aliaga, Arturo, Hopewell, Robert, Massarweh, Gassan, Rosa-Neto, Pedro, Shao, Xia, Bernard-Gauthier, Vadim, Scott, Peter J. H., and Vasdev, Neil
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POSITRON emission tomography ,MICROTUBULES ,AUTORADIOGRAPHY ,DIAGNOSTIC imaging ,RADIOACTIVE tracers - Abstract
[
11 C]Verubulin (a.k.a.[11 C]MCP-6827), [11 C]HD-800 and [11 C]colchicine have been developed for imaging microtubules (MTs) with positron emission tomography (PET). The objective of this work was to conduct an in vivo comparison of [11 C]verubulin for MT imaging in mouse and rat brain, as well as an in vitro study with this radiotracer in rodent and human Alzheimer's Disease tissue. Our preliminary PET imaging studies of [11 C]verubulin in rodents revealed contradictory results between mouse and rat brain uptake under pretreatment conditions. In vitro autoradiography with [11 C]verubulin showed an unexpected higher uptake in AD patient tissue compared with healthy controls. We also conducted the first comparative in vivo PET imaging study with [11 C]verubulin, [11 C]HD-800 and [11 C]colchicine in a non-human primate. [11 C]Verubulin and [11 C]HD-800 require pharmacokinetic modeling and quantification studies to understand the role of how these radiotracers bind to MTs before translation to human use. [ABSTRACT FROM AUTHOR]- Published
- 2021
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15. Effect of alpha‐Synuclein on the binding of [18F]MK‐6240 and [18F]AV‐1451.
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Kunach, Peter, Moquin, Luc, Hopewell, Robert, Aliaga, Arturo Aliaga, Tissot, Cécile, Therriault, Joseph, Zimmermann, Maria, Kulasek, Michal, Soucy, Jean‐Paul, Massarweh, Gassan, and Rosa‐Neto, Pedro
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- 2023
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16. [18F]TRACK, a PET tracer for imaging of tropomyosin receptor kinases (Trk): Efficient radiosynthesis and preliminary evaluation in the TgF344‐AD rat model of Alzheimer's disease.
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Kang, Min Su, Thiel, Alexander, Schirrmacher, Ralf, Bernard‐Gauthier, Vadim, Jaworski, Carolin, Dorian, Andreas, Hopewell, Robert, Singleton, Thomas A, Blinder, Stephan, Soucy, Jean‐Paul, Rosa‐Neto, Pedro, and Kostikov, Alexey
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- 2023
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17. 18F-MK-6240 PET for early and late detection of neurofibrillary tangles.
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Pascoal, Tharick A, Therriault, Joseph, Benedet, Andrea L, Savard, Melissa, Lussier, Firoza Z, Chamoun, Mira, Tissot, Cécile, Qureshi, Muhammad Naveed Iqbal, Kang, Min Su, Mathotaarachchi, Sulantha, Stevenson, Jenna, Hopewell, Robert, Massarweh, Gassan, Soucy, Jean-Paul, Gauthier, Serge, and Rosa-Neto, Pedro
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NEUROFIBRILLARY tangles ,FRONTOTEMPORAL lobar degeneration ,MILD cognitive impairment ,COGNITION disorders ,CEREBRAL amyloid angiopathy ,ALZHEIMER'S disease ,ALZHEIMER'S patients ,RESEARCH ,NEURONS ,CROSS-sectional method ,RESEARCH methodology ,ISOQUINOLINE ,RADIOISOTOPES ,EVALUATION research ,MEDICAL cooperation ,FLUORINE isotopes ,COMPARATIVE studies ,RESEARCH funding ,EARLY diagnosis - Abstract
Braak stages of tau neurofibrillary tangle accumulation have been incorporated in the criteria for the neuropathological diagnosis of Alzheimer's disease. It is expected that Braak staging using brain imaging can stratify living individuals according to their individual patterns of tau deposition, which may prove crucial for clinical trials and practice. However, previous studies using the first-generation tau PET agents have shown a low sensitivity to detect tau pathology in areas corresponding to early Braak histopathological stages (∼20% of cognitively unimpaired elderly with tau deposition in regions corresponding to Braak I-II), in contrast to ∼80-90% reported in post-mortem cohorts. Here, we tested whether the novel high affinity tau tangles tracer 18F-MK-6240 can better identify individuals in the early stages of tau accumulation. To this end, we studied 301 individuals (30 cognitively unimpaired young, 138 cognitively unimpaired elderly, 67 with mild cognitive impairment, 54 with Alzheimer's disease dementia, and 12 with frontotemporal dementia) with amyloid-β 18F-NAV4694, tau 18F-MK-6240, MRI, and clinical assessments. 