دورية أكاديمية
Introduction of a SiFA Moiety into the D-Glutamate Chain of DOTA-PP-F11N Results in Radiohybrid-Based CCK-2R-Targeted Compounds with Improved Pharmacokinetics In Vivo
| العنوان: | Introduction of a SiFA Moiety into the D-Glutamate Chain of DOTA-PP-F11N Results in Radiohybrid-Based CCK-2R-Targeted Compounds with Improved Pharmacokinetics In Vivo |
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| المؤلفون: | Nadine Holzleitner, Thomas Günther, Roswitha Beck, Constantin Lapa, Hans-Jürgen Wester |
| المصدر: | Pharmaceuticals, Vol 15, Iss 12, p 1467 (2022) |
| بيانات النشر: | MDPI AG, 2022. |
| سنة النشر: | 2022 |
| المجموعة: | LCC:Medicine LCC:Pharmacy and materia medica |
| مصطلحات موضوعية: | cholecystokinin-2 receptor (CCK-2R), cholecystokinin-B receptor (CCK-BR), medullary thyroid cancer (MTC), minigastrin analogues, radiohybrid, rhCCK, Medicine, Pharmacy and materia medica, RS1-441 |
| الوصف: | In order to enable 18F- and 177Lu-labelling within the same molecule, we introduced a silicon-based fluoride acceptor (SiFA) into the hexa-D-glutamate chain of DOTA-PP-F11N. In addition, minigastrin analogues with a prolonged as well as γ-linked D-glutamate chain were synthesised and evaluated. CCK-2R affinity (IC50, AR42J cells) and lipophilicity (logD7.4) were determined. Biodistribution studies at 24 h post-injection (p.i.) and µSPECT/CT imaging at 1, 4 and 24 h p.i. were carried out in AR42J tumour-bearing CB17-SCID mice. CCK-2R affinity of (R)-DOTAGA-rhCCK-1 to 18 was enhanced with increasing distance between the SiFA building block and the binding motif. Lipophilicity of [177Lu]Lu-(R)-DOTAGA-rhCCK-1 to 18 was higher compared to that of [177Lu]Lu-DOTA-PP-F11N and [177Lu]Lu-CP04. The respective α- and γ-linked rhCCK derivatives revealing the highest CCK-2R affinity were further evaluated in vivo. In comparison with [177Lu]Lu-DOTA-PP-F11N, [177Lu-]Lu-(R)-DOTAGA-rhCCK-9 and -16 exhibited three- to eight-fold increased activity levels in the tumour at 24 h p.i. However, activity levels in the kidneys were elevated as well. We could show that the introduction of a lipophilic SiFA moiety into the hydrophilic backbone of [177Lu]Lu-DOTA-PP-F11N led to a decelerated blood clearance and thus improved tumour retention. However, elevated kidney retention has to be addressed in future studies. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 1424-8247 |
| العلاقة: | https://www.mdpi.com/1424-8247/15/12/1467Test; https://doaj.org/toc/1424-8247Test |
| DOI: | 10.3390/ph15121467 |
| الوصول الحر: | https://doaj.org/article/2d1035715dfe4b689a613ea02639b385Test |
| رقم الانضمام: | edsdoj.2d1035715dfe4b689a613ea02639b385 |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 14248247 |
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| DOI: | 10.3390/ph15121467 |