RNA enzymes or ribozymes can act as endoribonucleases, catalyzing the cleavage of RNA molecules with a sequence specificity of cleavage greater than that of known ribonucleases and approaching that of the DNA restriction endonucleases, thus serving as RNA sequence specific endoribonucleases. An example is a shortened form of the self-splicing ribosomal RNA intervening sequence of Tetrahymena (L-19 IVS RNA). Site-specific mutagenesis of the enzyme active site of the L-19 IVS RNA alters the substrate sequence specificity in a predictable manner, allowing a set of sequence-specific endoribonucleases to be synthesized. Varying conditions allow the ribozyme to act as a polymerase (nucleotidyltransferase), a dephosphorylase (acid phosphatase or phosphotransferase) or a sequence-specific endoribonuclease.

Rna ribozyme polymerases, dephosphorylases, restriction endoribonucleases and methods.

2.1.8. Michael Reaction 2245 2.1.9. Others 2247 2.2. Cyclization Reactions 2248 2.2.1. Carbon Diels−Alder Reactions 2248 2.2.2. Aza-Diels−Alder Reactions 2252 2.2.3. Other Hetero-Diels−Alder Reactions 2255 2.2.4. Ionic Diels−Alder Reaction 2256 2.2.5. 1,3-Dipolar Cycloadditions 2256 2.2.6. Other Cycloaddition Reactions 2258 2.2.7. Prins-type Cyclization 2259 2.3. Friedel−Crafts Acylation and Alkylation 2259 2.4. Baylis−Hillman Reaction 2263 2.5. Radical Addition 2264 2.6. Heterocycle Synthesis 2267 2.7. Diazocarbonyl Insertion 2270 3. C−X (X ) N, O, P, Etc.) Bond Formation 2271 3.1. Aromatic Nitration and Sulfonylation 2271 3.2. Michael Reaction 2272 3.3. Glycosylation 2273 3.4. Aziridination 2275 3.5. Diazocarbonyl Insertion 2276 3.6. Ring-Opening Reactions 2277 3.7. Other C−X Bond Formations 2280 4. Oxidation and Reduction 2280 4.1. Oxidation 2280 4.2. Reduction 2281 5. Rearrangement 2283 6. Protection and Deprotection 2285 6.1. Protection 2285 6.2. Deprotection 2288 7. Polymerization 2291 8. Miscellaneous Reactions 2291 9. Lanthanide(II) Triflates in Organic Synthesis 2295 10. Conclusion 2295 11. Acknowledgment 2295 12. References 2295

Rare-earth metal triflates in organic synthesis

Reaction mechanism of alkaline phosphatase based on crystal structures. Two-metal ion catalysis.

Molecular imaging is the visualization, characterization and measurement of biological processes at the molecular and cellular levels in humans and other living systems. Molecular imaging agents are probes used to visualize, characterize and measure biological processes in living systems. These two definitions were put forth by the Sociey of Nuclear Medicine (SNM) in 2007 as a way to capture the interdisciplinary nature of this relatively new field. The emergence of molecular imaging as a scientific discipline is a result of advances in chemistry, biology, physics and engineering, and the application of imaging probes and technologies has reshaped the philosophy of drug discovery in the pharmaceutical sciences by providing more cost effective ways to evaluate the efficacy of a drug candidate and allowing pharmaceutical companies to reduce the time it takes to introduce new therapeutics to the marketplace. Finally the impact of molecular imaging on clinical medicine has been extensive since it allows a physician to diagnose a patient’s illness, prescribe treatment and monitor the efficacy of that treatment non-invasively.