18F-MK-6240 standardized uptake value ratio images were acquired at 90-110 min after the tracer injection. 18F-MK-6240 discriminated Alzheimer's disease dementia from mild cognitive impairment and frontotemporal dementia with high accuracy (∼85-100%). 18F-MK-6240 recapitulated topographical patterns consistent with the six hierarchical stages proposed by Braak in 98% of our population. Cognition and amyloid-β status explained most of the Braak stages variance (P < 0.0001, R2 = 0.75). No single region of interest standardized uptake value ratio accurately segregated individuals into the six topographic Braak stages. Sixty-eight per cent of the cognitively unimpaired elderly amyloid-β-positive and 37% of the cognitively unimpaired elderly amyloid-β-negative subjects displayed tau deposition, at least in the transentorhinal cortex (Braak I). Tau deposition solely in the transentorhinal cortex was associated with an elevated prevalence of amyloid-β, neurodegeneration, and cognitive impairment (P < 0.0001). 18F-MK-6240 deposition in regions corresponding to Braak IV-VI was associated with the highest prevalence of neurodegeneration, whereas in Braak V-VI regions with the highest prevalence of cognitive impairment. Our results suggest that the hierarchical six-stage Braak model using 18F-MK-6240 imaging provides an index of early and late tau accumulation as well as disease stage in preclinical and symptomatic individuals. Tau PET Braak staging using high affinity tracers has the potential to be incorporated in the diagnosis of living patients with Alzheimer's disease in the near future. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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18. [18F]TRACK, a PET tracer for imaging of tropomyosin receptor kinases (Trk): efficient radiosynthesis and preliminary evaluation in the TgF344‐AD rat model of Alzheimer's disease.
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Kang, Min Su, Thiel, Alexander, Schirrmacher, Ralf, Bernard‐Gauthier, Vadim, Jaworski, Carolin, Dorian, Andreas, Hopewell, Robert, Singleton, Thomas A, Blinder, Stephan, Soucy, Jean‐Paul, Rosa‐Neto, Pedro, and Kostikov, Alexey
- Published
- 2022
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19. A simplified radiosynthesis of [18F]MK‐6240 for tau PET imaging.
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Hopewell, Robert, Ross, Karen, Kostikov, Alexey, Pascoal, Tharick A., Alberti, Thais, Lacatus‐Samoila, Monica, Soucy, Jean‐Paul, Bennacef, Idriss, Kobayashi, Eliane, Kang, Min Su, Rosa‐Neto, Pedro, and Massarweh, Gassan
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POSITRON emission tomography , *RADIOACTIVE tracers , *NEUROFIBRILLARY tangles , *HIGH performance liquid chromatography , *ALZHEIMER'S disease - Abstract
[18F]MK‐6240 (6‐(fluoro)‐3‐(1H‐pyrrolo[2,3‐c]pyridin‐1‐yl)isoquinolin‐5‐amine) is a highly selective PET radiotracer for the in vivo imaging of neurofibrillary tangles (NFTs). [18F]MK‐6240 was synthesized in one step from its bis‐Boc protected precursor N‐[(tert‐butoxy)carbonyl]‐N‐(6‐nitro‐3‐[1H‐pyrrolo[2,3‐c]pyridin‐1‐yl]isoquinolin‐5‐yl) carbamate in DMSO using [18F] fluoride with TEA HCO3 with step‐wise heating up to 150°C, resulting in an isolated radiochemical yield of 9.8% ± 1.8% (n = 3) calculated from the end of bombardment (5.2% ± 1.0% calculated from the end of synthesis). This new synthetic approach eliminates the acidic deprotection of the bis‐Boc 18F‐labeled intermediate, which reduces the number of operations necessary for the synthesis as well as losses, which occur during deprotection and neutralization of the crude product mixture prior to the HPLC purification. The synthesis was performed automatically with a single‐use cassette on an IBA Synthera+ synthesis module. This synthesis method affords the radioligand with a reliable radiochemical yield, high radiochemical purity, and a high molar activity. [18F]MK‐6240 synthesized with this method has been regularly (n > 60) used in our ongoing human and animal PET imaging studies. [18F]MK‐6240, a highly selective positron emission tomography (PET) radiotracer for the in vivo imaging of neurofibrillary tangles, was prepared by a simple one‐step reaction and validated for use in humans. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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20. Highly efficient solid phase supported radiosynthesis of [11C]PiB using tC18 cartridge as a '3-in-1' production entity.
