Current Topics in Medicinal Chemistry - Volume 10, Issue 11, 2010

Molecular imaging is a recently emerged multidisciplinary field that spans from chemistry, biology, pharmacology, and medicine. The beauty of molecular imaging is its ability to visualize and quantify cellular and molecular event at real-time in a non-invasive manner, which has profoundly changed the way we perform biological and medical research. Molecular imaging has numerous potential applications to the diagnosis of diseases such as cancer, and neurological and cardiovascular diseases. This technique also contributes to improving the treatment of these disorders by optimizing the pre-clinical and clinical tests of new medication. They are also expected to have a major economic impact due to earlier and more precise diagnosis. Molecular imaging differs from traditional imaging in that probes known as biomarkers are used to help image particular targets or pathways. Biomarkers interact chemically with their surroundings and in turn alter the image according to molecular changes occurring within the area of interest. This process is markedly different from previous methods of imaging which primarily imaged differences in qualities such as volume, density or water content. This ability to image fine molecular changes opens up an incredible number of exciting possibilities for medical application, including early detection and treatment of disease and basic pharmaceutical development. This issue (volume 10, number 11) and the next issue (volume 10, number 12) of Current Topics in Medicinal Chemistry, dedicated to “The Medicinal Chemistry of Targeted Tumor Imaging,” are aimed at describing and highlighting the state-of-theart of current research and development in the field of molecular imaging probe development. In this issue a total 5 review articles covering the chemistry of positron emission tomography (PET), single-photon emission computed tomography (SPECT), and activatable optical fluorescence imaging. The remaining 7 review articles on other topics related to the chemistry of targeted tumor imaging will be included in the next issue. Orit Jacobson et al. start this issue with a review of fluorine-18 chemistry. 18F (t1/2 = 109.8 min) is one of the most commonly used PET isotopes for labeling small organic molecules and bioactive peptides/proteins and subsequent PET imaging in rodents and human beings. 18F can be directly coupled to molecules via nucleophilic or electrophilic substitution. For biomolecules that cannot tolerate harsh chemical reaction conditions, the labeling is typically done by coupling 18F-labeled prosthetic groups with the desired biomolecule, mostly through amino- or thiol-reactive groups via acylation, alkylation, amidation, imidation, oxime or hydrazone formations. Some recent new attempts to label biomolecules in a single-step were also discussed. The second review by Zhude Tu et al. focused on carbon-11 chemistry. 11C (t1/2 = 20 min) is another common PET isotope for labeling organic molecules that have rapid pharmacokinetics. One of the major advantages of 11C as compared to other PET isotopes is that radiotracers allow a “hot-for-cold” substitution of biologically active molecules. The short half-life of 11C creates special challenges for the synthesis of 11C-labeled tracers. This review described the N, O, and S-alkylations of [11C]methyl iodide/[11C]methyl triflate and analogues of [11C]methyl iodide and their applications for making 11C tracers. Some recent advances in exploring a transmetallic complex mediated [11C]carbonyl reaction for oncologic targets were also presented. The third review article by Guiyang Hao et al. summarized the chemistry of non-standard PET radionuclides, including 70/71/72/74As, 75/76/77Br, 55Co, 60/61/62/64Cu, 68Ga, 124I, 86Y, 82Rb, 94mTc, and 89Zr. Different from 15O, 13N, 11C, and 18F, the nonstandard PET isotopes are characterized by half-lives ranging from seconds to days, emitting high energy positrons and cascade of gamma rays. The unique features of their production, radiochemical procedures, and applications were described in details. The main drawbacks of each nuclide were also discussed along with special considerations that must be given towards its practical use in PET....

Positron emission tomography (PET) is a nuclear medicine imaging technology which allows for four-dimensional, quantitative determination of the distribution of labeled biological compounds within the human body. PET is becoming an increasingly important tool for the measurement of physiological, biochemical and pharmacological functions at the molecular level in healthy and pathological conditions. This review will focus on Flouride-18, one of the common isotopes used for PET imaging, which has a half life of 109.8 minutes. This isotope can be produced with an efficient yield in a cyclotron as a nucleophile or as an electrophile. Flouride-18 can be thereafter introduced into small molecules or biomolecules using various chemical synthetic routes, to give the desired imaging agent.

