DFT study of the complexation of NOTA chelator with alkali metal and radiometal ions for radiopharmaceutical applications.

Master degree. University of KwaZulu-Natal, Westville. 2016The application of chelators is an ongoing interest in diagnostic and therapeutic radiopharmaceuticals. Bifunctional chelators labelled with radiometal ions are covalently bonded with a lead compound to form complexes with targeted biomolecules. The binding affinity of a ligand is thus an exclusively essential feature of an ideal radiopharmaceutical ligand. 1,4,7 triazacyclononane-1,4,7 triacetic acid (NOTA) a key radiolabelling chelator in radiopharmaceuticals, which is studied in this project, has been identified as one of the popularly investigated chelators. NOTA is known with the ability to form a stable complex with radiometal ions. A number of experimental investigations have been performed to study the structure and the radiolabelling efficiency of NOTA chelator while little attention has been paid to exploiting the structure and the binding features of the ligand at the molecular level. In this project, an investigation was made of the structure of NOTA and it complexation with alkali metal and radiometal ions, using density functional theory. In the first step, efforts were made to evaluate the complexation of NOTA with alkali metal ions (Na+ , Li+ , K+ and Rb+ ) with the intention of assessing the level of competition of alkali metal ions, found in the body. The complexation of NOTA with radiometal ions (Cu2+, Ga3+, In3+, Sc3+) was also investigated. This study reveals that nitrogen and oxygen atoms in the NOTA molecule are important for complexation processes. Interaction and relaxation energies, Gibbs free energies and entropies show that the stability of NOTA― alkali metal ion complexes decreases down the group of the periodic table. In the case of NOTA―radiometal ions complexes, NOTA― Ga3+ is identified to be more stable than the remaining radiometal complexes, which is in good agreement with experimentally reported binding constants. For both alkali metal and radiometal ion complexes, implicit water solvation affects the NOTA―ion complexation, causing a decrease in the stability of the system. NBO analysis performed through the natural population charges and second order perturbation theory reveals the charge transfer between NOTA and both alkali metal and radiometal ions. The theoretical 1H NMR chemical shifts of NOTA complexes, in vacuum and water, are in good agreement with experiment; these values are influenced by the presence of the ions, which have a deshielding effect on the protons of NOTA. A noteworthy conclusion from the investigation is that the interaction of NOTA with radiometal ions is stronger than the interaction of NOTA with alkali metal ions. Thus, confirming that the presence of alkali metal in human body may not interfere with the binding of radiometal to NOTA chelator. This study serves as a guide to researchers in the field of organometallic chelators, particularly, radio-pharmaceuticals in finding the efficient optimal match between chelators and different metal ions

Matching a chelator (DOTA) with ions for radio-pharmaceutical applications using DFT study.

Masters Degree. University of KwaZulu-Natal, Durban.Organometallic chelators can be potentially used for radiometal-based pharmaceuticals. The bifunctional chelator, which is covalently bound to a lead compound, forms a stable chelator―ion complex to deliver an isotope, as a labelling agent, towards a specific in vivo target. The quest to find the optimal match between chelators and radiometal ions is of interest in the field of radio pharmaceuticals. A loss of radiometal ion from a chelator without reaching to its specific target organ in vivo could be disastrous to the body. The present project is focused on the complexation of 1, 4, 7, 10-tetraazacyclododecane-1, 4, and 7, 10-tetraacetic acid (DOTA) with alkali metals and radiometal ions. Herein, we investigated DOTA―alkali metal ions complexes with density functional theory using B3LYP and ωB97XD functionals and the 6-311+G(2d,2p) basis set for Li+, Na+ and K+ and Def2-TZVPD for Rb+. Conformational possibilities, starting from x-ray crystal structures and considering a different number of arms (2, 3 and 4) interacting with the ions were explored. Interaction and relaxation energies, thermochemical parameters, HOMO/LUMO energies, ΔEHOMO-LUMO and chemical hardness indicate the decrease in the stability of DOTA―ions down the alkali metal series. Natural bond orbital analysis reveals charge transfer between DOTA and alkali metals. Regarding radiometal ions, the geometries for the various complexes were consistent with experimentally reported binding constants. NBO analysis indicates charge transfer from the chelator to the radio metals resulting in reduced positive atomic charge values for all the ions. DOTA―Ga3+, DOTA―In3+ and DOTA―Sc3+ complexes recorded higher ΔELUMO-HOMO energies and chemical hardness values. The DOTA―Cu2+ complex was the least stable among the selected complexes. This study serves as a guide to researchers in the field of organometallic chelators, particularly; radio-pharmaceuticals in finding the efficient optimal match between chelators and different metal ions