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Boudjemeline, Mehdi, Hopewell, Robert, Rochon, Pierre‐Luc, Jolly, Dean, Hammami, Iness, Villeneuve, Sylvia, and Kostikov, Alexey
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DIAGNOSTIC imaging , *RADIONUCLIDE imaging , *AMYLOID plaque , *POSITRON emission tomography , *POSITRON emission - Abstract
Pittsburgh compound B ([11C]PiB) is the gold standard positron emission tomography (PET) tracer for the in vivo imaging of amyloid plaques. Currently, it is synthesized by either solution chemistry or using a 'dry loop' approach followed by HPLC purification within 30 minutes starting from [11C]CO2. Here, we report a novel, highly efficient solid phase supported carbon-11 radiolabeling procedure using commercially available disposable tC18 cartridge as a '3-in-1' entity: reactor, purifier, and solvent replacement system. [11C]PiB is synthesized by passing gaseous [11C]CH3OTf through a tC18 cartridge preloaded with a solution of precursor. Successive elution with aqueous ethanol solutions allows for nearly quantitative separation of the reaction mixture to provide chemically and radiochemically pure PET tracer. [11C]PiB suitable for human injection is produced within 10 minutes starting from [11C]CH3OTf (20 min from [11C]CO2) in 22% isolated yield not corrected for decay and molar activity of 190 GBq/μmol using 0.2 mg of precursor. This technique reduces the amount of precursor and other supplies, avoids use of preparative HPLC and toxic solvents, and decreases the time between consecutive production batches. Solid phase supported technique can facilitate [11C]PiB production compliant with Good Manufacturing Practice (GMP) and improve synthesis reliability. [ABSTRACT FROM AUTHOR]
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- 2017
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21. N-Aminoimidazolidin-2-onePeptidomimetics.
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Doan, Ngoc-Duc, Hopewell, Robert, and Lubell, William D.
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IMIDAZOLIDINES , *PEPTIDOMIMETICS , *CRYSTAL structure , *ELECTRONIC structure , *ETHYLENE dibromide , *SEMICARBAZONES , *ALKYLATION - Abstract
Thesynthesis of N-aminoimidazolidin-2-one (Aid)peptidomimetics has been achieved by alkylation of the urea nitrogenof a semicarbazone residue using ethylene bromide. The Aid scaffoldcombines electronic and structural constraints to rigidify the peptidebackbone in the equivalent of an aza variant of a Freidinger–Veberlactam. The syntheses and isolation of 25 Aid peptides, includingeight GHRP-6 analogues, are reported to demonstrate the utility ofthis method for controlling conformation. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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22. In vivo quantification of neurofibrillary tangles with [18F]MK-6240.
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Pascoal, Tharick A., Shin, Monica, Kang, Min Su, Chamoun, Mira, Chartrand, Daniel, Mathotaarachchi, Sulantha, Bennacef, Idriss, Therriault, Joseph, Ng, Kok Pin, Hopewell, Robert, Bouhachi, Reda, Hsiao, Hung-Hsin, Benedet, Andrea L., Soucy, Jean-Paul, Massarweh, Gassan, Gauthier, Serge, and Rosa-Neto, Pedro
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NEUROFIBRILLARY tangles ,ALZHEIMER'S disease diagnosis ,POSITRON emission tomography ,AUTORADIOGRAPHY ,MILD cognitive impairment ,PATIENTS - Abstract
Background: Imaging agents capable of quantifying the brain's tau aggregates will allow a more precise staging of Alzheimer's disease (AD). The aim of the present study was to examine the in vitro properties as well as the in vivo kinetics, using gold standard methods, of the novel positron emission tomography (PET) tau imaging agent [
18 F]MK-6240. Methods: In vitro properties of [18 F]MK-6240 were estimated with autoradiography in postmortem brain tissues of 14 subjects (seven AD patients and seven age-matched controls). In vivo quantification of [18 F]MK-6240 binding was performed in 16 subjects (four AD patients, three mild cognitive impairment patients, six healthy elderly individuals, and three healthy young individuals) who underwent 180-min dynamic scans; six subjects had arterial sampling for metabolite correction. Simplified approaches for [18 F]MK-6240 quantification were validated using full kinetic modeling with metabolite-corrected arterial input function. All participants also underwent amyloid-PET and structural magnetic resonance imaging. Results: In vitro [18 F]MK-6240 uptake was higher in AD patients than in age-matched controls in brain regions expected to contain tangles such as the hippocampus, whereas no difference was found in the cerebellar gray matter. In vivo, [18 F]MK-6240 displayed favorable kinetics with rapid brain delivery and washout. The cerebellar gray matter had low binding across individuals, showing potential for use as a reference region. A reversible two-tissue compartment model well described the time–activity curves across individuals and brain regions. Distribution volume ratios using the plasma input and standardized uptake value ratios (SUVRs) calculated after the binding approached equilibrium (90 min) were correlated and higher in mild cognitive impairment or AD dementia patients than in controls. Reliability analysis revealed robust SUVRs calculated from 90 to 110 min, while earlier time points provided inaccurate estimates. Conclusions: This evaluation shows an [18 F]MK-6240 distribution in concordance with postmortem studies and that simplified quantitative approaches such as the SUVR offer valid estimates of neurofibrillary tangle load 90 min post injection. [18 F]MK-6240 is a promising tau tracer with the potential to be applied in the disease diagnosis and assessment of therapeutic interventions. [ABSTRACT FROM AUTHOR]- Published
- 2018
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23. Ciprofloxacin and the fluoroquinolones: New concepts on the mechanism of action and resistance
- Author
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Fisher, L.Mark, Lawrence, James M., Josty, Ian C., Hopewell, Robert, Margerrison, Edward E.C., and Cullen, Martin E.
