Synthesis of novel Thiosemicarbazone-Azamacrocyclic Ligands for PET Imaging
Positron Emission Tomography (PET) is a non-invasive method of medical imaging that allows clinicians to produce images of the human body.1 High quality images can be produced of both metabolic and physiological processes, allowing PET to be used for both diagnosis and treatment of a variety of diseases as it enables physicians to look for particular biological functions using specific radiotracers in both plants and animals.1-4 PET utilises positron emitting radionuclides such as 18F, 68Ga and 64Cu.5,2 The radionuclide emits a positron that annihilates a nearby electron and results in the production of two high energy photons that are 180° apart.1 A ring of detectors is positioned around the individual being imaged in order to detect the two photons, and from these the 3D image of the area is generated.5 Different radionuclides are appropriate for different biological applications of PET. The half-life of the radionuclide must be matched with the appropriate biological half-life of the drug.
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In contrast to the only recently emerging PET, Single Photon Emission Computed Tomography (SPECT) has long been the method of preference. PET has advantages over SPECT, such as the spatial resolution and quantification within certain areas around the body. Increasing the stability and increasing the longer half-life of the isotopes can increase the quality of these PET images.6
Some copper isotopes such as 60Cu, 61Cu, 62Cu and 64Cu have been investigated for use in PET as they can form stable complexes with ligands mimicing those used in biological processes. One of the copper isotopes, 64Cu, has a longer half life than many PET radionuclides currently used that makes it effective due to the ease it provides with synthesis, transport and use of the imaging agents.5 64Cu is commonly produced through the proton bombardment of isotopically enriched 64Ni in a cyclotron and decays to 64Ni.7,8 It is readily available, and emits both positron emission and beta negative emission, and has a half-life of 12.7 hrs, therefore offering support for both PET imaging and radiotherapy.2,9,10 Higher resolution imaging is ensured by the low beta energy of 64Cu.2
However, the ability of 64Cu to be used effectively in radio imaging is reliant on the ability to safely and selectively deliver the radioisotope to the target tissue. One method by which to achieve this involves incorporating the radioisotope into a stable coordination complex.5
The various metal ions and ligands used in these coordination complexes give rise to a very diverse group of pharmaceuticals with many different functions.11 Sarcophagine ligands are particularly efficient at complexing metals ions, resulting in thermodynamically and kinetically stable complexes.11,12 These complexes also contain other metal coordination sites that can bind to anions such as phosphates, amino acids, DNA and peptides. This, along with their low toxicity, makes them promising potential agents for imaging or therapy.11
DOTA (Figure 1) is a very versatile complex based on cyclen that is often used in radiopharmaceuticals due to its easy conjugation and high radiochemical yields.7
Figure 1. The Structure of Cyclen and DOTA
Thiosemicarbazones have a wide range of pharmacological activity that is linked to their ability to chelate transition metals such as copper, iron or zinc.1 They form stable membrane permeable copper complexes that are susceptible to reduction once inside the cell.10 Previously they have been found to have antibacterial, antifungal, antitumor and antiviral activity.13 This biological activity is useful for both the imaging and therapeutic activity of the thiosemicarbazone complexes. Previously, they have been shown to inhibit tumor growth through the chelation of essential metal ions within tumor cells.1 One such example of this is a thiosemicarbazone complex that inhibited tumor growth in swiss mice when administered orally.14 This antitumor activity was specific to the presence of the copper, and this antitumor agent required the copper in order to function.15, 16 The altered redox conditions that result from reduction of ligands within the cell play a role in tumor progression and metastasis.17 Combining these thiosemicarbazones with a tetramacrocycle such as DOTA can increase the stability of these thiosemicarbazones.
64Cu-DOTA-AE105 is based on a urokinase-type plaminogen activator receptor that is expressed in many types of human cancers.7 The expression of this receptor is predictive and indicates the probably prognosis of the cancer. It can therefore be used as a new improved method for cancer diagnosis. The DOTA based complex was developed to incorporate the receptor and indicate where it is located throughout the body. It has been used in clinical trials. However, the release of the copper cation from the ligand was indicated by the large amounts of activity in the liver and bowel. Another complex with a more stable incorporation of the copper cation would be preferable in order to achieve clearer images.
