Current Pharmaceutical Design - Volume 6, Issue 10, 2000
Volume 6, Issue 10, 2000
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Non-Invasive Radiotracer Imaging as a Tool for Drug Development
Authors: R.E. Gibson, H.D. Burns, T.G. Hamill, W-s. Eng, B.E. Francis and C. RyanNon-Invasive Radiotracer Imaging (NIRI) uses either short-lived positron-emitting isotopes, such as 11 C and 18 F, for Positron Emission Tomography (PET) or single photon emitting nuclides, e.g., 123 I, which provide images using planar imaging or Single-Photon Emission Computed Tomography (SPECT). These high-resolution imaging modalities provide anatomical distribution and localization of radiolabeled drugs, which can be used to generate real time receptor occupancy and off-rate studies in humans. This can be accomplished by either isotopically labeling a potential new drug (usually with 11 C), or indirectly by studying how the unlabelled drug inhibits specific radioligand binding in vivo. Competitive blockade studies can be accomplished using a radiolabeled analogue which binds to the site of interest, rather than a radiolabeled version of the potential drug. Imaging, particularly PET imaging, can be used to demonstrate the effect of a drug through a biochemical marker of processes such as glucose metabolism or blood flow. NIRI as a development tool in the pharmaceutical industry is gaining increased acceptance as its unique ability to provide such critical information in human subjects is recognized. This section will review recent examples that illustrate the utility of NIRI, principally PET, in drug development, and the potential of imaging advances in the development of cancer drugs and gene therapy. Finally, we provide a brief overview of the design of new radiotracers for novel targets.
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Bioanalytical Applications of Accelerator Mass Spectrometry for Pharmaceutical Research
Authors: K.W. Turteltaub and J.S. VogelAccelerator mass spectrometry (AMS) is a mass spectrometric method for quantifying isotopes. It has had great impact in the geosciences and is now being applied in the biomedical fields. AMS measures radioisotopes such as 14 C, 3 H, 41 Ca, and 36 Cl, and others, with attomole sensitivity and high precision. Its use is allowing absorption, distribution, metabolism and elimination studies, as well as detailed pharmacokinetics, to be carried out directly in humans with very low chemi-cal or radiological hazard. It is used in combination with standard separation methodologies, such as chromatography, in identification of metabolites and molecular targets for both toxicants and pharmacologic agents. AMS allows the use of very low specific activity chemicals ( less than or equal to1 mCi/mmol), creating opportunities to use compounds not available in a high specific activity form, such as those that must be biosynthesized, produced in combinatorial libraries, or made through inefficient synthesis. AMS is allowing studies to be carried out with agents having low bioavailability, low systemic distributions, or high toxicity where administered doses must be kept low (less than or equal to1 micro g/kg). It may have uses in tests for idiosyncratic metabolism, drug interaction, or individual susceptibility, among others. The ability to use very low chemical doses, low radiological doses, small samples and conduct multiple dose studies may help move drug candidates into humans faster and safer than before. The uses of AMS are growing and its potential for drug development is only now beginning to be realized.
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Recent Advances in the Applications of Radioisotopes in Drug Metabolism, Toxicology and Pharmacokinetics
By D. DalvieRadioisotopes have proven to be an indispensable tool in biomedical research and have played a pivotal role in the investigation of absorption, distribution, metabolism and excretion (ADME) properties of new chemical entities over the past several decades. The main advantage of using radioisotopes in studying the disposition of new drug candidates is the ease of detection and the achievement of high sensitivity, especially when compounds with high specific activity are used. The recent advances and applications of radioisotopes in designing and conducting ADME studies and its impact in the field of drug metabolism and pharmacokinetics are discussed in this review.
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Recent Developments in Tritium Incorporation for Radiotracer Studies
Authors: M. Saljoughian and P.G. WilliamsThe essential nature of rapid radiotracer synthesis very early in drug discovery programs has driven the need for better and more varied tritium incorporation methods. This review presents a summary of recent advances for tritium introduction via tritiated water, tritium gas, complex tritides, and a range of recently improved tritiation reagents. Access to a wider range of tritiated reagents (for tritioacetylation, tritioformylation, methylation, etc.) and commercial manifolds for the transfer and use of tritium gas is also discussed.
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Recent Advances in the Design and Synthesis of Carbon-14 Labelled Pharmaceuticals from Small Molecule Precursors
More LessOver the past decade, the increased chemical complexity of new drug candidates has resulted in a parallel need to develop innovative syntheses of carbon-14 labelled pharmaceuticals. Faced with short time-lines and a limited number of labelled precursors, radiochemists have addressed this challenge by developing new reagents and adapting existing technology to labelled syntheses. Selected examples from the recent radiochemical literature illustrate some of the creative strategies used to rapidly solve these synthetic challenges. Examples describing the handling and use of common small molecule reagents, such as carbon-14 labelled carbon dioxide, methyl iodide, cyanide, acetic acids, sulfur and phosphorous stabilized ylides for the synthesis of labelled steroids, prostanoids, nucleosides, pyridines, quinolines, benzazepines and other heterocycles are presented. Several general strategies for radiolabelling are also discussed including the degradation strategy for accessing necessary intermediates and precursors, the radiolabelling of aromatic substrates, transition metal mediated cross-couplings, and the use of chiral auxiliaries for the enantioselective syntheses of radiolabelled pharmaceuticals.
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Volumes & issues
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Volume 31 (2025)
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Volume (2025)
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Volume 30 (2024)
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Volume 29 (2023)
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Volume 28 (2022)
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Volume 27 (2021)
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Volume 26 (2020)
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Volume 25 (2019)
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Volume 24 (2018)
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Volume 23 (2017)
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Volume 22 (2016)
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Volume 21 (2015)
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Volume 20 (2014)
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Volume 19 (2013)
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Volume 18 (2012)
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Volume 17 (2011)
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Volume 16 (2010)
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Volume 15 (2009)
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Volume 14 (2008)
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Volume 13 (2007)
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Volume 12 (2006)
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Volume 11 (2005)
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Volume 10 (2004)
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Volume 9 (2003)
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Volume 8 (2002)
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Volume 7 (2001)
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Volume 6 (2000)
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