- Published
- 1989
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24. Co-registration of Imaging Modalities (MRI, CT and PET) to Perform Frameless Stereotaxic Robotic Injections in the Common Marmoset.
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Kwan, Cynthia, Kang, Min Su, Nuara, Stephen G., Gourdon, Jim C., Bédard, Dominique, Tardif, Christine L., Hopewell, Robert, Ross, Karen, Bdair, Hussein, Hamadjida, Adjia, Massarweh, Gassan, Soucy, Jean-Paul, Luo, Wen, del Cid Pellitero, Esther, Shlaifer, Irina, Durcan, Thomas M., Fon, Edward A., Rosa-Neto, Pedro, Frey, Stephen, and Huot, Philippe
- Subjects
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CALLITHRIX jacchus , *POSITRON emission tomography , *MAGNETIC resonance imaging , *ROBOTICS , *INJECTIONS , *BRAIN imaging , *SURGICAL technology - Abstract
• Stereotaxic atlases of the marmoset brain limit accurate identification of targets. • Co-registration of imaging data located the surgical target in each subject. • Frameless stereotaxic surgery with a robotic arm led to injection in the putamen. • Combined approach accurately locates target; useful for longitudinal studies. The common marmoset has emerged as a popular model in neuroscience research, in part due to its reproductive efficiency, genetic and neuroanatomical similarities to humans and the successful generation of transgenic lines. Stereotaxic procedures in marmosets are guided by 2D stereotaxic atlases, which are constructed with a limited number of animals and fail to account for inter-individual variability in skull and brain size. Here, we developed a frameless imaging-guided stereotaxic system that improves upon traditional approaches by using subject-specific registration of computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET) data to identify a surgical target, namely the putamen, in two marmosets. The skull surface was laser-scanned to create a point cloud that was registered to the 3D reconstruction of the skull from CT. Reconstruction of the skull, as well as of the brain from MR images, was crucial for surgical planning. Localisation and injection into the putamen was done using a 6-axis robotic arm controlled by a surgical navigation software (Brainsight™). Integration of subject-specific registration and frameless stereotaxic navigation allowed target localisation specific to each animal. Injection of alpha-synuclein fibrils into the putamen triggered progressive neurodegeneration of the nigro-striatal system, a key feature of Parkinson's disease. Four months post-surgery, a PET scan found evidence of nigro-striatal denervation, supporting accurate targeting of the putamen during co-registration and subsequent surgery. Our results suggest that this approach, coupled with frameless stereotaxic neuronavigation, is accurate in localising surgical targets and can be used to assess endpoints for longitudinal studies. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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25. Cryo-EM structure of Alzheimer's disease tau filaments with PET ligand MK-6240.
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Kunach P, Vaquer-Alicea J, Smith MS, Hopewell R, Monistrol J, Moquin L, Therriault J, Tissot C, Rahmouni N, Massarweh G, Soucy JP, Guiot MC, Shoichet BK, Rosa-Neto P, Diamond MI, and Shahmoradian SH
- Abstract
Positron Emission Tomography (PET) ligands have advanced Alzheimer's disease (AD) diagnosis and treatment. Using autoradiography and cryo-EM, we identified AD brain tissue with elevated tau burden, purified filaments, and determined the structure of second-generation high avidity PET ligand MK-6240 at 2.31 Å resolution, which bound at a 1:1 ratio within the cleft of tau paired-helical filament (PHF), engaging with glutamine 351, lysine K353, and isoleucine 360. This information elucidates the basis of MK-6240 PET in quantifying PHF deposits in AD and may facilitate the structure-based design of superior ligands against tau amyloids., Competing Interests: Competing Interests The authors declare no competing interests.
