Benjamin H Rotstein

Massachusetts General Hospital, Boston, Massachusetts, United States

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Publications (19)139.08 Total impact

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    ABSTRACT: Fatty acid amide hydrolase (FAAH) is one of the principle enzymes for metabolizing endogenous cannabinoid neurotransmitters such as anandamide, and thus regulates endocannabinoid (eCB) signaling. Selective pharmaco-logical blockade of FAAH has emerged as a potential therapy to discern the endogenous functions of anandamide-mediated eCB pathways in anxiety, pain and addiction. Quantification of FAAH in the living brain by positron emission tomography (PET) would help our understanding of the endocannabinoid system in these conditions. While most FAAH radiotracers operate by an irreversible ('suicide') binding mechanism, a FAAH tracer with reversibility would facilitate quantitative analysis. We have identified and radiolabeled a reversible FAAH inhibitor, 7-(2-[(11)C]methoxyphenyl)-1-(5-(pyridin-2-yl)oxazol-2-yl)heptan-1-one ([(11)C]MPPO) in 13% radiochemical yield (non-decay corrected) with >99% radiochemical purity and 2 Ci/µmol (74 GBq/µmol) specific activity. The tracer showed moderate brain uptake (0.8 SUV) with heterogeneous brain distribution. However, blocking studies with a potent FAAH inhibitor URB597 demonstrated a low to modest specificity to the target. Measurement of lipophilicity, metabolite and efflux pathway analysis were also performed to study the pharmacokinetic profile of [(11)C]MPPO. In all, we reported an efficient radiolabeling and preliminary evaluation of the first-in-class FAAH inhibitor [(11)C]MPPO with α-ketoheterocyclic scaffold.
    ACS Chemical Neuroscience 10/2015; DOI:10.1021/acschemneuro.5b00248 · 4.36 Impact Factor
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    ABSTRACT: Azido (18) F-arenes are important and versatile building blocks for the radiolabeling of biomolecules via Huisgen cycloaddition ("click chemistry") for positron emission tomography (PET). However, routine access to such clickable agents is challenged by inefficient and/or poorly defined multistep radiochemical approaches. A high-yielding direct radiofluorination for azido (18) F-arenes was achieved through the development of an ortho-oxygen-stabilized iodonium derivative (OID). This OID strategy addresses an unmet need for a reliable azido (18) F-arene clickable agent for bioconjugation reactions. A ssDNA aptamer was radiolabeled with this agent and visualized in a xenograft mouse model of human colon cancer by PET, which demonstrates that this OID approach is a convenient and highly efficient way of labeling and tracking biomolecules. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
    Angewandte Chemie International Edition 08/2015; 54(43). DOI:10.1002/anie.201505927 · 11.26 Impact Factor
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    ABSTRACT: In the interest of developing in vivo positron emission tomography (PET) probes for neuroimaging of calcium channels, we have prepared a carbon-11 isotopologue of a dihydropyridine Ca2+-channel antagonist, isradipine. Desmethyl isradipine (4-(benzo[c][1,2,5]oxadiazol-4-yl)-5-(isopropoxycarbonyl)-2,6-dimethyl-1,4-dihydropyridine -3-carboxylic acid) was reacted with [11C]CH3I in the presence of tetrabutylammonium hydroxide in DMF in an HPLC injector loop to produce the radiotracer in a good yield (6 ± 3% uncorrected radiochemical yield) and high specific activity (143 ± 90 GBq·µmol-1 at end-of-synthesis). PET imaging of normal rats revealed rapid brain uptake at baseline (0.37 ± 0.08% ID/cc (percent of injected dose per cubic centimeter) at peak, 15-60 s), which was followed by fast washout. After pretreatment with isradipine (2 mg·kg-1, i.p.), whole brain radioactivity uptake was diminished by 25%-40%. This preliminary study confirms that [11C]isradipine can be synthesized routinely for research studies and is brain penetrating. Further work on Ca2+-channel radiotracer development is planned.
