Giesen, Kai
(2020).
Radiochemische Separation von 45Ti und 52gMn zur Herstellung radiomarkierter Komplexe.
PhD thesis, Universität zu Köln.
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Abstract
With regard to special diagnostic applications, non-standard radionuclides often represent suitable alternatives to standard radionuclides like 11C and 18F due to their physical decay characteristics such as half-life (t1/2) and decay modes. Furthermore, non-standard positron emission tomography (PET) nuclides enable a novel design and synthesis of specific PET tracers to study a variety of biological processes. However, their clinical application in diagnostics is hampered by their limited availability owing to the lack of suitable radiochemical separation techniques. The positron emitter 45Ti (t½: 3.1 h, Iβ+ = 84.8 %, Eβ+max = 439 keV) is of high importance for imaging studies since Ti-complexes have shown therapeutic efficacy in cancer treatment as cytostatic agents. 45Ti can be easily produced at a small cyclotron by proton bombardment of a Sc target via the 45Sc(p,n)45Ti nuclear reaction. Unfortunately, efficient separation methods to isolate 45Ti from the irradiated target are still missing. Therefore, this work aimed to develop a novel separation technique to obtain 45Ti in high purity and radiochemical yield. The separation method was based on a thermochromatographic approach via the formation of volatile [45Ti]TiCl4 in a chlorine gas stream, enabling the separation from low volatile ScCl3. The separation apparatus and the individual steps were adjusted to enable trapping of [45Ti]Cl4 for further chemical conversions. The most relevant separation parameters like reaction temperature, volume flow, separation time, and chlorine concentration in the carrier gas were optimized to achieve efficient formation and trapping of [45Ti]TiCl4 in high separation yields. Finally, [45Ti]TiCl4 was obtained with a recovery yield of 76% ± 5% (n=5) (n.d.c. 48% ± 3% (n=5)) and a radionuclidic purity of >99%, facilitating subsequent labeling steps. To this end, [45Ti]TiCl4 was reacted with the complex ligand H4(2,4-salan) [6,6'-((ethane-1,2-diylbis((2-hydroxyethyl)azanediyl))-bis(methylene))-bis(2, 4-dimethyl-phenol)] or with H4(3,4-salane) [6,6'-((ethane-1,2-diylbis((2-hydroxyethyl)azanediyl))-bis(methylene))bis(3,4-dimethyl-phenol)] in THF to form the corresponding 45Ti complexes. Thus, [45Ti][Ti(2,4-salan)] and [45Ti][Ti(3,4-salan)] were afforded in radiochemical yields of 15% ± 7% (n=7) and 13% ± 6% (n=3), respectively. Furthermore, [45Ti][Ti(HBED)] was obtained from [45Ti]TiCl4 by reaction with the chelator N,N-bis(2-hydroxybenzyl)ethylenediamine-N,N-diacetic acid (HBED). However, radiochemical yield of the latter was poor (3% ± 1% (n=3)) after isolation by high performance liquid chromatography. The stability of the titanium complexes under physiological conditions was studied using human blood plasma. It was shown that [45Ti][Ti(HBED)] dissociates rapidly in buffered aqueous media, as well as human blood plasma. In contrast, [45Ti][Ti(2,4-salan)] seems to be more compatible for in vivo applications since it was stable in all tested media and blood plasma for two hours. The second part of this work focused on the non-standard radionuclide 52gMn. The application of isotopic mixtures of 52gMn and the non-radioactive 55Mn facilitates bimodal PET/MR imaging since Mn, due to its paramagnetic properties, is NMR-active. Bimodal PET/MR imaging synergistically combines the sensitivity and quantification of PET with the high spatial resolution of magnetic resonance imaging (MRI). Based on previous work at the INM-5, a bifunctional PSMA-specific ligand with a cyclohexyl-1,2-diaminoacetic acid function (CDTA) was prepared via copper(I)-catalyzed alkyne-azide cycloaddition with a total yield of 37 %. CDTA and divalent manganese form complexes exhibiting high in vivo stability and relaxivity, which are especially important for contrast imaging. Radiochemical yields for the carrier-added as well as the non-carrier-added Mn-complex were almost quantitative within 20 min. The carrier-added version of the Mn-complex has a high potential for bimodal imaging applications. The preliminary biological evaluation of [52gMn][Mn(CDTA-PSMA)] in a rat glioma model by ex vivo autoradiography demonstrated high accumulation in the peritumoral region of the brain tumor. Further studies using 45Ti-labeled PSMA-selective ligands are underway. Additionally, the 52gMn-labeled PSMA ligand will be examined in preclinical prostate cancer models.
| Item Type: | Thesis (PhD thesis) | ||||||||
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| URN: | urn:nbn:de:hbz:38-296919 | ||||||||
| Date: | 2020 | ||||||||
| Language: | German | ||||||||
| Faculty: | Faculty of Mathematics and Natural Sciences | ||||||||
| Divisions: | Außeruniversitäre Forschungseinrichtungen > Forschungszentrum Jülich | ||||||||
| Subjects: | Chemistry and allied sciences | ||||||||
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| Date of oral exam: | 19 October 2020 | ||||||||
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| Refereed: | Yes | ||||||||
| URI: | http://kups.ub.uni-koeln.de/id/eprint/29691 |
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