14 results on '"Quesada, Carole A."'
Search Results
2. Synthesis of Diverse 11C-Labeled PET Radiotracers via Direct Incorporation of [11C]CO2.
- Author
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Mossine, Andrew V., Brooks, Allen F., Jackson, Isaac M., Quesada, Carole A., Sherman, Phillip, Cole, Erin L., Donnelly, David J., Scott, Peter J. H., and Xia Shao
- Published
- 2016
- Full Text
- View/download PDF
3. 4-[18F]Fluoro-m-hydroxyphenethylguanidine:A Radiopharmaceutical for QuantifyingRegional Cardiac Sympathetic Nerve Density with Positron EmissionTomography.
- Author
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Jang, Keun Sam, Jung, Yong-Woon, Gu, Guie, Koeppe, Robert A., Sherman, Phillip S., Quesada, Carole A., and Raffel, David M.
- Published
- 2013
- Full Text
- View/download PDF
4. [ 18 F]Fluoro-Hydroxyphenethylguanidines: Efficient Synthesis and Comparison of Two Structural Isomers as Radiotracers of Cardiac Sympathetic Innervation.
- Author
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Jung YW, Jang KS, Gu G, Koeppe RA, Sherman PS, Quesada CA, and Raffel DM
- Subjects
- Animals, Drug Evaluation, Preclinical, Heart diagnostic imaging, In Vitro Techniques, Isomerism, Kinetics, Macaca mulatta, Male, Molecular Structure, Rats, Sprague-Dawley, Guanidines blood, Guanidines chemical synthesis, Guanidines chemistry, Heart innervation, Positron-Emission Tomography, Radiopharmaceuticals blood, Radiopharmaceuticals chemical synthesis, Radiopharmaceuticals chemistry, Sympathetic Nervous System diagnostic imaging
- Abstract
Fluorine-18 labeled phenethylguanidines are currently under development in our laboratory as radiotracers for quantifying regional cardiac sympathetic nerve density using PET imaging techniques. In this study, we report an efficient synthesis of
18 F-hydroxyphenethylguanidines consisting of nucleophilic aromatic [18 F]fluorination of a protected diaryliodonium salt precursor followed by a single deprotection step to afford the desired radiolabeled compound. This approach has been shown to reliably produce 4-[18 F]fluoro-m-hydroxyphenethylguanidine ([18 F]4F-MHPG, [18 F]1) and its structural isomer 3-[18 F]fluoro-p-hydroxyphenethylguanidine ([18 F]3F-PHPG, [18 F]2) with good radiochemical yields. Preclinical evaluations of [18 F]2 in nonhuman primates were performed to compare its imaging properties, metabolism, and myocardial kinetics with those obtained previously with [18 F]1. The results of these studies have demonstrated that [18 F]2 exhibits imaging properties comparable to those of [18 F]1. Myocardial tracer kinetic analysis of each tracer provides quantitative metrics of cardiac sympathetic nerve density. Based on these findings, first-in-human PET studies with [18 F]1 and [18 F]2 are currently in progress to assess their ability to accurately measure regional cardiac sympathetic denervation in patients with heart disease, with the ultimate goal of selecting a lead compound for further clinical development.- Published
- 2017
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5. Investigation of Proposed Activity of Clarithromycin at GABAA Receptors Using [(11)C]Flumazenil PET.
- Author
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Scott PJ, Shao X, Desmond TJ, Hockley BG, Sherman P, Quesada CA, Frey KA, Koeppe RA, Kilbourn MR, and Bohnen NI
- Abstract
Clarithromycin is a potential treatment for hypersomnia acting through proposed negative allosteric modulation of GABAA receptors. We were interested whether this therapeutic benefit might extend to Parkinson's disease (PD) patients because GABAergic neurotransmission is implicated in postural control. Prior to initiating clinical studies in PD patients, we wished to better understand clarithromycin's mechanism of action. In this work we investigated whether the proposed activity of clarithromycin at the GABAA receptor is associated with the benzodiazepine binding site using in vivo [(11)C]flumazenil positron emission tomography (PET) in primates and ex vivo [(3)H]flumazenil autoradiography in rat brain. While the studies demonstrate that clarithromycin does not change the K d of FMZ, nor does it competitively displace FMZ, there is preliminary evidence from the primate PET imaging studies that clarithromycin delays dissociation and washout of flumazenil from the primate brain in a dose-dependent fashion. These findings would be consistent with the proposed GABAA allosteric modulator function of clarithromycin. While the results are only preliminary, further investigation of the interaction of clarithromycin with GABA receptors and/or GABAergic medications is warranted, and therapeutic applications of clarithromycin alone or in combination with flumazenil, to treat hyper-GABAergic status in PD at minimally effective doses, should also be pursued.