    Molecules 06/2015; 20(6):9550-9. DOI:10.3390/molecules20069550 · 2.42 Impact Factor
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    ABSTRACT: Fluorine-18 labeled 2-fluoro-8-hydroxyquinoline ([18F]CABS13) is a promising positron emission tomography (PET) radiopharmaceutical based on a metal chelator developed to probe the "metal hypothesis of Alzheimer's disease". Herein, a practical radiosynthesis of [18F]CABS13 was achieved by radiofluorination followed by deprotection of an O-benzyloxymethyl group. Automated production and formulation of [18F]CABS13 resulted in 19 ± 5% uncorrected radiochemical yield, relative to starting [18F]fluoride, with ≥95% chemical and radiochemical purities, and high specific activity (>2.5 Ci/μmol) within 80 minutes. Temporal PET neuroimaging studies were carried out in female transgenic B6C3-Tg(APPswe,PSEN1dE9)85Dbo/J (APP/PS1) and age-matched wild-type (WT) B6C3F1/J control mice at 3, 7 and 10 months of age. [18F]CABS13 showed an overall higher uptake and retention of radioactivity in the central nervous system of APP/PS1 mice versus WT mice with increasing age. However, PET/magnetic resonance imaging in normal non-human primates revealed that the tracer had low uptake in the brain and rapid formation of a hydrophilic radiometabolite. Identification of more metabolically stable 18F-hydroxyquinolines that can be readily accessed by the radiochemical strategy presented herein is underway.
    ACS Chemical Neuroscience 03/2015; 6(4). DOI:10.1021/acschemneuro.5b00055 · 4.36 Impact Factor
  • Benjamin H. Rotstein · Serge Zaretsky · Vishal Rai · Andrei K. Yudin ·

    ChemInform 10/2014; 45(41). DOI:10.1002/chin.201441280
  • Lee Belding · Serge Zaretsky · Benjamin H Rotstein · Andrei K Yudin · Travis Dudding ·
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    ABSTRACT: A multicomponent reaction between an aziridine aldehyde dimer, isocyanide, and l-proline to afford a chiral piperazinone was studied to gain insight into the stereodetermining and rate-limiting steps of the reaction. The stereochemistry of the reaction was found to be determined by isocyanide addition, while the rate-limiting step was found to deviate from traditional isocyanide-based multicomponent reactions. A first-order rate dependence on aziridine aldehyde dimer and a zero-order rate dependence on all other reagents have been obtained. Computations at the MPWPW91/6-31G(d) level supported the experimental kinetic results and provide insight into the overall mechanism and the factors contributing to stereochemical induction. These factors are similar to traditional isocyanide-based multicomponent reactions, such as the Ugi reaction. The computations revealed that selective formation of a Z-iminium ion plays a key role in controlling the stereoselectivity of isocyanide addition, and the carboxylate group of l-proline mediates stereofacial addition. These conclusions are expected to be applicable to a wide range of reported stereoselective Ugi reactions and provide a basis for understanding the related macrocyclization of peptides with aziridine aldehydes.
    The Journal of Organic Chemistry 09/2014; 79(20). DOI:10.1021/jo501242r · 4.72 Impact Factor
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    ABSTRACT: The factors determining diastereoselectivity observed in the multicomponent conversion of amino acids, aziridine aldehyde dimers, and isocyanides into chiral piperazinones, have been investigated. Amino acid-dependent selectivity for either trans- or cis-substituted piperazinone products has been achieved. An experimentally determined diastereoselectivity model for the three-component reaction driven by aziridine aldehyde dimers has predictive value for different substrate classes. Moreover, this model is useful in reconciling the previously reported observations in multicomponent reactions between isocyanides, alpha-amino acids, and monofunctional aldehydes.
    The Journal of Organic Chemistry 09/2014; 79(21). DOI:10.1021/jo5018316 · 4.72 Impact Factor
  • Benjamin H Rotstein · Serge Zaretsky · Vishal Rai · Andrei K Yudin ·
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    ABSTRACT: The progress made in multicomponent reactions (MCRs) that either produce small heterocycles or employ them as starting materials are investigated. Driven by strain release, multicomponent reactions employing small ring heterocycles offer opportunities for atom-economical synthesis of organic molecules. Isocyanide-based MCRs are made possible by the 1,1-amphoteric nature of the isocyanide functional group. Passerini and Ugi reactions are the two most well-known isocyanide-based MCRs. One strategy to extend MCR reactivity is to substitute one component of a known MCR with a small heterocycle. A second strategy for MCRs that employ epoxides for attack on bromonium ions is the introduction of an additional nucleophile to conduct the terminal ring opening, rather than bromide formed in situ. It is noteworthy that alternate factors can also provide the driving force, leading to opportunities to retain the core structures of small heterocycles in products. In some cases, small ring heterocycles can even be built during multicomponent synthesis.