- Published
- 2023
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26. High-yielding, automated radiosynthesis of [ 11 C]martinostat using [ 11 C]methyl triflate.
- Author
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Hopewell R, Jolly D, Li QY, Ross K, Tsai IH, Lacatus-Samoila M, Soucy JP, Kobayashi E, Rosa-Neto P, and Massarweh G
- Subjects
- Adamantane analogs & derivatives, Carbon Radioisotopes chemistry, Humans, Hydroxamic Acids, Mesylates, Positron-Emission Tomography methods, Ethanol, Radiopharmaceuticals
- Abstract
Histone deacetylases (HDACs) mediate epigenetic mechanisms implicated in a broad range of central nervous system dysfunction, including neurodegenerative diseases and neuropsychiatric disorders. [
11 C]Martinostat allows in vivo quantification of class I/IIb HDACs and may be useful for the quantification of drug-occupancy relationship, facilitating drug development for disease modifying therapies. The present study reports a radiosynthesis of [11 C]martinostat using [11 C]methyl triflate in ethanol, as opposed to the originally described synthesis using [11 C]methyl iodide and DMSO. [11 C]Methyl triflate is trapped in a solution of 2 mg of precursor 1 dissolved in anhydrous ethanol (400 μl), reacted at ambient temperature for 5 min and purified by high-performance liquid chromatography; 1.5-1.8 GBq (41-48 mCi; n = 3) of formulated [11 C]martinostat was obtained from solid-phase extraction using a hydrophilic-lipophilic cartridge in a radiochemical yield of 11.4% ± 1.1% (nondecay corrected to trapped [11 C]MeI), with a molar activity of 369 ± 53 GBq/μmol (9.97 ± 1.3 Ci/μmol) at the end of synthesis (40 min) and validated for human use. This methodology was used at our production site to produce [11 C]martinostat in sufficient quantities of activity to scan humans, including losses incurred from decay during pre-release quality control testing., (© 2022 John Wiley & Sons, Ltd.)- Published
- 2022
- Full Text
- View/download PDF
27. Preliminary Evaluations of [ 11 C]Verubulin: Implications for Microtubule Imaging With PET.
- Author
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Lindberg A, Mossine AV, Aliaga A, Hopewell R, Massarweh G, Rosa-Neto P, Shao X, Bernard-Gauthier V, Scott PJH, and Vasdev N
- Abstract
[
11 C]Verubulin (a.k.a.[11 C]MCP-6827), [11 C]HD-800 and [11 C]colchicine have been developed for imaging microtubules (MTs) with positron emission tomography (PET). The objective of this work was to conduct an in vivo comparison of [11 C]verubulin for MT imaging in mouse and rat brain, as well as an in vitro study with this radiotracer in rodent and human Alzheimer's Disease tissue. Our preliminary PET imaging studies of [11 C]verubulin in rodents revealed contradictory results between mouse and rat brain uptake under pretreatment conditions. In vitro autoradiography with [11 C]verubulin showed an unexpected higher uptake in AD patient tissue compared with healthy controls. We also conducted the first comparative in vivo PET imaging study with [11 C]verubulin, [11 C]HD-800 and [11 C]colchicine in a non-human primate. [11 C]Verubulin and [11 C]HD-800 require pharmacokinetic modeling and quantification studies to understand the role of how these radiotracers bind to MTs before translation to human use., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lindberg, Mossine, Aliaga, Hopewell, Massarweh, Rosa-Neto, Shao, Bernard-Gauthier, Scott and Vasdev.)- Published
- 2021
- Full Text
- View/download PDF
28. 18F-MK-6240 PET for early and late detection of neurofibrillary tangles.