- Published
- 2016
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- View/download PDF
6. Synthesis of Diverse (11)C-Labeled PET Radiotracers via Direct Incorporation of [(11)C]CO2.
- Author
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Mossine AV, Brooks AF, Jackson IM, Quesada CA, Sherman P, Cole EL, Donnelly DJ, Scott PJ, and Shao X
- Subjects
- Animals, Chemistry Techniques, Synthetic, Cyclization, Mice, Radioactive Tracers, Rats, Carbon Dioxide chemical synthesis, Carbon Dioxide chemistry, Carbon Radioisotopes, Positron-Emission Tomography
- Abstract
Three new positron emission tomography (PET) radiotracers of interest to our functional neuroimaging and translational oncology programs have been prepared through new developments in [(11)C]CO2 fixation chemistry. [(11)C]QZ (glutaminyl cyclase) was prepared via a tandem trapping of [(11)C]CO2/intramolecular cyclization; [(11)C]tideglusib (glycogen synthase kinase-3) was synthesized through a tandem trapping of [(11)C]CO2 followed by an intermolecular cycloaddition between a [(11)C]isocyanate and an isothiocyanate to form the 1,2,4-thiadiazolidine-3,5-dione core; [(11)C]ibrutinib (Bruton's tyrosine kinase) was synthesized through a HATU peptide coupling of an amino precursor with [(11)C]acrylic acid (generated from [(11)C]CO2 fixation with vinylmagnesium bromide). All radiochemical syntheses are fully automated on commercial radiochemical synthesis modules and provide radiotracers in 1-5% radiochemical yield (noncorrected, based upon [(11)C]CO2). All three radiotracers have advanced to rodent imaging studies and preliminary PET imaging results are also reported.
- Published
- 2016
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7. Synthesis and Evaluation of [(18)F]RAGER: A First Generation Small-Molecule PET Radioligand Targeting the Receptor for Advanced Glycation Endproducts.
- Author
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Cary BP, Brooks AF, Fawaz MV, Drake LR, Desmond TJ, Sherman P, Quesada CA, and Scott PJ
- Subjects
- Alzheimer Disease metabolism, Animals, Autoradiography, Brain metabolism, Chromatography, High Pressure Liquid, Fluorine Radioisotopes pharmacokinetics, Humans, Immunohistochemistry, Macaca mulatta, Molecular Docking Simulation, Positron-Emission Tomography, Rats, Rats, Sprague-Dawley, Radiopharmaceuticals chemical synthesis, Radiopharmaceuticals pharmacokinetics, Receptor for Advanced Glycation End Products analysis
- Abstract
The receptor for advanced glycation endproducts (RAGE) is a 35 kDa transmembrane receptor that belongs to the immunoglobulin superfamily of cell surface molecules. Its role in Alzheimer's disease (AD) is complex, but it is thought to mediate influx of circulating amyloid-β into the brain as well as amplify Aβ-induced pathogenic responses. RAGE is therefore of considerable interest as both a diagnostic and a therapeutic target in AD. Herein we report the synthesis and preliminary preclinical evaluation of [(18)F]RAGER, the first small molecule PET radiotracer for RAGE (Kd = 15 nM). Docking studies proposed a likely binding interaction between RAGE and RAGER, [(18)F]RAGER autoradiography showed colocalization with RAGE identified by immunohistochemistry in AD brain samples, and [(18)F]RAGER microPET confirmed CNS penetration and increased uptake in areas of the brain known to express RAGE. This first generation radiotracer represents initial proof-of-concept and a promising first step toward quantifying CNS RAGE activity using PET. However, there were high levels of nonspecific [(18)F]RAGER binding in vitro, likely due to its high log P (experimental log P = 3.5), and rapid metabolism of [(18)F]RAGER in rat liver microsome studies. Therefore, development of second generation ligands with improved imaging properties would be advantageous prior to anticipated translation into clinical PET imaging studies.
- Published
- 2016
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8. In Vivo Metabolic Trapping Radiotracers for Imaging Monoamine Oxidase-A and -B Enzymatic Activity.