Fundamental Chemistry Related to the Separations and Coordination of Actinium-225, Thorium-227, and Technetium-99

This work explores the fundamental chemistry of actinium, thorium, and technetium in an effort to develop methodologies which help to address complications specific to each of these elements. Developing fundamental knowledge in inorganic chemistry has the power to meaningfully address a number of real world problems. By using simple systems and experiments like following an electron or changing the solvent system, we are able to gain invaluable information which can be used to address major issues. Actinium-225 (t½: 9.92 d) is an alpha-emitting radionuclide with nuclear properties well suited for alpha therapy of malignant tumors. The present global supply of 225Ac is 1.7 Ci per year yet the global demand is 50-100 Ci. Currently, the production of 225Ac from proton irradiation of 232Th metal targets is being investigated at Brookhaven National Laboratory. One proposed method for separation of 225Ac from bulk thorium targets involves the use of polyoxometalates (POMs), large metal oxide clusters that have been used to chelate high-valent actinides and lanthanides. The modified Wells-Dawson POM ([P2W17O61]10-) has a very high affinity for thorium. Our study seeks to take advantage of the affinity of POMs for thorium to separate 225Acfrom bulk thorium for 225Acproduction. The separation is carried out by adding the POM to aqueous solutions of thorium, lanthanum, and actinium as individual metals and as mixed metal solutions, and contacting those solutions with 3% octylamine in chloroform. The extractions are quantified using ICP-OES. This study has shown that the POM completely extracts the thorium from the aqueous solution and preferentially extracts thorium over lanthanum and actinium. Thorium-227 (t½:18.7 d) is an alpha emitting nuclide which may also be a candidate for targeted alpha therapy. With its longer half-life, 227Th delivers a lower dose of radiation over time, which may make it a better isotope for treating malignant tumors. Thorium has been found to treat ovarian and bone cancers in mice. In the past 3,4,3-LI(1,2-HOPO) was successfully coordinated to zirconium, found to exhibit high stability in vivoand ultimately built into an 89Zr-based imaging agent. Thorium and zirconium have very similar chemical behavior. Both are +4 oxophilic metals which prefer octadentate ligands. This work investigated the labeling and stability of Th-HOPO in comparison to the standard ligand for labeling, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). It was found that HOPO had higher yields and higher stability. The development of radiolabeling methods required additional purification of the thorium to separate its many daughter radionuclides. Purification of the thorium was carried out using 8M nitric acid and an anion exchange resin. Technetium-99 (99Tc, t½: 2.1 x 105years; bmax: 293.7 keV) is a high-yield fission product (6%) in light-water reactors. The removal and permanent storage of technetium from nuclear waste streams is of great importance for the nuclear fuel cycle and for remediation of legacy waste. A fundamental study of the reduction, coordination, and spectroscopic behavior of technetium has been conducted in aqueous and organic media including ionic liquids (ILs). In order to ascertain the value of using ILs in nuclear waste remediation, the behavior of technetium in ILs must be understood. This work sought to understand the behavior of technetium, using electrochemistry and spectroscopy to investigate the behavior of well-known technetium complexes in neat ILs and acid-IL mixtures to probe the effect of ILs on technetium redox chemistry. Titration of bistriflimidic acid (HNTf2) into TcO4-in the IL trimethylbutylammonium bistriflimide (N1114NTf2) showed that the TcO4-anion is protonated in the IL to form HTcO4(pertechnic acid). This protonation was monitored using UV-Vis and x-ray absorption spectroscopy, specifically, EXAFS and XANES, to understand the speciation of TcO4-in this IL. This study has found that technetium is more reactive in ILs

