Preparation of bifunctional ligands for radiometals conjugation to biomolecules

master's thesis

• Title (croatian): Priprava bifunkcionalnih liganada za konjugaciju s radiometalima u biomolekulama
• Author: Marina Marinović
• Mentor: Silvana Raić-Malić (mentor)
• Committee member: Silvana Raić-Malić (predsjednik povjerenstva)
• Committee member: Andrijana Meščić (član povjerenstva)
• Committee member: Danijela Ašperger (član povjerenstva)
• Granter: University of Zagreb; Faculty of Chemical Engineering and Technology; Zagreb
• Defense date and country: 2016-07-15, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Chemistry; Organic Chemistry

Abstract

The choice of the chelating fragment of bifunctional ligand depends on the nature and oxidation state of the radiometal. There are numerous examples in the literature, which show that the nature of a bifunctional metal complex such as geometry, lipophilicity, overall charge plays a crucial role in determining the biodistribution of targeted radiopharmaceuticals. Furthermore, in designing of novel radiopharmaceuticals energy of the radionuclide should be taken into account. Cyclen and cyclam based macrocycles are known to form kinetically inert and thermodynamically stable complexes with a wide range of metal ions. Several classes of structurally different phosphonate ligands labeled with β emitting radionuclides such as 166Ho-DOTMP complex are being used clinically for the treatment of painful bone metastases. The choice of used cyclic chelating agents is also based on the more pronounced thermodynamic stability and kinetic inertness of their lanthanide complexes when compared to that of their acyclic analog. The physical, magnetic and nuclear properties of the lanthanide ions have made them ideal for use in both diagnostic and therapeutic radiopharmaceuticals. The aim of this work was to prepare bifunctional ligands based on cyclen and cyclam structures, test their labelling conditions with europium as a model radionuclide, in order to develop potential new radiopharmaceuticals. Through this aim, cyclen and selected tetraphosphonate derivative of cyclam (TETP) were synthesized. Obtained data show that all used ligands, DOTA, TETP, NOTA and TRAP-Pr, form complexes with Eu(III) at 95 °C and in the pH range from 2 to 6. They also show excellent kinetic stability at pH 4.

Abstract (croatian)

Izbor kelatnog fragmenta bifunkcionalnog liganda ovisi o prirodi te oksidacijskom stanju radiometala. Postoje brojni primjeri u literaturi, koji pokazuju da priroda bifunkicionalnog metalnog kompleksa kao što je geometrija, lipofilnost, ukupni naboj, ima ključnu ulogu u određivanju biodistribucije ciljanih radiofarmaceutika. Nadalje, u razvoju novih radiofarmaceutika također se treba uzeti u obzir i energija radionuklida. Poznato je da makrociklički spojevi temeljeni na strukturi ciklena i ciklama tvore kinetički inertne i termodinamički stabilne komplekse sa širokim rasponom metalnih iona. Nekoliko klasa strukturno različitih fosfonatnih liganada obilježenih s β-emitirajućim radionuklidima kao što je 166Ho-DOTMP kompleks se koriste klinički za liječenje bolnih koštanih metastaza. Izbor korištenih cikličkih kelatnih agensa se također temelji na naglašenoj termodinamičkoj stabilnosti i kinetičkoj inertnosti njihovih kompleksa s lantanidima u odnosu na koje njihove acikličke analoge. Fizikalna i magnetska svojstva iona lantanida čine ih idealnim za primjenu u dijagnostičke i terapijske svrhe radiofarmaceutika. Cilj ovog rada bio je pripraviti bifunkcionalne ligande temeljene na strukturi ciklena i ciklama, testirati njihove uvjete obilježavanja s europijem kao modelnim radionuklidom, u cilju razvoja novih potencijalnih radiofarmaceutika. Imajući to na umu, ciklen i odabrani tetrafosfonatni derivat ciklama (TETP) su pripravljeni. Dobiveni podaci pokazuju da svi korišteni ligandi, DOTA, TETP, NOTA i TRAP-Pr, tvore komplekse s Eu(III) pri 95 °C u rasponu pH vrijednosti od 2 do 6, te također pokazuju odličnu kinetičku stabilnost pri pH 4.

• Keywords: radiopharmaceuticals; chelating agents; DOTA; TETP; europium
• Keywords (croatian): radiofarmaceutici; kelatni agensi; DOTA; TETP; europij
• Language: english
• URN:NBN: urn:nbn:hr:149:737280
• Study programme: Title: Applied Chemistry - Graduate study; specializations in: Environmental chemistry and green technologies, Advanced materials and technologies, Applied organic chemistry; Course: Applied organic chemistry; Study programme type: university; Study level: graduate; Academic / professional title: magistar/magistra primijenjene kemije (magistar/magistra primijenjene kemije)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2017-10-02 12:28:16