- Author
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Brooks AF, Shao X, Quesada CA, Sherman P, Scott PJ, and Kilbourn MR
- Subjects
- Animals, Carbon Isotopes pharmacology, Diagnostic Imaging, Humans, Monoamine Oxidase chemistry, Monoamine Oxidase Inhibitors pharmacology, Monoamine Oxidase metabolism, Radiochemistry
- Abstract
The isozymes of monoamine oxidase (MAO-A and MAO-B) are important enzymes involved in the metabolism of numerous biogenic amines, including the neurotransmitters serotonin, dopamine, and norepinephrine. Recently, changes in concentrations of MAO-B have been proposed to be an in vivo marker of neuroinflammation associated with Alzheimer's disease. Previous developments of in vivo radiotracers for imaging changes in MAO enzyme expression or activity have utilized the irreversible propargylamine-based suicide inhibitors or high-affinity reversibly binding inhibitors. As an alternative approach, we have investigated 1-[(11)C]methyl-4-aryloxy-1,2,3,6-tetrahydropyridines as metabolic trapping agents for the monoamine oxidases. MAO-mediated oxidation and spontaneous hydrolysis yield 1-[(11)C]methyl-2,3-dihydro-4-pyridinone as a hydrophilic metabolite that is trapped within brain tissues. Radiotracers with phenyl, biphenyl, and 7-coumarinyl ethers were evaluated using microPET imaging in rat and primate brains. No isozyme selectivity for radiotracer trapping was observed in the rat brain for any compound, but in the monkey brain, the phenyl ether demonstrated MAO-A selectivity and the coumarinyl ether showed MAO-B selectivity. These are lead compounds for further development of 1-[(11)C]methyl-4-aryloxy-1,2,3,6-tetrahydropyridines with optimized brain pharmacokinetics and isozyme selectivity.
- Published
- 2015
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9. Synthesis and Initial in Vivo Studies with [(11)C]SB-216763: The First Radiolabeled Brain Penetrative Inhibitor of GSK-3.
- Author
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Li L, Shao X, Cole EL, Ohnmacht SA, Ferrari V, Hong YT, Williamson DJ, Fryer TD, Quesada CA, Sherman P, Riss PJ, Scott PJ, and Aigbirhio FI
- Abstract
Quantifying glycogen synthase kinase-3 (GSK-3) activity in vivo using positron emission tomography (PET) imaging is of interest because dysregulation of GSK-3 is implicated in numerous diseases and neurological disorders for which GSK-3 inhibitors are being considered as therapeutic strategies. Previous PET radiotracers for GSK-3 have been reported, but none of the published examples cross the blood-brain barrier. Therefore, we have an ongoing interest in developing a brain penetrating radiotracer for GSK-3. To this end, we were interested in synthesis and preclinical evaluation of [(11)C]SB-216763, a high-affinity inhibitor of GSK-3 (K i = 9 nM; IC50 = 34 nM). Initial radiosyntheses of [(11)C]SB-216763 proved ineffective in our hands because of competing [3 + 3] sigmatropic shifts. Therefore, we have developed a novel one-pot two-step synthesis of [(11)C]SB-216763 from a 2,4-dimethoxybenzyl-protected maleimide precursor, which provided high specific activity [(11)C]SB-216763 in 1% noncorrected radiochemical yield (based upon [(11)C]CH3I) and 97-100% radiochemical purity (n = 7). Initial preclinical evaluation in rodent and nonhuman primate PET imaging studies revealed high initial brain uptake (peak rodent SUV = 2.5 @ 3 min postinjection; peak nonhuman primate SUV = 1.9 @ 5 min postinjection) followed by washout. Brain uptake was highest in thalamus, striatum, cortex, and cerebellum, areas known to be rich in GSK-3. These results make the arylindolemaleimide skeleton our lead scaffold for developing a PET radiotracer for quantification of GSK-3 density in vivo and ultimately translating it into clinical use.
- Published
- 2015
- Full Text
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10. Targeting Metal-Aβ Aggregates with Bifunctional Radioligand [ 11 C]L2-b and a Fluorine-18 Analogue [ 18 F]FL2-b.
- Author
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Cary BP, Brooks AF, Fawaz MV, Shao X, Desmond TJ, Carpenter GM, Sherman P, Quesada CA, Albin RL, and Scott PJ
- Abstract
Interest in quantifying metal-Aβ species in vivo led to the synthesis and evaluation of [
11 C]L2-b and [18 F]FL2-b as radiopharmaceuticals for studying the metallobiology of Alzheimer's disease (AD) using positron emission tomography (PET) imaging. [11 C]L2-b was synthesized in 3.6% radiochemical yield (nondecay corrected, n = 3), >95% radiochemical purity, from the corresponding desmethyl precursor. [18 F]FL2-b was synthesized in 1.0% radiochemical yield (nondecay corrected, n = 3), >99% radiochemical purity, from a 6-chloro pyridine precursor. Autoradiography experiments with AD positive and healthy control brain samples were used to determine the specificity of binding for the radioligands compared to [11 C]PiB, a known imaging agent for β-amyloid (Aβ) aggregates. The Kd for [11 C]L2-b and [18 F]FL2-b were found to be 3.5 and 9.4 nM, respectively, from those tissue studies. Displacement studies of [11 C]L2-b and [18 C]L2-b was examined through microPET imaging in healthy rhesus macaque, which revealed a maximum uptake at 2.5 min (peak SUV = 2.0) followed by rapid egress (11 C]L2-b was examined through microPET imaging in healthy rhesus macaque, which revealed a maximum uptake at 2.5 min (peak SUV = 2.0) followed by rapid egress ( n = 2).- Published
- 2014
- Full Text
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11. High affinity radiopharmaceuticals based upon lansoprazole for PET imaging of aggregated tau in Alzheimer's disease and progressive supranuclear palsy: synthesis, preclinical evaluation, and lead selection.