    Chemical Reviews 07/2014; 114(16). DOI:10.1021/cr400615v · 46.57 Impact Factor
  • Benjamin H Rotstein · Nickeisha A Stephenson · Neil Vasdev · Steven H Liang ·
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    ABSTRACT: Fluorine-18 (t½=109.7 min) is the most commonly used isotope to prepare radiopharmaceuticals for molecular imaging by positron emission tomography (PET). Nucleophilic aromatic substitution reactions of suitably activated (electron-deficient) aromatic substrates with no-carrier-added [(18)F]fluoride ion are routinely carried out in the synthesis of radiotracers in high specific activities. Despite extensive efforts to develop a general (18)F-labelling technique for non-activated arenes there is an urgent and unmet need to achieve this goal. Here we describe an effective solution that relies on the chemistry of spirocyclic hypervalent iodine(III) complexes, which serve as precursors for rapid, one-step regioselective radiofluorination with [(18)F]fluoride. This methodology proves to be efficient for radiolabelling a diverse range of non-activated functionalized arenes and heteroarenes, including arene substrates bearing electron-donating groups, bulky ortho functionalities, benzylic substituents and meta-substituted electron-withdrawing groups. Polyfunctional molecules and a range of previously elusive (18)F-labelled building blocks, compounds and radiopharmaceuticals are synthesized.
    Nature Communications 07/2014; 5:4365. DOI:10.1038/ncomms5365 · 11.47 Impact Factor
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    ABSTRACT: Fatty acid amide hydrolase (FAAH) regulates endocannabinoid signaling. [11C]CURB, an irreversibly binding FAAH inhibitor, has been developed for clinical research imaging with PET. However no fluorine-18 labeled radiotracer for FAAH has yet advanced to human studies. [18F]DOPP ([18F]3-(4,5-dihydrooxazol-2-yl)phenyl (5-fluoropentyl)carbamate) has been identified as a promising 18F-labeled analog based on rodent studies. The goal of this work is to evaluate [18F]DOPP in non-human primates to support its clinical translation. High specific activity [18F]DOPP (5 - 6 Ci•µmol-1) was administered intravenously (i.v.) to three baboons (2M/1F, 3 - 4 yr). The distribution and pharmacokinetics were quantified following a 2 h dynamic imaging session using a simultaneous PET/MR scanner. Pretreatment with the FAAH-selective inhibitor, URB597, was carried out at 200 or 300 µg/kg i.v., 10 min prior to [18F]DOPP administration. Rapid arterial blood sampling for the first 3 min was followed by interval sampling with metabolite analysis to provide a parent radiotracer plasma input function that indicated ~95% baseline metabolism at 60 min and a reduced rate of metabolism after pretreatment with URB597. Regional distribution data were analyzed with 1-, 2-, and 3-tissue compartment models (TCMs), with and without irreversible trapping since [18F]DOPP is believed to covalently link to the active site of FAAH. Consistent with previous findings for [11C]CURB, the 2TCM with irreversible binding was found to provide the best fit for modeling the data in all regions. The composite parameter λk3 was therefore used to evaluate whole brain (WB) and regional binding of [18F]DOPP. Pretreatment studies showed inhibition of λk3 across all brain regions (WB baseline: 0.112 mL/cm3/min; 300 µg/kg URB597: 0.058 mL/cm3/min) suggesting that [18F]DOPP binding is specific for FAAH, consistent with previous rodent data.
    Molecular Pharmaceutics 07/2014; 11(11). DOI:10.1021/mp500316h · 4.38 Impact Factor
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    ABSTRACT: Bexarotene (Targretin) is a retinoid X receptor (RXR) agonist that has applications for treatment of T cell lymphoma and proposed mechanisms of action in Alzheimer's disease that have been the subject of recent controversy. Carbon-11 labeled bexarotene ([(11)C-carbonyl]4-[1-(3,5,5,8,8-pentamethyltetralin-2-yl)ethenyl]benzoic acid) was synthesized using a Cu-mediated cross-coupling reaction employing an arylboronate precursor 1 and [(11)C]carbon dioxide under atmospheric pressure in 15 ± 2% uncorrected radiochemical yield (n = 3), based on [(11)C]CO2. Judicious choice of solvents, catalysts, and additives, as well as precursor concentration and purity of [(11)C]CO2, enabled the preparation of this (11)C-labeled carboxylic acid. Formulated [(11)C]bexarotene was isolated (>37 mCi) with >99% radiochemical purity in 32 min. Preliminary positron emission tomography-magnetic resonance imaging revealed rapid brain uptake in nonhuman primate in the first 75 s following intravenous administration of the radiotracer (specific activity >0.3 Ci/μmol at time of injection), followed by slow clearance (Δ = -43%) over 60 min. Modest uptake (SUVmax = 0.8) was observed in whole brain and regions with high RXR expression.