68Ga- ja 177Lu-radiolääkkeiden laadunvalvontamenetelmien kehitys

68Ga- ja 177Lu-radiolääkkeitä käytetään isotooppilääketieteessä. 68Ga-radiolääkkeet ovat diagnostisia aineita, joita käytetään neuroendokriinisyövän ja eturauhassyövän diagnostiikassa. 177Lu-radiolääkkeet ovat terapeuttisia aineita, joilla voidaan hoitaa 68Ga-merkkiaineilla diagnosoituja syöpiä. 68Ga-isotooppi on melko lyhytikäinen (t1/2=68 min) positroniemitteri, jota valmistetaan 68Ge/68Ga generaattorilla. 177Lu-isotooppi on lyhyen kantaman beetasäteilijä, jonka hajoamisessa muodostuu beetasäteilyn lisäksi myös kuvantamiseen käytettävää gammasäteilyä. 177Lu-radiolääkkeiden terapeuttinen käyttö perustuu siihen, että peptidi kuljettaa lääkeaineen oikeaan kohteeseen ja beetasäteily tuhoaa siellä syöpäsoluja. Radiolääkkeille tehdään valmistuksen jälkeen, ennen potilaalle antamista, laadunvalvonta, jossa määritetään radiolääkkeen puhtaus ensisijaisesti kromatografisilla menetelmillä. Radioaktiivisten aineiden hajoamisen, lääkeaineiden korkeiden laatuvaatimusten ja potilasturvallisuuden takia laadunvalvontamenetelmien tulee olla tarkkoja, nopeita ja luotettavia. Tämän tutkimuksen keskeisessä asemassa olivat 68Ga- ja 177Lu-radiolääkkeiden laadunvalvonnassa käytettävien ohutkerroskromatografia-(TLC) ja korkean erotuskyvyn kromatografia-(HPLC)menetelmien kehittäminen. Tutkimuksessa kehitettiin HPLC-menetelmä [177Lu]Lu-PSMA-617:n laadunvalvontaa varten ja menetelmällä tehtiin massakvantitoiminen PSMA-617-lähtöaineelle. [177Lu]Lu-DOTATOC:n, [68Ga]Ga-DOTANOC:n ja [68Ga]Ga -PSMA:n laadunvalvonnassa käytettyjä TLC-menetelmiä yhtenäistettiin ajoliuosten suhteen sekä optimoitiin TLC-menetelmissä käytettäviä skannausnopeuksia ja -jännitteitä. Lisäksi tutkittiin rauta(III)kontaminaatioiden vaikutusta 177Lu- ja 68Ga-radiolääkkeiden retentioaikoihin HPLC-menetelmässä. [177Lu]Lu -PSMA-617:n HPLC-menetelmällä saatiin 7,4 minuutin retentioajalla lähes symmetrinen piikki ja PSMA-617:n massakvantitoinnissa saatiin lineaarinen suora 0,9978 korrelaatiokertoimella. 1M ammoniumasetaatti-MeOH-liuoksen todettiin sopivan [177Lu]Lu -DOTATOC:n,[68Ga]Ga -DOTANOC:n ja [68Ga]Ga -PSMA:n laadunvalvonnan TLC-menetelmiin. Skannausnopeus 1 mm/s ja skannausjännite 900 V olivat optimiasetukset TLC- menetelmässä, kun käsiteltiin tuoreita radiolääkkeitä ja raudan havaittiin kasvattavan lääkeaineen retentioaikaa HPLC-menetelmässä