SYNTHESIS OF RADIOLABELLED COMPOUNDS

Phosgene is a versatile reagent for the isotopic labelling of organic molecules and its use for the preparation of a variety of radiopharmaceuticals is well established. In particular, the synthesis of C-labelled compounds is possible owing to the frequently rapid reactions 

The preparations of labelled phosgene, COClj, cqCIj or COClj, have been described in Section 5.8. 

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By carefully controlling the molar ratio of the reactants micro and macro scale syntheses can be performed. DCC In DMF Is typically mixed with the nucleophile dissolved In DMF prior to the addition of H2SO4. The reaction Is performed at O c and Is finished In less than 30 min. Since small volumes of solutions are mixed the method Is applicable for synthesis of radiolabeled compounds (86). 

Synthesis of radiolabeled compounds for p-amyloid targeting of Alzheimer s disease 12EJ01279. 

Against this background, this chapter focuses on selected examples, showing the development in the synthesis and handling of explosive and/or toxic substances in liquid phase and recent progress in the synthesis of radiolabeled compounds for medicinal imaging techniques, ultrasound-supported reactions, and biphasic reaction systems. 

Richard Heys received his Ph.D. in organic chemistry from Stanford University in 1976 and conducted postdoctoral research in the chemistry department at Yale both involved the synthesis of radiolabeled compounds and their use in elucidation of biosynthetic pathways. His subsequent 29-year career in organic radiochemical synthesis both in the laboratory and as a manager took him to the Radiochemistry Department of Midwest Research Institute (now part of Aptuit, Inc.), Smith Kline French Laboratories/SmithKline Beecham Pharmaceuticals (now GlaxoSmithKline) and AstraZeneca Pharmaceuticals. Author or coauthor of over 85 publications, 8 patents and a previous conference proceedings volume in the field, organizer of an international symposium on the synthesis of isotopicaUy labeled compound and holder of leadership positions (including president and CFO) in the International Isotope Society for 9 years, he is retired and lives in northwestern Connecticut. 

The introduction of tritium into molecules is most commonly achieved by reductive methods, including catalytic reduction by tritium gas, PH2], of olefins, catalytic reductive replacement of halogen (Cl, Br, or I) by H2, and metal pH] hydride reduction of carbonyl compounds, eg, ketones (qv) and some esters, to tritium-labeled alcohols (5). The use of tritium-labeled building blocks, eg, pH] methyl iodide and pH]-acetic anhydride, is an alternative route to the preparation of high specific activity, tritium-labeled compounds. The use of these techniques for the synthesis of radiolabeled receptor ligands, ie, dmgs and dmg analogues, has been described ia detail ia the Hterature (6,7). 

Chemical synthesis of labeled compounds suffers from some limitations and problems, though. One limitation concerns the amount and cost of the radioactive starting material. This factor necessitates devising synthetic routes to the desired compounds in which the radiolabel can be introduced near the end of the sequence of reactions, so as to secure as high an overall yield of labeled material as possible. At present, numerous labeled compounds are available commercially as starting materials for syntheses. Still, in planning a new synthetic route, it is necessary to consider its compatibility with the specific stalling material available. 

Radiolabelled compounds the use of radiolabelled compounds in synthetic and tracer studies is important as it allows the scientist to locate the labelled atom, i.e. in, for example, chemical synthesis and... 

Radiolabelled compounds the use of radiolabelled compounds in synthetic and tracer studies is important as it allows the scientist to locate the labelled atom, i.e. 14C, 3H, in, for example, chemical synthesis and laboratory environmental fate (degradation) studies. If using radiolabelled compounds several issues arise and these include deciding upon the radionuclide itself, its position in the molecule, the specific activity, the solvent and cost. 

One of the first reports was published by Lu and coworkers [46], who demonstrated the use of a glass microreactor [channel dimensions, 220 pm (wide) x 60 pm (deep) X 1.4cm (length)] for the rapid synthesis of a series of radiolabeled compounds (Scheme 6.14). A premixed solution of 3-pyridin-3-yl-propionic acid (41) (0.01 M) and tetra-n-butylammonium hydroxide (0.01 M in DMF) was introduced from one inlet of the reactor and a solution of premade radioactive tosylate (42) (0.01 M in DMF) was added from the other inlet. A residence time of 12 s afforded the respective labeled ester (43) (Scheme 6.14) with a radiochemical yield (RCY) of 10%. Although, in this first example, the yield was not significantly better than other techniques, the advantage was that the overall processing time was reduced to just 10 min, which is ideal for PET tracer synthesis. 

The monitoring of carbon-14 labeled carbon dioxide evolution detected by scintillation counting is a very sensitive method but requires the expensive synthesis of radiolabeled test substrates. It is closely related to the ultimate degradation of the test material. H-PE is also used in biodegradation testing [121]. Rate of biodegradation is measured by CO2 production relative to that of compounds of similar chemical structure produced in nature which are known not to accumulate in the environment [117]. 

Young and co-workers have described the synthesis of radiolabelled bisphosphonates conjugates (486), (487) and (488). All compounds have... 

Examples of PLC with autoradiography detection include the published studies on labeling of l- H-PAF-aceter [25] diazinon and related compounds from plant material [26] metabolic fate of triamcinolone acetonide in laboratory animals [27] synthesis of 4-S-cysteaminyl-[U- " C]phenol antimelanoma agent [28] radiolabeled... 

The synthesis of the title compound, 214, the active-site-directed photoaffinity radiolabel for androgen-binding proteins ( ABP ), has been accomplished180,181 by treatment of excess 17a-[( )-2-tributyltin(IV)ethenyl]androsta-4,6-dien-17 -ol-3-one, 215, with sodium iodide-125 of specific activity 27 Cimmol-1 in a sodium acetate-AcOH buffered solution and a solution of 30% H2O2 in glacial AcOH (equation 77). 

The next two chapters are dedicated to radiopharmaceutical contrast agents starting with a detailed description of the chemistry of p -emitting compounds based on fluorine-18. Particular emphasis is laid on the different radiolabeled precursors and their suitability for the rapid synthesis of compounds useful for positron emission tomography. 

To make these substrates suitable for biological assays, the introduction of functional groups that can be traced with the proper analytical techniques is essential. The use of radio-, fluorescent-, and biotin-labeled lipidated peptides has been reported. The synthesis of fluorescent substrates is chemically straightforward and allows for production of larger quantities than the enzymatic synthesis used for radiolabeled peptides and is thus preferred over the use of radioactive compounds. [1 21] Common fluorescent probes can be introduced by conjugation to a free functional group present in the peptide. The fluorescent moiety is... 

Utilizing the Grubbs alkene metathesis reaction, Katzenellenbogen et al. 164 described the synthesis of the ten-membered-ring lactam p-turn mimetic 129 (Scheme 47, some experimental details given below) and prepared a mimetic 130 of the neuropeptide substance P, and in particular of the four C-terminal amino acid sequence -Phe8-Gly-Leu-Metn-. Compound 130 was unable to inhibit the binding of radiolabeled substance P. 

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