    ACS Medicinal Chemistry Letters 06/2014; 5(6):668-72. DOI:10.1021/ml500065q · 3.12 Impact Factor
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    ABSTRACT: Alzheimer's disease (AD) and related dementias show increasing clinical prevalence, yet our understanding of the etiology and pathobiology of disease-related neurodegeneration remains limited. In this regard, noninvasive imaging with radiotracers for positron emission tomography (PET) presents a unique tool for quantifying spatial and temporal changes in characteristic biological markers of brain disease and for assessing potential drug efficacy. PET radiotracers targeting different protein markers are being developed to address questions pertaining to the molecular and/or genetic heterogeneity of AD and related dementias. For example, radiotracers including [(11) C]-PiB and [(18) F]-AV-45 (Florbetapir) are being used to measure the density of Aβ-plaques in AD patients and to interrogate the biological mechanisms of disease initiation and progression. Our focus is on the development of novel PET imaging agents, targeting proteins beyond Aβ-plaques, which can be used to investigate the broader mechanism of AD pathogenesis. Here, we present the chemical basis of various radiotracers which show promise in preclinical or clinical studies for use in evaluating the phenotypic or biochemical characteristics of AD. Radiotracers for PET imaging neuroinflammation, metal ion association with Aβ-plaques, tau protein, cholinergic and cannabinoid receptors, and enzymes including glycogen-synthase kinase-3β and monoamine oxidase B amongst others, and their connection to AD are highlighted. Copyright © 2013 John Wiley & Sons, Ltd.
    Journal of Labelled Compounds 04/2014; 57(4). DOI:10.1002/jlcr.3158 · 1.27 Impact Factor
  • Steven H Liang · Thomas Lee Collier · Benjamin H Rotstein · Rebecca Lewis · Mia Steck · Neil Vasdev ·
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    ABSTRACT: We have combined the benefits of both microfluidics and flow hydrogenation to provide facile access to previously underutilized reduction and protecting group chemistries for PET imaging applications. The rapid removal of an O-benzyl protecting group to prepare 2-[(18)F]fluoroquinolin-8-ol and the reduction of a nitro group in the synthesis of 4-[(18)F]fluoroaniline were achieved within 3 minutes.
    Chemical Communications 08/2013; 49(78). DOI:10.1039/c3cc45166f · 6.83 Impact Factor
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    ABSTRACT: Carbon-11 labelled carbon dioxide is the cyclotron-generated feedstock reagent for most positron emission tomography (PET) tracers using this radionuclide. Most carbon-11 labels, however, are installed using derivative reagents generated from [(11)C]CO2. In recent years, [(11)C]CO2 has seen a revival in applications for the direct incorporation of carbon-11 into functional groups such as ureas, carbamates, oxazolidinones, carboxylic acids, esters, and amides. This review summarizes classical [(11)C]CO2 fixation strategies using organometallic reagents and then focuses on newly developed methods that employ strong organic bases to reversibly capture [(11)C]CO2 into solution, thereby enabling highly functionalized labelled compounds to be prepared. Labelled compounds and radiopharmaceuticals that have been translated to the clinic are highlighted.
    Chemical Communications 05/2013; 49(50). DOI:10.1039/c3cc42236d · 6.83 Impact Factor
  • Benjamin H. Rotstein · Andrei K. Yudin ·
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    ABSTRACT: Enantiopure aziridine-substituted bicyclic oxazolidines, so called α-aziridine aldehydes, are applied as substrates in Ugi and Passerini reactions to give highly functionalized scaffolds as diastereomeric mixtures.