- Author
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Pascoal TA, Therriault J, Benedet AL, Savard M, Lussier FZ, Chamoun M, Tissot C, Qureshi MNI, Kang MS, Mathotaarachchi S, Stevenson J, Hopewell R, Massarweh G, Soucy JP, Gauthier S, and Rosa-Neto P
- Subjects
- Aged, Aged, 80 and over, Cross-Sectional Studies, Early Diagnosis, Female, Humans, Male, Middle Aged, Neurofibrillary Tangles pathology, Young Adult, Alzheimer Disease diagnostic imaging, Alzheimer Disease metabolism, Fluorine Radioisotopes metabolism, Isoquinolines metabolism, Neurofibrillary Tangles metabolism, Positron-Emission Tomography methods
- Abstract
Braak stages of tau neurofibrillary tangle accumulation have been incorporated in the criteria for the neuropathological diagnosis of Alzheimer's disease. It is expected that Braak staging using brain imaging can stratify living individuals according to their individual patterns of tau deposition, which may prove crucial for clinical trials and practice. However, previous studies using the first-generation tau PET agents have shown a low sensitivity to detect tau pathology in areas corresponding to early Braak histopathological stages (∼20% of cognitively unimpaired elderly with tau deposition in regions corresponding to Braak I-II), in contrast to ∼80-90% reported in post-mortem cohorts. Here, we tested whether the novel high affinity tau tangles tracer 18F-MK-6240 can better identify individuals in the early stages of tau accumulation. To this end, we studied 301 individuals (30 cognitively unimpaired young, 138 cognitively unimpaired elderly, 67 with mild cognitive impairment, 54 with Alzheimer's disease dementia, and 12 with frontotemporal dementia) with amyloid-β 18F-NAV4694, tau 18F-MK-6240, MRI, and clinical assessments. 18F-MK-6240 standardized uptake value ratio images were acquired at 90-110 min after the tracer injection. 18F-MK-6240 discriminated Alzheimer's disease dementia from mild cognitive impairment and frontotemporal dementia with high accuracy (∼85-100%). 18F-MK-6240 recapitulated topographical patterns consistent with the six hierarchical stages proposed by Braak in 98% of our population. Cognition and amyloid-β status explained most of the Braak stages variance (P < 0.0001, R2 = 0.75). No single region of interest standardized uptake value ratio accurately segregated individuals into the six topographic Braak stages. Sixty-eight per cent of the cognitively unimpaired elderly amyloid-β-positive and 37% of the cognitively unimpaired elderly amyloid-β-negative subjects displayed tau deposition, at least in the transentorhinal cortex (Braak I). Tau deposition solely in the transentorhinal cortex was associated with an elevated prevalence of amyloid-β, neurodegeneration, and cognitive impairment (P < 0.0001). 18F-MK-6240 deposition in regions corresponding to Braak IV-VI was associated with the highest prevalence of neurodegeneration, whereas in Braak V-VI regions with the highest prevalence of cognitive impairment. Our results suggest that the hierarchical six-stage Braak model using 18F-MK-6240 imaging provides an index of early and late tau accumulation as well as disease stage in preclinical and symptomatic individuals. Tau PET Braak staging using high affinity tracers has the potential to be incorporated in the diagnosis of living patients with Alzheimer's disease in the near future., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.)
- Published
- 2020
- Full Text
- View/download PDF
29. Solid Phase 11C-Methylation, Purification and Formulation for the Production of PET Tracers.
- Author
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Singleton TA, Boudjemeline M, Hopewell R, Jolly D, Bdair H, and Kostikov A
- Subjects
- Humans, Methylation, Reproducibility of Results, Carbon Radioisotopes metabolism, Positron-Emission Tomography methods
- Abstract
Routine production of radiotracers used in positron emission tomography (PET) mostly relies on wet chemistry where the radioactive synthon reacts with a non-radioactive precursor in solution. This approach necessitates purification of the tracer by high performance liquid chromatography (HPLC) followed by reformulation in a biocompatible solvent for human administration. We recently developed a novel
11 C-methylation approach for the highly efficient synthesis of carbon-11 labeled PET radiopharmaceuticals, taking advantage of solid phase cartridges as disposable "3-in-1" units for the synthesis, purification and reformulation of the tracers. This approach obviates the use of preparative HPLC and reduces the losses of the tracer in transfer lines and due to radioactive decay. Furthermore, the cartridge-based technique improves synthesis reliability, simplifies the automation process and facilitates compliance with the Good Manufacturing Practice (GMP) requirements. Here, we demonstrate this technique on the example of production of a PET tracer Pittsburgh compound B ([11 C]PiB), a gold standard in vivo imaging agent for amyloid plaques in the human brains.- Published
