Andrew S. Craig

Bio: Andrew S. Craig is an academic researcher from Durham University. The author has contributed to research in topics: Crystal structure & X-ray crystallography. The author has an hindex of 11, co-authored 17 publications receiving 595 citations.

Structure and solution stability of indium and gallium complexes of 1,4,7-triazacyclononanetriacetate and of yttrium complexes of 1,4,7,10-tetraazacyclododecanetetraacetate and related ligands: kinetically stable complexes for use in imaging and radioimmunotherapy. X-Ray molecular structure of the indium and gallium complexes of 1,4,7-triazacyclononane-1,4,7-triacetic acid

Abstract: Of the four triazacycloalkanetriacetic acids screened for their ability to bind 111ln, triazacyclononanetriacetate bound indium most quickly and formed a complex whose dissociation as a function of pD was monitored by 13C NMR spectrometry using a labelled ligand (k296 1.8 × 10–1 dm3 mol–1 s–1) in the pD range 0 to –0.6. The corresponding gallium complex is even more stable with respect to acid dissociation and may be observed by 71Ga NMR spectrometry both in vitro(δGa+ 171 ppm) and in vivo. Crystal structures of the neutral gallium and of the protonated indium complexes are reported. The syntheses of a series of octadentate ligands are described and their relative efficiency to bind 90Y reported. Ligands based on tetraazacyclododecane bind 90Y most rapidly, and tetraazacyclododecanetetraacetate forms a strong complex with yttrium (log Ks 24.9, 298 K) which dissociates at low pH (< 2) as measured by HPLC and 13C NMR spectrometry.

Synthesis of C- and N-functionalised derivatives of 1,4,7-triazacyclononane-1,4,7-triyltriacetic acid (NOTA), 1,4,7,10-tetra-azacyclododecane-1,4,7,10-tetrayltetra-acetic acid (DOTA), and diethylenenetriaminepenta-acetic acid (DTPA): bifunctional complexing agents for the derivatisation of antibodies

Abstract: Using (2S)-lysine as a precursor, the syntheses of aminobutyl derivatives of 1,4,7-triazacyclononane, 1,4,7,10-tetra-azacyclododecane, and 3-azapentane-1,5-diamine are described. Transformation into their reactive maleimide derivatives is described and alternative strategies for synthesising the title complexing agents involving nitrogen functionalisation are defined.

Stability, 71Ga NMR, and crystal structure of a neutral gallium(III) complex of 1,4,7-triazacyclononanetriacetate: a potential radiopharmaceutical?

Abstract: The gallium complex of 1,4,7-triazacyclononanetriacetate is C3-symmetric both in solution and in the solid state and may be observed by 71Ga NMR in aqueous solution in the pH range –0.8 to +12.

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

Abstract: 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.

Matching chelators to radiometals for radiopharmaceuticals.

Abstract: Radiometals comprise many useful radioactive isotopes of various metallic elements When properly harnessed, these have valuable emission properties that can be used for diagnostic imaging techniques, such as single photon emission computed tomography (SPECT, eg67Ga, 99mTc, 111In, 177Lu) and positron emission tomography (PET, eg68Ga, 64Cu, 44Sc, 86Y, 89Zr), as well as therapeutic applications (eg47Sc, 114mIn, 177Lu, 90Y, 212/213Bi, 212Pb, 225Ac, 186/188Re) A fundamental critical component of a radiometal-based radiopharmaceutical is the chelator, the ligand system that binds the radiometal ion in a tight stable coordination complex so that it can be properly directed to a desirable molecular target in vivo This article is a guide for selecting the optimal match between chelator and radiometal for use in these systems The article briefly introduces a selection of relevant and high impact radiometals, and their potential utility to the fields of radiochemistry, nuclear medicine, and molecular imaging A description of radiometal-based radiopharmaceuticals is provided, and several key design considerations are discussed The experimental methods by which chelators are assessed for their suitability with a variety of radiometal ions is explained, and a large selection of the most common and most promising chelators are evaluated and discussed for their potential use with a variety of radiometals Comprehensive tables have been assembled to provide a convenient and accessible overview of the field of radiometal chelating agents

68Ga-PET: a powerful generator-based alternative to cyclotron-based PET radiopharmaceuticals

Abstract: PET (positron emission tomography) is a powerful diagnostic and imaging technique which requires short-lived positron emitting isotopes. The most commonly used are accelerator-produced (11)C and (18)F. An alternative is the use of metallic positron emitters. Among them (68)Ga deserves special attention because of its availability from long-lived (68)Ge/(68)Ga generator systems which render (68)Ga radiopharmacy independent of an onsite cyclotron. The coordination chemistry of Ga(3+) is dominated by its hard acid character. A variety of mono- and bifunctional chelators have been developed which allow the formation of stable (68)Ga(3+)complexes and convenient coupling to biomolecules. (68)Ga coupling to small biomolecules is potentially an alternative to (18)F- and (11)C-based radiopharmacy. In particular, peptides targeting G-protein coupled receptors overexpressed on human tumour cells have shown preclinically and clinically high and specific tumour uptake. Kit-formulated precursors along with the generator may be provided, similar to the (99)Mo/(99m)Tc-based radiopharmacy, still the mainstay of nuclear medicine.