Current Pharmaceutical Design
Volume 6, Number 10, July 2000

Preface Pp.i-i Dennis C. Dean [View Abstract] [Free Full text Article]

Radiolabeled compounds have long been invaluable tools for drug discovery and development. The ability to precisely detect and quantitate pharmacologically active substances in vitro and in vivo confers vital information regarding macromolecular target binding, anatomical distribution and bioconversion which is often difficult or impossible to obtain by other means. Changes in the way in which drugs are discovered and developed has presented new challenges for the detection and preparation of radiotracers. This issue of Current Pharmaceutical Design highlights recent developments in the applications and synthesis of radiolabeled compounds which are of particular importance to pharmaceutical research. The emergence of positron emission tomography (PET) utilization in drug development presents exciting new prospects, especially in the area of CNS pharmacology. PET imaging using short-lived positron-emitting isotopes such as 11C and 18F provides high resolution images from which anatomical distribution and localization of radiolabeled drug can be determined. While well-established as a diagnostic clinical technique and for mechanistic studies in animals, the use of PET for drug development has only recently gained widespread acceptance. Ray Gibson and coworkers review the unique advantages non-invasive PET imaging presents and important issues which must be considered in the design of site-specific radiotracers for targeting receptors. A second technique which has potential to greatly impact pharmaceutical research is accelerator mass spectrometry (AMS), which directly quantifies isotopic nuclei through mass spectrometry as an alternative to nuclear decay detection. In optimal cases, AMS can measure levels of rare and long-lived isotopes with sensitivity up to one million fold that of conventional decay counting techniques. Recent studies have demonstrated the unique potential of AMS as a bioanalytical tool in the areas of drug metabolism and toxicology where quantitation of carbon-14 and tritium labeled tracers is possible using as little as 1 nanocurie of iadioactivity. Kenneth Turteltaub and John Vogel provide a summarization of AMS instrumentation, sample preparation, and accuracy of measurement, as well as current and future directions for application to pharmaceutical research. Although new mass spectrometric techniques have revolutionized the way drugs and metabolites are detected, the use of radioisotopically labeled tracers of drug candidates remains an indispensable method for obtaining crucial drug metabolism and phamacokinetic information. Obtaining the maximum amount of quality data from these studies depends on many parameters such as isotope selection, specific activity, label position, counting efficiency, radioactive dose, sample processing and methods of detection. Deepak Dalvie provides an overview of the current role radiotracers play in pharmaceutical ADME and toxicology studies using pertinent examples from the drug metabolism literature. To round-out this hot topics issue of Current Pharmaceutical Design, two reviews which update the current state of radioisotopically labeled compound synthesis using the two most prominent isotopes, tritium and carbon-14, are included. Rapid access to radiolabeled drug candidates is directly dependent on the arsenal of procedures and reagents available to the synthetic chemist for isotope introduction. Tritium offers advantages of high specific activity for radioligand applications and rapid synthesis for early ADME tracer studies. Phil Williams provides a summary of the current options for tritium incorporation highlighting advances in reduction techniques using tritium gas and new tritide reagents which permit high levels of isotopic purity to be attained. Unlike tritium, syntheses with carbon-14 are usually conducted on larger mass scale which can more closely parallel preparation of unlabeled drug candidates. However, limited carbon-14 reagent availability and inherent limitations in laboratory manipulations make effective 14C-tracer synthetic planning vitally important. Keith McCarthy describes some of the newer methods and strategies available for synthesis with carbon-14 which allow higher throughput tracer synthesis. I'd like to thank all of the authors for their informative contributions to this issue.

Non-Invasive Radiotracer Imaging as a Tool for Drug Development Pp.973-989 Raymond E. Gibson, H. Donald Burns, Terence G. Hamill, Wai-si Eng, Barbara E. Francis and Christine Ryan [View Abstract] [Purchase Article]

Non-Invasive Radiotracer Imaging (NIRI) uses either short-lived positron-emitting isotopes, such as 11C and 18F, for Positron Emission Tomography (PET) or single photon emitting nuclides, e.g., 123I, 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.

Bioanalytical Applications of Accelerator Mass Spectrometry for Pharmaceutical Research Pp.991-1007 Kenneth W. Turteltaub and John S. Vogel [View Abstract] [Purchase Article]

Accelerator 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 14C, 3H, 41Ca, and 36Cl, 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 chemical 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 ( 1 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 (1 μg/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.

Recent Advances in the Applications of Radioisotopes in Drug Metabolism,Toxicology and Pharmacokinetics Pp.1009-1028 Deepak Dalvie [View Abstract] [Purchase Article]

Radioisotopes 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.

Recent Developments in Tritium Incorporation for Radiotracer Studies Pp.1029-1056 Manouchehr Saljoughian and Philip G. Williams [View Abstract] [Purchase Article]

The 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.

Recent Advances in the Design and Synthesis of Carbon-14 Labelled Pharmaceuticals from Small Molecule Precursors Pp.1057-1083 Keith E. McCarthy [View Abstract] [Purchase Article]

Over 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 crosscouplings, and the use of chiral auxiliaries for the enantioselective syntheses of radiolabelled pharmaceuticals.