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Novel NK1R-Targeted 68Ga-/177Lu-Radioconjugates with Potential Application against Glioblastoma Multiforme:
Joanna Matalińska1, Katarzyna Kosińska1, Paweł K Halik2
1Department of Neuropeptides, Mossakowski Medical Research Institute Polish Academy of Sciences, 5 Pawińskiego Street, 02-106 Warsaw, Poland.
Abstract:
Locoregionally administered, NK1 receptor (NK1R) targeted radionuclide therapy is a promising strategy for the treatment of glioblastoma multiforme. So far, the radiopharmaceuticals used in this approach have been based on the endogenous agonist of NK1R, Substance P or on its close analogues. Herein, we used a well-known, small molecular NK1R antagonist, L732,138, as the basis for the radiopharmaceutical vector. First, 14 analogues of this compound were evaluated to check whether extending the parent structure with linkers of different lengths would not deteriorate the NK1R binding. The tested analogues had affinity similar to or better than the parent compound, and none of the linkers had a negative impact on the binding. Next, five DOTA conjugates were synthesized and used for labelling with 68Ga and 177Lu. The obtained radioconjugates turned out to be fairly lipophilic but showed rather limited stability in human plasma. Evaluation of the receptor affinity of the (radio)conjugates showed that neither the chelator nor the metal negatively impacts the NK1R binding. The 177Lu-radioconjugates exhibited the binding characteristics towards NK1R similar or better than that of the 177Lu-labelled derivative of Substance P, which is in current clinical use. The experimental results presented herein, along with their structural rationalization provided by modelling, give insight for the further molecular design of small molecular NK1R-targeting vectors.
Insights
New small molecules targeting NK1 receptors show promise for glioblastoma radionuclide therapy. These novel radioconjugates, based on L732,138, offer improved NK1 receptor binding compared to existing treatments.
Area of Science:
- Oncology
- Radiochemistry
- Molecular Imaging
Background:
- Glioblastoma multiforme (GBM) treatment benefits from locoregional radionuclide therapy targeting Neurokinin-1 Receptors (NK1R).
- Current NK1R-targeted therapies utilize Substance P analogues, but novel small molecules offer alternative vectors.
Purpose of the Study:
- To develop and evaluate novel small molecular NK1R antagonists as radiopharmaceutical vectors for GBM therapy.
- To assess the NK1R binding affinity and stability of new radioconjugates based on L732,138.
Main Methods:
- Synthesis and evaluation of 14 analogues of L732,138 to assess NK1R binding with varying linker lengths.
- Preparation of five DOTA conjugates and their radiolabeling with Gallium-68 (68Ga) and Lutetium-177 (177Lu).
- Assessment of radioconjugate lipophilicity, plasma stability, and NK1R binding affinity.
Main Results:
- Analogues of L732,138 demonstrated NK1R binding affinity comparable or superior to the parent compound, unaffected by linker modifications.
- 177Lu-labeled radioconjugates exhibited favorable NK1R binding characteristics, outperforming 177Lu-labeled Substance P derivatives.
- While lipophilic, the radioconjugates showed limited stability in human plasma.
Conclusions:
- Small molecular NK1R antagonists, like L732,138 derivatives, are viable scaffolds for developing targeted radionuclide therapies for glioblastoma.
- Further molecular design based on these findings could lead to more effective NK1R-targeted radiopharmaceuticals.
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