{"@context":"http://iiif.io/api/presentation/2/context.json","@id":"https://repo.library.stonybrook.edu/cantaloupe/iiif/2/manifest.json","@type":"sc:Manifest","label":"Synthesis of Carbon-11 Labeled Organic Molecules for PET Studies","metadata":[{"label":"dc.description.sponsorship","value":"This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree."},{"label":"dc.format","value":"Monograph"},{"label":"dc.format.medium","value":"Electronic Resource"},{"label":"dc.identifier.uri","value":"http://hdl.handle.net/11401/77119"},{"label":"dc.language.iso","value":"en_US"},{"label":"dc.publisher","value":"The Graduate School, Stony Brook University: Stony Brook, NY."},{"label":"dcterms.abstract","value":"PET has played a key role in the field of molecular imaging and nuclear medicine over the past decades.  PET represents a non-invasive molecular imaging technique to study and visualize human physiology by detecting positron-emitting radiopharmaceuticals labeled with short half-live radioisotopes (i.e., 11C, 13N, 15O, and 18F) that visualize in vivo biochemical processes and metabolic pathways (i.e., glycolysis and protein/DNA synthesis).  PET is also an emerging method for measuring body function and tailoring disease treatment in living human by detecting biochemical changes preceding anatomical changes occurring a disease.  The capability of imaging quantitatively and with high sensitivity without limitation in tissue penetration has facilitated development of PET imaging probes.  Therefore normal biological processes and their malfunctions are the targets of PET.   Blood-brain barrier (BBB) permeability is one of the most important criteria for PET radiotracers targeting different cellular elements in the brain as well as for the development of drugs for treating brain diseases.  However, there is no quantitative prediction tool for in vivo pharmacokinetic properties of radiotracer such as rate constants of plasma-to-brain transfer (K1) and brain-to-plasma transfer (k2). Instead of relying on trial-and-error based strategy, we designed a set of model compounds based on the benzamide structure, which is a widely used structural element in drugs and radiotracers (e.g., histone deacetylase (HDAC) inhibitors, [11C]raclopride), to build up the quantitative structure-property relationship (QSPR) as a prediction tool for dynamic modeling of BBB permeability. Parallel synthesis was performed to provide seven benzamides and the corresponding precursor molecules for high yield C-11 labelling using [11C]methyl iodide and [11C]methyl triflate.  PET imaging studies in the female baboon along with collecting blood samples over a scan time of 60 min revealed high brain uptake and rapid washout.  Kinetic modeling enabled the calculation of pharmacokinetic properties of this series of benzamides and their relationship to physicochemical properties and to BBB penetration. .   PET imaging is also a very useful method to develop and use radiotracers as scientific tools to understand signaling pathways controlling plant growth and development by imaging the biosynthesis and movement of plant hormones in the whole plant in vivo.  Plant oriented PET studies are meaningful to gain new knowledge on whole plant physiology for basic research and for developing better biofuel plants. Auxins are important plant hormones that play an essential role in plant growth and development.  Indole-3-acetic acid (IAA) is the most common and potent among naturally occurring auxins.  Although IAA was structurally characterized in the 1930s, its translocation in the whole plant in response to growth and environmental stimuli is still not completely understood.  The development and application of PET radiotracers to probe the auxin biosynthesis pathway, to study sites of auxin biosynthesis, and auxin distribution and metabolism builds on our recent development of tetraethylene glycol promoted two-step, one-pot rapid synthesis of [11C]IAA from [11C]cyanide and its use in studies of root herbivory.  Based on this study, routine production of [11C]IAA has become reliable and can be accomplished within 45 \u2013 50 min in high radiochemical yield and high specific activity for plant studies.  