Figure 2. Structure of and PET imaging using 64Cu-DOTA-AE105
Novel 64Cu compounds using ligands comprised of tetramacrocycles and thiosemicarbazones could solve many of the issues with current pharmaceuticals and therefore provide a promising avenue of further research.
The aim of this project is to formulate a synthesis method for compound A (Figure 3) and characterise the complex. Compound A is a thiosemicarbazone tetramacrocycle complex. Compound A will then be investigated as a copper chelator, a likely coordination of which is shown in Figure 3.
Figure 3. Compound A with and without the Cu centre
The synthetic method for the synthesis of Compound A involves a number of steps (Figure 3). For each step of this synthesis, this project aims to determine the reaction conditions under which this reaction will proceed.
Figure 3: The synthetic method for formation of Compound A.
Characterisation of each of these compounds will occur through the use of 1H NMR Spectroscopy and Mass Spectroscopy.
- B. M. Paterson and P. S. Donnelly, Chem. Soc. Rev. 2011, 40, 3005-3018
- J. Šimeček, H.-J. Wester and J. Notni, Dalton Trans. 2012, 41, 13803-13806
- K. A. Wood, W. L. Wong and M. I. Saunders, Nucl. Med. Biol. 2008, 35, 393-400
- C. S. Cutler, H. M. Hennkens, N. Sisay, S. Huclier-Markai and S. S. Jurisson, Chem. Rev. 2013, 113, 858-883
- L. E. McInnes, S. E. Rudd and P. S. Donnelly, Coord. Chem. Rev. 2017, 352, 499-516
- R. A. Werner, X. Chen, M. Hirano, S. P. Rowe, C. Lapa, M. S. Javadi and T. Higuchi, Clin. Transl. Imaging 2018, 6, 293-303
- A. R. Jalilian and J. Osso Jr, Iran J Nuc.l Med. 2017, 25, 1-10
- P. Christmas, S. M. Judge, T. B. Ryves, D. Smith and G. Winkler, Nucl. Instr. Meth. Phys Res 1983, 215, 397-408
- T. David, V. Hlinová, V. Kubicek, R. Bergmann, F. Striese, N. Berndt, D. Szöllősi, T. Kovács, D. Máthé, M. Bachmann, H.-J. Pietzsch and P. Hermann, J Med. Chem. 2018
- B. M. Paterson, J. A. Karas, D. B. Scanlon, J. M. White and P. S. Donnelly, Inorg. Chem. 2010, 49, 1884-1893
- C. Dolan, F. Drouet, D. C. Ware, P. J. Brothers, J. Jin, M. A. Brimble and D. E. Williams, RSC Adv. 2016, 6, 23645-23652
- B. M. Paterson and P. S. Donnelly in Chapter Five – Macrocyclic Bifunctional Chelators and Conjugation Strategies for Copper-64 Radiopharmaceuticals, Vol. 68 Eds.: R. van Eldik and C. D. Hubbard), Academic Press, 2016, pp. 223-251
- H. Beraldo and D. Gambinob, Mini-Rev. Med. Chem. 2004, 4, 31-39
- F. A. French and B. L. Freedlander, Cancer Res. 1960, 20, 505
- B. Pastakia, L. M. Lieberman, S. J. Gatley, D. Young, D. H. Petering and D. Minkel J. Nucl. Med. 1980, 21, 67
- H. G. Petering, H. H. Buskirk and J. A. Crim, Cancer Res. 1967, 27, 1115
- N. Raghunand, G. P. Guntle, V. Gokhale, G. S. Nichol, E. A. Mash and B. Jagadish, J. Med. Chem. 2010, 53, 6747-6757
Chelation is a way to remove toxins (or chemicals with negative effects) from the blood. The process can have several steps, and one of the key steps is using other chemicals to ‘flush out’ the system.Chelation usually aims to remove heavy metals like lead or mercury.
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