- Author
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Fawaz MV, Brooks AF, Rodnick ME, Carpenter GM, Shao X, Desmond TJ, Sherman P, Quesada CA, Hockley BG, Kilbourn MR, Albin RL, Frey KA, and Scott PJ
- Subjects
- Alzheimer Disease metabolism, Amyloid beta-Peptides metabolism, Animals, Autoradiography, Brain diagnostic imaging, Brain metabolism, Carbon Radioisotopes chemistry, Carbon Radioisotopes pharmacokinetics, Drug Evaluation, Preclinical, Fluorine Radioisotopes chemistry, Fluorine Radioisotopes pharmacokinetics, Humans, Mice, Peptide Fragments metabolism, Primates, Rats, Supranuclear Palsy, Progressive metabolism, tau Proteins metabolism, Alzheimer Disease diagnostic imaging, Lansoprazole chemistry, Lansoprazole pharmacokinetics, Positron-Emission Tomography methods, Radiopharmaceuticals chemical synthesis, Radiopharmaceuticals chemistry, Radiopharmaceuticals pharmacokinetics, Supranuclear Palsy, Progressive diagnostic imaging
- Abstract
Abnormally aggregated tau is the hallmark pathology of tauopathy neurodegenerative disorders and is a target for development of both diagnostic tools and therapeutic strategies across the tauopathy disease spectrum. Development of carbon-11- or fluorine-18-labeled radiotracers with appropriate affinity and specificity for tau would allow noninvasive quantification of tau burden using positron emission tomography (PET) imaging. We have synthesized [(18)F]lansoprazole, [(11)C]N-methyl lansoprazole, and [(18)F]N-methyl lansoprazole and identified them as high affinity radiotracers for tau with low to subnanomolar binding affinities. Herein, we report radiosyntheses and extensive preclinical evaluation with the aim of selecting a lead radiotracer for translation into human PET imaging trials. We demonstrate that [(18)F]N-methyl lansoprazole, on account of the favorable half-life of fluorine-18 and its rapid brain entry in nonhuman primates, favorable kinetics, low white matter binding, and selectivity for binding to tau over amyloid, is the lead compound for progression into clinical trials.
- Published
- 2014
- Full Text
- View/download PDF
12. 4-[18F]Fluoro-m-hydroxyphenethylguanidine: a radiopharmaceutical for quantifying regional cardiac sympathetic nerve density with positron emission tomography.
- Author
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Jang KS, Jung YW, Gu G, Koeppe RA, Sherman PS, Quesada CA, and Raffel DM
- Subjects
- Adrenal Glands metabolism, Animals, Biological Transport, Female, Fluorine Radioisotopes, Haplorhini, Humans, Male, Radiation Dosage, Radiochemistry, Rats, Guanidines chemistry, Guanidines metabolism, Guanidines pharmacokinetics, Heart innervation, Phenethylamines chemistry, Phenethylamines metabolism, Phenethylamines pharmacokinetics, Positron-Emission Tomography methods, Radiopharmaceuticals chemistry, Radiopharmaceuticals metabolism, Radiopharmaceuticals pharmacokinetics, Sympathetic Nervous System diagnostic imaging
- Abstract
4-[(18)F]Fluoro-m-hydroxyphenethylguanidine ([(18)F]4F-MHPG, [(18)F]1) is a new cardiac sympathetic nerve radiotracer with kinetic properties favorable for quantifying regional nerve density with PET and tracer kinetic analysis. An automated synthesis of [(18)F]1 was developed in which the intermediate 4-[(18)F]fluoro-m-tyramine ([(18)F]16) was prepared using a diaryliodonium salt precursor for nucleophilic aromatic [(18)F]fluorination. In PET imaging studies in rhesus macaque monkeys, [(18)F]1 demonstrated high quality cardiac images with low uptake in lungs and the liver. Compartmental modeling of [(18)F]1 kinetics provided net uptake rate constants Ki (mL/min/g wet), and Patlak graphical analysis of [(18)F]1 kinetics provided Patlak slopes Kp (mL/min/g). In pharmacological blocking studies with the norepinephrine transporter inhibitor desipramine (DMI), each of these quantitative measures declined in a dose-dependent manner with increasing DMI doses. These initial results strongly suggest that [(18)F]1 can provide quantitative measures of regional cardiac sympathetic nerve density in human hearts using PET.