- 2019
- Full Text
- View/download PDF
30. A simplified radiosynthesis of [ 18 F]MK-6240 for tau PET imaging.
- Author
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Hopewell R, Ross K, Kostikov A, Pascoal TA, Alberti T, Lacatus-Samoila M, Soucy JP, Bennacef I, Kobayashi E, Kang MS, Rosa-Neto P, and Massarweh G
- Subjects
- Chemistry Techniques, Synthetic instrumentation, Chemistry Techniques, Synthetic methods, Positron-Emission Tomography methods, tau Proteins metabolism, Fluorine Radioisotopes chemistry, Isoquinolines chemistry, Radiopharmaceuticals chemical synthesis
- Abstract
[
18 F]MK-6240 (6-(fluoro)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine) is a highly selective PET radiotracer for the in vivo imaging of neurofibrillary tangles (NFTs). [18 F]MK-6240 was synthesized in one step from its bis-Boc protected precursor N-[(tert-butoxy)carbonyl]-N-(6-nitro-3-[1H-pyrrolo[2,3-c]pyridin-1-yl]isoquinolin-5-yl) carbamate in DMSO using [18 F] fluoride with TEA HCO3 with step-wise heating up to 150°C, resulting in an isolated radiochemical yield of 9.8% ± 1.8% (n = 3) calculated from the end of bombardment (5.2% ± 1.0% calculated from the end of synthesis). This new synthetic approach eliminates the acidic deprotection of the bis-Boc18 F-labeled intermediate, which reduces the number of operations necessary for the synthesis as well as losses, which occur during deprotection and neutralization of the crude product mixture prior to the HPLC purification. The synthesis was performed automatically with a single-use cassette on an IBA Synthera+ synthesis module. This synthesis method affords the radioligand with a reliable radiochemical yield, high radiochemical purity, and a high molar activity. [18 F]MK-6240 synthesized with this method has been regularly (n > 60) used in our ongoing human and animal PET imaging studies., (© 2018 John Wiley & Sons, Ltd.)- Published
- 2019
- Full Text
- View/download PDF
31. Highly efficient solid phase supported radiosynthesis of [ 11 C]PiB using tC18 cartridge as a "3-in-1" production entity.
- Author
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Boudjemeline M, Hopewell R, Rochon PL, Jolly D, Hammami I, Villeneuve S, and Kostikov A
- Subjects
- Chemistry Techniques, Synthetic instrumentation, Chemistry Techniques, Synthetic methods, Chemistry Techniques, Synthetic standards, Aniline Compounds chemical synthesis, Radiopharmaceuticals chemical synthesis, Thiazoles chemical synthesis
- Abstract
Pittsburgh compound B ([
11 C]PiB) is the gold standard positron emission tomography (PET) tracer for the in vivo imaging of amyloid plaques. Currently, it is synthesized by either solution chemistry or using a "dry loop" approach followed by HPLC purification within 30 minutes starting from [11 C]CO2 . Here, we report a novel, highly efficient solid phase supported carbon-11 radiolabeling procedure using commercially available disposable tC18 cartridge as a "3-in-1" entity: reactor, purifier, and solvent replacement system. [11 C]PiB is synthesized by passing gaseous [11 C]CH3 OTf through a tC18 cartridge preloaded with a solution of precursor. Successive elution with aqueous ethanol solutions allows for nearly quantitative separation of the reaction mixture to provide chemically and radiochemically pure PET tracer. [11 C]PiB suitable for human injection is produced within 10 minutes starting from [11 C]CH3 OTf (20 min from [11 C]CO2 ) in 22% isolated yield not corrected for decay and molar activity of 190 GBq/μmol using 0.2 mg of precursor. This technique reduces the amount of precursor and other supplies, avoids use of preparative HPLC and toxic solvents, and decreases the time between consecutive production batches. Solid phase supported technique can facilitate [11 C]PiB production compliant with Good Manufacturing Practice (GMP) and improve synthesis reliability., (Copyright © 2017 John Wiley & Sons, Ltd.)- Published
- 2017
- Full Text
- View/download PDF
32. Syntheses and evaluation of carbon-11- and fluorine-18-radiolabeled pan-tropomyosin receptor kinase (Trk) inhibitors: exploration of the 4-aza-2-oxindole scaffold as Trk PET imaging agents.