Single Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET) were the first molecular imaging modalities used clinically. SPECT requires the use of a contrast agent labeled with a gamma emitting radionuclide, which should have an ideal gamma energy of 100-250 keV. These gamma rays are recorded by the detectors of a dedicated gamma camera or SPECT instrument and after signal processing can be converted into an image indentifying the localization of the radiotracer. PET requires the injected radiopharmaceutical to be labeled with a positron emitting radionuclide. As the radionuclide decays it ejects a positron from its nucleus which travels a short distance before being annihilated with an electron to release two 511 keV gamma rays 180° apart that are detected by the PET scanner (Figure 1). After sufficient acquisition time the data are reconstructed using computer based algorithms to yield images of the radiotracer’s location within the organism. When compared to SPECT, PET has greater advantages with respect to sensitivity and resolution and has been gaining in clinical popularity, with the number of PET-based studies expected to reach 3.2 million by 2010.1 While SPECT and PET technology has been around for decades, its use remained limited because of the limited availability of relevant isotopes which had to be produced in nuclear reactors or particle accelerators. However, the introduction of the small biomedical cyclotron, the self-contained radionuclide generator and the dedicated small animal or clinical SPECT and PET scanners to hospitals and research facilities has increased the demand for SPECT and PET isotopes.



Figure 1

Cartoon depicting the fundamental principle of Positron Emission Tomography (PET). As the targeting group interacts with the cell surface receptor, the positron emitting radio-metal decays by ejecting β+ particles from its nucleus. After traveling ...



Traditional PET isotopes such as 18F, 15O, 13N and 11C have been developed for incorporation into small molecules, but due to their often lengthy radio-syntheses, short half-lives and rapid clearance, only early time points were available for imaging, leaving the investigation of biological processes, which occur over the duration of hours or days, difficult to explore. With the continuing development of biological targeting agents such as proteins, peptides, antibodies and nanoparticles, which demonstrate a range of biological half-lives, a need arose to produce new radionuclides with half-lives complementary with their biological properties. As a result, the production and radiochemistry of radiometals such as Zr, Y, In, Ga and Cu have been investigated as radionuclide labels for biomolecules since they have the potential to combine their favorable decay characteristics with the biological characteristics of the targeting molecule to become a useful radiopharmaceutical (Tables ​(Tables11 and ​and22).2



Table 1

Gamma- and Beta-Emitting Radiometals





Table 2

Positron-Emitting Radiometals



The number of papers published describing the production or use of these radiometals continues to expand rapidly, and in recognition of this fact, the authors have attempted to present a comprehensive review of this literature as it relates to the production, ligand development and radiopharmaceutical applications of radiometals (excluding 99mTc) since 1999. While numerous reviews have appeared describing certain aspects of the production, coordination chemistry or application of these radiometals,2-18 very few exhaustive reviews have been published.10,12 Additionally, this review has been written to be used as an individual resource or as a companion resource to the review written by Anderson and Welch in 1999.12 Together, they provide a literature survey spanning 50 years of scientific discovery. To accomplish this goal, this review has been organized into three sections: the first section discusses the coordination chemistry of the metal ions Zr, Y, In, Ga and Cu and their chelators in the context of radiopharmaceutical development; the second section describes the methods used to produce Zr, Y, In, Ga and Cu radioisotopes; and the final section describes the application of these radiometals in diagnostic imaging and radiotherapy.

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Coordinating Radiometals of Copper, Gallium, Indium, Yttrium and Zirconium for PET and SPECT Imaging of Disease

More than a quarter of a century after the first metal template synthesis of a [2]catenane in Strasbourg, there now exists a plethora of strategies available for the construction of mechanically bonded and entwined molecular level structures. Catenanes, rotaxanes, knots and Borromean rings have all been successfully accessed by methods in which metal ions play a pivotal role. Originally metal ions were used solely for their coordination chemistry; acting either to gather and position the building blocks such that subsequent reactions generated the interlocked products or by being an integral part of the rings or "stoppers" of the interlocked assembly. Recently the role of the metal has evolved to encompass catalysis: the metal ions not only organize the building blocks in an entwined or threaded arrangement but also actively promote the reaction that covalently captures the interlocked structure. This Review outlines the diverse strategies that currently exist for forming mechanically bonded molecular structures with metal ions and details the tactics that the chemist can utilize for creating cross-over points, maximizing the yield of interlocked over non-interlocked products, and the reactions-of-choice for the covalent capture of threaded and entwined intermediates.

Strategies and tactics for the metal-directed synthesis of rotaxanes, knots, catenanes, and higher order links.