- Published
- 2013
- Full Text
- View/download PDF
13. Evaluation of [(11)C]N-Methyl Lansoprazole as a Radiopharmaceutical for PET Imaging of Tau Neurofibrillary Tangles.
- Author
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Shao X, Carpenter GM, Desmond TJ, Sherman P, Quesada CA, Fawaz M, Brooks AF, Kilbourn MR, Albin RL, Frey KA, and Scott PJ
- Abstract
[(11)C]N-Methyl lansoprazole ([(11)C]NML, 3) was synthesized and evaluated as a radiopharmaceutical for quantifying tau neurofibrillary tangle (NFT) burden using positron emission tomography (PET) imaging. [(11)C]NML was synthesized from commercially available lansoprazole in 4.6% radiochemical yield (noncorrected RCY, based upon [(11)C]MeI), 99% radiochemical purity, and 16095 Ci/mmol specific activity (n = 5). Log P was determined to be 2.18. A lack of brain uptake in rodent microPET imaging revealed [(11)C]NML to be a substrate for the rodent permeability-glycoprotein 1 (PGP) transporter, but this could be overcome by pretreating with cyclosporin A to block the PGP. Contrastingly, [(11)C]NML was not found to be a substrate for the primate PGP, and microPET imaging in rhesus revealed [(11)C]NML uptake in the healthy primate brain of ∼1600 nCi/cc maximum at 3 min followed by rapid egress to 500 nCi/cc. Comparative autoradiography between wild-type rats and transgenic rats expressing human tau (hTau +/+) revealed 12% higher uptake of [(11)C]NML in the cortex of brains expressing human tau. Further autoradiography with tau positive brain samples from progressive supranuclear palsy (PSP) patients revealed colocalization of [(11)C]NML with tau NFTs identified using modified Bielschowsky staining. Finally, saturation binding experiments with heparin-induced tau confirmed K d and Bmax values of [(11)C]NML as 700 pM and 0.214 fmol/μg, respectively.
- Published
- 2012
- Full Text
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14. 125I-labeled gold nanorods for targeted imaging of inflammation.
- Author
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Shao X, Zhang H, Rajian JR, Chamberland DL, Sherman PS, Quesada CA, Koch AE, Kotov NA, and Wang X
- Subjects
- Animals, Ankle Joint diagnostic imaging, Antibodies chemistry, Antibodies immunology, Arthritis diagnostic imaging, Arthritis metabolism, Arthritis microbiology, Biological Transport, Contrast Media metabolism, Cytokines metabolism, Feasibility Studies, Female, Gene Expression Regulation, Inflammation diagnostic imaging, Inflammation metabolism, Intercellular Adhesion Molecule-1 immunology, Iodine Radioisotopes, Isotope Labeling, Mycobacterium physiology, Rats, Contrast Media chemistry, Gold chemistry, Nanoconjugates chemistry, Nanotubes chemistry, Radionuclide Imaging methods
- Abstract
For better examination of inflammation, we designed inflammation-targeted nuclear and optical dual-modality contrast agents prepared by I-125 radiolabeling of gold nanorods (GdNRs) conjugated with anti-intercellular adhesion molecule 1 (ICAM-1) antibody. The bioactivity and specific binding of the PEGylated (125)I-ICAM-GdNR conjugates to the ICAM-1 was validated through ELISA testing. Inflammation-targeted imaging was then conducted on an adjuvant-induced arthritic rat model which demonstrated an elevation of ICAM-1 level in the affected ankle joints. Facilitated by the I-125 radioisotope and the whole-body imaging via the Gamma camera, the time-dependent distribution of the systemically injected agent as well as the uptake of the agent in the inflammatory articular tissues could be examined conveniently and quantitatively. The success in targeted delivery of gold nanoparticles to inflammatory tissue enables both nuclear and optical imaging of inflammation at molecular or cellular level. Other than diagnosis, radiolabeled gold nanoparticles also hold promise for targeted therapy of a variety of disorders., (© 2011 American Chemical Society)
- Published
- 2011
- Full Text
- View/download PDF
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