- Author
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Bernard-Gauthier V, Aliaga A, Aliaga A, Boudjemeline M, Hopewell R, Kostikov A, Rosa-Neto P, Thiel A, and Schirrmacher R
- Subjects
- Animals, Autoradiography, Brain diagnostic imaging, Brain metabolism, Carbon Radioisotopes, Drug Design, Drug Evaluation, Fluorine Radioisotopes, Humans, Indoles chemical synthesis, Membrane Glycoproteins antagonists & inhibitors, Membrane Glycoproteins metabolism, Molecular Docking Simulation, Molecular Structure, Neuroblastoma diagnostic imaging, Neuroblastoma metabolism, Photochemical Processes, Protein-Tyrosine Kinases antagonists & inhibitors, Protein-Tyrosine Kinases metabolism, Pyrrolidines chemical synthesis, Quinolines chemical synthesis, Rats, Sprague-Dawley, Receptor, trkB, Positron-Emission Tomography methods, Protein Kinase Inhibitors chemical synthesis, Radiopharmaceuticals chemical synthesis
- Abstract
Tropomyosin receptor kinases (TrkA/B/C) are critically involved in the development of the nervous system, in neurological disorders as well as in multiple neoplasms of both neural and non-neural origins. The development of Trk radiopharmaceuticals would offer unique opportunities toward a more complete understanding of this emerging therapeutic target. To that end, we first developed [(11)C]GW441756 ([(11)C]9), a high affinity photoisomerizable pan-Trk inhibitor, as a lead radiotracer for our positron emission tomography (PET) program. Efficient carbon-11 radiolabeling afforded [(11)C]9 in high radiochemical yields (isolated RCY, 25.9% ± 5.7%). In vitro autoradiographic studies in rat brain and TrkB-expressing human neuroblastoma cryosections confirmed that [(11)C]9 specifically binds to Trk receptors in vitro. MicroPET studies revealed that binding of [(11)C]9 in the rodent brain was mostly nonspecific despite initial high brain uptake (SUVmax = 2.0). Modeling studies of the 4-aza-2-oxindole scaffold led to the successful identification of a small series of high affinity fluorinated and methoxy derivatized pan-Trk inhibitors based on our lead compound 9. Out of this series, the fluorinated compound 10 was selected for initial evaluation and radiolabeled with fluorine-18 (isolated RCY, 2.5% ± 0.6%). Compound [(18)F]10 demonstrated excellent Trk selectivity in a panel of cancer relevant kinase targets and a promising in vitro profile in tumors and brain sections but high oxidative metabolic susceptibility leading to nonspecific brain distribution in vivo. The information gained in this study will guide further exploration of the 4-aza-2-oxindole scaffold as a lead for Trk PET ligand development.
- Published
- 2015
- Full Text
- View/download PDF
33. MCEF is localized to the nucleus by protein sequences encoded within three distinct exons, where it represses HIV-1 Tat-transactivation of LTR-directed transcription.
- Author
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Niedzielski MF, Hopewell R, Ismail Z, and Estable MC
- Subjects
- Active Transport, Cell Nucleus, Amino Acid Sequence, Animals, Consensus Sequence, DNA, Complementary genetics, Evolution, Molecular, Exons genetics, Genes, Reporter, HIV Long Terminal Repeat, HeLa Cells, Humans, Invertebrates genetics, Molecular Sequence Data, Nuclear Proteins classification, Phylogeny, RNA Polymerase II metabolism, RNA Splicing, Recombinant Fusion Proteins metabolism, Repressor Proteins chemistry, Repressor Proteins genetics, Sequence Analysis, DNA, Sequence Homology, Species Specificity, Transcription Factors chemistry, Transcription Factors genetics, Transcriptional Elongation Factors, Vertebrates genetics, tat Gene Products, Human Immunodeficiency Virus, Gene Products, tat antagonists & inhibitors, HIV-1 physiology, Nuclear Proteins genetics, Repressor Proteins physiology, Transcription Factors physiology, Transcriptional Activation
- Abstract
Translocations between the human Mixed Lineage Leukemia (MLL) and AF4 Family (AFF) member genes, are implicated in leukemia. Mutations to AFFs can disrupt lymphopoesis, CNS development and spermatogenesis. However, despite the growing list of pathologies linked to AFF members, their evolutionary relationship and the structure/function of individual members, remain to be elucidated. Here, we first report that database mining and phylogenetic analysis with AFF proteins from multiple species, revealed two monophyletic sister clades, suggesting a common Bilateria ancestor. We then examined the structure/function of the most recently discovered AFF member, MCEF (also known as AF5q31 or AFF4). In silico, the human MCEF gene was found to have 21 exons, and code for a protein with seven nuclear localization sequences (NLS). In HeLa cells, an MCEF-EGFP fusion protein, localized exclusively to the nucleus. Consequently, we made twenty constructs, expressing MCEF deletion mutants fused to EGFP and/or DsRed fluorescent proteins. Three distinct protein sequences, encoded by three separate MCEF exons, were found to mediate nuclear localization, only two of which were predicted in silico. Importantly, we also found that ectopic expression of MCEF, repressed HIV-1 LTR-directed RNA Polymerase II transcription, at the level of Tat-transactivation. We suggest that portions of MCEF could be exploited for chimeric transcription factor repression (CTFR) of HIV-1.
- Published
- 2007
- Full Text
- View/download PDF
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