Sepulchrate: a macrobicyclic nitrogen cage for metal ions

Synthesis and reactivity of aza-capped encapsulated cobalt(III) ions

The crystal structures of the nonahydrates of the rare earth trifluoromethanesulfonates, [M(OH2)9] [CF3SO3]3 have been determined at 295 K for the configurations fO, f7, f14, i.e. M = La, Gd, Lu, together with that of the yttrium analogue. The structures are similar to those of the rare earth ethyl sulfate nonahydrates, belonging to space group P6,/m (hexagonal) with cell dimensions a ≈ 13.7, c ≈ 7.5 A, Z 2, with the coordination about the rare earth atom being a tricapped trigonal prism. The structure is compared with that found from repulsion energy calculations.

Structure and stereochemistry in 'f-block' complexes of high coordination number. VIII. The [M(unidentate)9] system. Crystal structures of [M(OH2)9] [CF3SO3]3, M = La, Gd, Lu, Y

The synthesis and room-temperature single-crystal X-ray structure determination are recorded for a 1:1 adduct of lead(II) thiocyanate with pyridine (' py '). [( py ) Pb (SCN)2](∞|∞) is triclinic, Pī , a 10.544(1), b 7.3729(7), c 6.705(2) Ǻ, α 103.91(2), β 95.99(2), γ 100.51(1)°, Z = 2 f.u .; R was 0.041 for 3226 'observed' (I > 3σ(I)) reflections. The structure is a two-dimensional polymer in the be plane with eight-coordinate ( py -N)PbN3S4 linked by the familiar four- membered Pb2S2 and eight-membered Pb2(NCS)2 motifs by way of bridging thiocyanate groups; one of the latter, unusually, has a bifurcating bridging nitrogen atom leading to the introduction of Pb2N2 motifs. The structure of the parent lead(II) thiocyanate is also discussed.

Lewis-Base Adducts of Lead(II) Compounds. XX. Synthesis and Structure of the 1:1 Adduct of Pyridine With Lead(II) Thiocyanate

Template syntheses based on tris (ethane-1,2-diamine)cobalt(III) lead to cobalt(III) complexes of cage hexamines of the ' sarcophagine ' type ( sarcophagine = sar = 3,6,10,13,16,19- hexaazabicyclo [6.6.6] icosane ) rapidly and in high yield. Reduction of these species to their cobalt(II) forms enables the ligands to be removed in concentrated acids at elevated temperatures, and in hot aqueous solutions containing excess cyanide ion. The free sarcophagine and 1,8-diaminosarcophagine [(NH2)2sar or diamsar] ligands are strong bases, accepting up to four and five protons, respectively, in aqueous solution. In chloride medium, I = 1.0, at 298 K, pK1 = 11.95, pK2 = 10.33, pK3 = 7.17, pK4 ≈ 0 for sarcophagine , and pK1 = 11.44, pK2 = 9.64, pK3 = 6.49, pK4 = 5.48, pK5 ≈ 0 for diaminosarcophagine , with very similar values being found for triflate medium. Crystal structure determinations for both free bases, the chloride, sulfate, perchlorate and nitrate salts of diamsar , the complex of zinc chloride with sar, and the magnesium nitrate complex with diamsar show remarkably small variations in the cavity defined by the bicyclic ligands, though relatively subtle bond length and bond angle changes can be rationalized in terms of the effects of proton and metal ion binding. Exhaustive methylation of sarcophagine produces the highly lipophilic, hexatertiary base hexamethylsarcophagine , which, in the solid state, adopts quite different conformations and nitrogen-atom configurations to those of sar itself. All the ligands rapidly form metal ion complexes of generally exceptional kinetic and thermodynamic stability.

John M. Harrowfield

Papers

Sepulchrate: a macrobicyclic nitrogen cage for metal ions

Synthesis and reactivity of aza-capped encapsulated cobalt(III) ions

Structure and stereochemistry in 'f-block' complexes of high coordination number. VIII. The [M(unidentate)9] system. Crystal structures of [M(OH2)9] [CF3SO3]3, M = La, Gd, Lu, Y

Lewis-Base Adducts of Lead(II) Compounds. XX. Synthesis and Structure of the 1:1 Adduct of Pyridine With Lead(II) Thiocyanate

The Synthesis and Structure of Encapsulating Ligands: Properties of Bicyclic Hexamines