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| Home > Publications database > 2,6-Bis-(N-hydroxylamino)-1,3,5-triazines as ligands for 45Ti-chelation |
| Home > Publications database > 2,6-Bis-(N-hydroxylamino)-1,3,5-triazines as ligands for 45Ti-chelation |
| Conference Presentation (After Call) | FZJ-2024-03434 |
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2023
Abstract: Objectives: 45Ti (T½ = 3.1 h) is a promising PET radionuclide thatcan be produced by proton irradiation of nat Sc targets. While fasthydrolysis of most Ti(IV) complexes has hampered their application forthe preparation of 45Ti-labeled PET tracers[1] , some recently reportedbis(hydroxyamino)triazine (BHT) complexes[2,3] are hydrolyticallystable for several hours. Therefore, in this study differently substitutedBHT ligands including a bridged one were prepared and evaluated withregard to their potential to form stable complexes with 45Ti.Additionally, a novel procedure for the separation of 45Ti from the45 Sc target material by cation exchange chromatography was devel-oped[4]. Finally, a conjugate of a BHT-ligand with a prostate-specificmembrane antigen (PSMA)-binding moiety potentially suitable for thepreparation of 45 Ti-labeled probes for imaging of prostate carcinomawas synthesized.Methods: BHT ligands were prepared by substitution of chlorinesubstituents in cyanuric chloride first with secondary amines (R 3-NH-C 2 H4C(O)R4 ) followed by hydroxylamines (R1-NH-OH, R2 -NH-OH)(Fig. 1)[2].Two PSMA-selective probes were synthesized starting from methyl3{-[(4,6-bis(chloro)-1,3,5-triazin-2-yl](R3 )amino}propanoate by sub-stitution of the chlorine atoms with benzyl protected hydroxylamines,NaOH hydrolysis of CO 2Me to CO 2 H, conversion of the carboxylic groupinto a succinimidyl ester, its reaction with t-butyl-protected Lys-C(O)-Glu and, finally, two step deprotection of the resulting intermediatewith HCl and H2 .For preparation of the non-radioactive BHT-type complexes, asolution of the corresponding BHT ligand, DIPEA and TiCl4 inanhydrous THF was stirred for 30 min at room temperature.Subsequent evaporation of the solvent provided the complexes asred powders.For radiochemical separation of 45Ti the scandium target was firstdissolved in 10 m HCl. The 45Ti-containing solution was loaded onto aZR hydroxamate resin column (Triskem, France). The column waswashed with 10 m HCl and water to remove Sc and 45 Ti was eluted with 0.1 m oxalic acid in phosphate buffer (pH = 8). Separation took 30minutes. For radiometal complex formation, the respective ligand wasadded to the 45Ti-solution and the mixture was stirred at roomtemperature for 45 min. Stability tests were performed by incubationin phosphate-buffered saline (PBS, pH = 7.4) at 36 °C followed by radio-TLC analysis.Results: The separation and preparation protocols developed in thiswork enabled the synthesis of 45Ti-labeled BHT complexes inradiochemical conversions of 55% - 90%, as determined by HPLC andradio-TLC analysis of the reaction mixtures. The radiolabeled com-plexes including PSMA-targeting conjugate showed a high stability inPBS (t 1/2 > 250 h). Conclusions: Easily accessible BHT ligands, which form hydro-lytically stable Ti(IV) complexes, are valuable tools for the develop-ment of 45Ti-labeled PET-probes.References[1] Chaple F., et al. Appl. Radiat. 2020, 166, 109398.[2] Ekeltchik I. et al. Dalton Trans. 2006, 10, 1285–1293.[3] Peri D., et al. Dalton Trans. 2006, 34, 4169–4172.[4] Radchenko V. et al. J. Chromatogr. A. 2016, 1477, 39–46
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