Labeling indole, the first substrate in auxin synthesis, with carbon-11 builds on a new method to incorporate C-11 into ring positions including indole.  It can assumed that the ring label will be present in all intermediates in auxin biosynthesis, since indole is a key intermediate in auxin biosynthesis.  Accordingly radiolabeling indole allows tracer studies of auxin biosynthesis in vivo in plants.  Therefore, we developed a radiosynthesis of [2-11C]indole via rapid [11C]cyanation followed by reductive cyclization.  Our approach involved the reaction of 2-nitrobenzyl bromide with no-carrier-added [11C]cyanide to form [11C]2-nitrophenylacetonitrile followed by reductive cyclization with Raney nickel and hydrazinium monoformate to form [11C]indole.  Each step for the synthesis of [2-11C]indole was fully controlled and systematically optimized to give a high radiochemical yield and high specific activity of [2-11C]indole in 45 minutes.  This new radiosynthetic method feeds into studies of signaling molecule biosynthesis and movement in whole plants. There is evidence that asparagine, similar to glutamine, plays an important role as a nitrogen source in plants.  Our objective was to develop a stereospecific synthesis of 11C-labeled L-asparagine, using a five-membered ring sulfamidate precursor and nucleophilic ring-opening with carbon-11 labeled hydrogen cyanide ([11C]HCN) as a radioprecursor.  For that, efficient preparation of the cyclic sulfamidate and model reaction without radioisotope (cold chemistry) has been developed.  The synthesis of (S)-di-tert-butyl 1,2,3-oxathiazolidine-3,4-dicarboxylate 2,2-dioxide started from commercially available Boc-O-benzyl-L-serine was accomplished in four steps.   Based on the success of model reactions in cold chemistry, selective radiosynthesis of L[4-11C]asparagine was accomplished via [11C]cyanation of the sulfamidate followed by hydrolysis with strong acid (TFA/H2SO4) through selective deprotection. Further biological studies via PET imaging are in progress."},{"label":"dcterms.available","value":"2017-09-20T16:52:00Z"},{"label":"dcterms.contributor","value":"Ojima, Iwao"},{"label":"dcterms.creator","value":"Lee, So Jeong"},{"label":"dcterms.dateAccepted","value":"2017-09-20T16:52:00Z"},{"label":"dcterms.dateSubmitted","value":"2017-09-20T16:52:00Z"},{"label":"dcterms.description","value":"Department of Chemistry."},{"label":"dcterms.extent","value":"266 pg."},{"label":"dcterms.format","value":"Application/PDF"},{"label":"dcterms.identifier","value":"http://hdl.handle.net/11401/77119"},{"label":"dcterms.issued","value":"2015-12-01"},{"label":"dcterms.language","value":"en_US"},{"label":"dcterms.provenance","value":"Made available in DSpace on 2017-09-20T16:52:00Z (GMT). No. of bitstreams: 1\nLee_grad.sunysb_0771E_12450.pdf: 11929023 bytes, checksum: e7c649e24cf66e356c2ace260b4c4678 (MD5)\n  Previous issue date:    1"},{"label":"dcterms.publisher","value":"The Graduate School, Stony Brook University: Stony Brook, NY."},{"label":"dcterms.subject","value":"Carbon-11, Molecular Imaging, Positron Emission Tomography (PET)"},{"label":"dcterms.title","value":"Synthesis of Carbon-11 Labeled Organic Molecules for PET Studies"},{"label":"dcterms.type","value":"Dissertation"},{"label":"dc.type","value":"Dissertation"}],"description":"This manifest was generated dynamically","viewingDirection":"left-to-right","sequences":[{"@type":"sc:Sequence","canvases":[{"@id":"https://repo.library.stonybrook.edu/cantaloupe/iiif/2/canvas/page-1.json","@type":"sc:Canvas","label":"Page 1","height":1650,"width":1275,"images":[{"@type":"oa:Annotation","motivation":"sc:painting","resource":{"@id":"https://repo.library.stonybrook.edu/cantaloupe/iiif/2/35%2F16%2F27%2F35162733371916552498589144210735667814/full/full/0/default.jpg","@type":"dctypes:Image","format":"image/jpeg","height":1650,"width":1275,"service":{"@context":"http://iiif.io/api/image/2/context.json","@id":"https://repo.library.stonybrook.edu/cantaloupe/iiif/2/35%2F16%2F27%2F35162733371916552498589144210735667814","profile":"http://iiif.io/api/image/2/level2.json"}},"on":"https://repo.library.stonybrook.edu/cantaloupe/iiif/2/canvas/page-1.json"}]}]}]}