Carbon-11 (C-11) radiotracers are widely used for the early diagnosis of cancer, monitoring therapeutic response to cancer treatment, and pharmacokinetic investigations of anticancer drugs. PET imaging permits non-invasive monitoring of metabolic processes and molecular targets, while carbon-11 radiotracers allow a “hot for cold” substitution of biologically active molecules. Advances in organic synthetic chemistry and radiochemistry as well as improved automated techniques for radiosynthesis have encouraged investigators in developing carbon-11 tracers for use in oncology imaging studies. The short half-life of carbon-11 (20.38 minutes) creates special challenges for the synthesis of C-11 labeled tracers; these include the challenges of synthesizing C-11 target compounds with high radiochemical yield, high radiochemical purity and high specific activity in a short time and on a very small scale. The optimization of conditions for making a carbon-11 tracer include the late introduction of the C-11 isotope, the rapid formation and purification of the target compound, and the use of automated systems to afford a high yield of the target compound in a short time. In this review paper, we first briefly introduce some basic principles of PET imaging of cancer; we then discuss principles of carbon-11 radiochemistry, focus on specific advances in radiochemistry, and describe the synthesis of C-11 radiopharmaceuticals developed for cancer imaging. The carbon-11 radiochemistry approaches described include the N,O, and S-alkylations of [11C]methyl iodide/[11C]methyl triflate and analogues of [11C]methyl iodide and their applications for making carbon-11 tracers; we then address recent advances in exploring a transmetallic complex mediated [11C]carbonyl reaction for oncologic targets.

Driven by the ever-increasing availability of preclinical and clinical Positron Emission Tomography (PET) scanners, the use of non-standard PET nuclides has been growing exponentially in the past decade. Largely complementary to the roles of the four standard PET nuclides (15O, 13N, 11C, and 18F) in PET, non-standard PET nuclides enable the novel design and synthesis of a wider range of PET tracers to probe a variety of biological events. However, characterized by emitting high energy positrons and cascade gamma rays, non-standard PET nuclides with half-lives ranging from seconds to days must be judiciously chosen for specific applications. Generally, chemistries with non-standard PET nuclides are more manageable given a wealth of existing standard operation procedures for the preparation of radiotracers for gamma scintigraphy or Single Photon Emission Computed Tomography (SPECT). This review describes most of the non-standard PET nuclides that have recently been reported for basic PET research or clinical studies with focus on the unique features of their productions, radiochemical procedures, and applications. The main drawbacks of each nuclide are also discussed along with special considerations that must be given towards its practical use in PET.

Radiolabeled small biomolecules provide a unique tool for target-specific delivery of radionuclides to the diseased tissues and have emerged as promising candidates in molecular imaging and radiotherapy of cancers. In general, a target-specific radiopharmaceutical can be divided into four parts: targeting biomolecule (BM), pharmacokinetic modifying (PKM) linker, bifunctional coupling or chelating agent (BFC), and radionuclide. The targeting biomolecule serves as a “carrier” for specific delivery of the radionuclide. PKM linkers are used to modify the radiotracer's pharmacokinetics. BFC is needed for radiolabeling of biomolecules with a metallic radionuclide. Different radiometals have significant difference in their coordination chemistry, and require BFCs with different donor atoms and chelator frameworks. Since the radiometal chelate can have a significant impact on biological properties of the target-specific radiopharmaceutical, its in vivo pharmacokinetics can be altered by modifying the coordination environment with various chelators or coligand. Among various SPECT radionuclides, 99mTc remains to be the most prominent radionuclide for the development of diagnostic radiopharmaceuticals because of its ideal nuclear properties and easy availability at low cost. 111In is also widely used in gamma scintigraphy (only second to 99mTc). In addition, 111In-labeld radiotracers are often used as the imaging surrogates for biodistribution and dosimetry determination of their corresponding 90Y analogs due to their similar coordination chemistry. This chapter will focus on the on the use of different BFCs for 99mTc and 111In-labeling of small biomolecules and the related coordination chemistry.

The development of highly sensitive and specific molecular probes for cancer imaging still remains a daunting challenge. Recently, interdisciplinary research at the interface of imaging sciences and bionanoconjugation chemistry has generated novel activatable imaging probes that can provide high-resolution imaging with ultra-low background signals. Activatable imaging probes are designed to amplify output imaging signals in response to specific biomolecular recognition or environmental changes in real time. This review introduces and highlights the unique design strategies and applications of various activatable imaging probes in cancer imaging.