    ChemInform 12/2012; 43(52). DOI:10.1002/chin.201252096
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    Áron Roxin · Juan Chen · Conor C G Scully · Benjamin H Rotstein · Andrei K Yudin · Gang Zheng ·
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    ABSTRACT: Here, we demonstrate a conjugation strategy whereby cyclic RGD-containing macrocycles are prepared using aziridine aldehydes, isocyanides, and linear peptides, followed by conjugation to a cysteamine linker. Our method involves site-selective aziridine ring-opening with the nucleophilic sulfhydryl group of cysteamine. Fluorescein was then efficiently conjugated to the primary amine of cysteamine by NHS-chemistry. This strategy may be expanded to provide easy access to a wide variety of fluorescent dyes or radiometal chelators. Modeling studies showed that aziridine aldehyde cyclization chemistry stabilized the RGD motif into the required bioactive conformation and that this cyclization chemistry modulated the geometry of macrocycles of different residue lengths. In vitro studies showed that cPRGDA and cPRGDAA both selectively bound to α(V)β(3)-overexpressing U87 glioblastoma cells, and that cPRGDA had a better binding affinity compared to cPRGDAA. The improved binding affinity of cPRGDA was attributed to the fixed Pro-C(α)-Asp-C(α) distance surrounding the stabilized RGD motif in cPRGDA.
    Bioconjugate Chemistry 06/2012; 23(7):1387-95. DOI:10.1021/bc300239a · 4.51 Impact Factor
  • Benjamin H Rotstein · David J Winternheimer · Lois M Yin · Charles M Deber · Andrei K Yudin ·
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    ABSTRACT: A novel class of reagents, thioester isocyanides, have been prepared and applied in the synthesis of peptide macrocycles. The isocyanide part of the molecule is deployed in a multicomponent macrocyclization step. This step is followed by chemoselective peptide ligation at the thioester part of the macrocycle. Our method can now be used for rapid assembly and evaluation of cycle-tail peptides.
    Chemical Communications 04/2012; 48(31):3775-7. DOI:10.1039/c2cc16027g · 6.83 Impact Factor
  • Benjamin H Rotstein · Rida Mourtada · Shana O Kelley · Andrei K Yudin ·
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    ABSTRACT: Sensitive scaffolds: An isocyanide equipped with an environment-sensitive fluorophore was used to synthesize peptide macrocycles. The photophysical properties of the product macrocycles are sensitive to both peptide sequence and configuration. A mitochondria-penetrating peptide was constrained within a cyclic peptide framework and showed increased uptake and localization relative to a linear control (see scheme).
    Chemistry - A European Journal 10/2011; 17(44):12257-61. DOI:10.1002/chem.201102096 · 5.73 Impact Factor
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    Benjamin H Rotstein · Vishal Rai · Ryan Hili · Andrei K Yudin ·
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    ABSTRACT: This protocol describes a method for synthesizing peptide macrocycles from linear peptide precursors, isocyanides and aziridine aldehydes. The effects of the reaction components on the efficiency of the process are discussed. Macrocyclization is exemplified by the preparation of a nine-membered ring peptide macrocycle. The product is further functionalized by nucleophilic opening of the aziridine ring with a fluorescent thiol. This transformation constitutes a useful late-stage functionalization of a macrocyclic peptide molecule. The experimental section describes the selection of the required starting materials, and the preparation of a representative aziridine-2-carboxaldehyde dimer. The synthesis and isolation of the peptide macrocycle can be accomplished in 6 h, and the ring-opening requires approximately 6-8 h. The aziridine-2-carboxaldehyde reagent is commercially available or can be synthesized from readily available starting materials in approximately 4 d. The strategy described is not limited to the specific peptide, isocyanide, aziridine aldehyde or nucleophile used in the representative synthesis.
    Nature Protocol 10/2010; 5(11):1813-22. DOI:10.1038/nprot.2010.127 · 9.67 Impact Factor

Publication Stats

173 Citations
139.08 Total Impact Points


  • 2014-2015
    • Massachusetts General Hospital
      • Division of Nuclear Medicine and Molecular Imaging
      Boston, Massachusetts, United States
  • 2013-2014
    • Harvard University
      Cambridge, Massachusetts, United States
    • Harvard Medical School
      • Department of Radiology
      Boston, Massachusetts, United States
  • 2010-2014
    • University of Toronto
      • Department of Chemistry
      Toronto, Ontario, Canada