Novel NK1R-Targeted 68Ga-/177Lu-Radioconjugates with Potential Application against Glioblastoma Multiforme: Preliminary Exploration of Structure–Activity Relationships

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...

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Bibliographic Details
Published in:International journal of molecular sciences 2022-01, Vol.23 (3), p.1214
Main Authors: Matalińska, Joanna, Kosińska, Katarzyna, Halik, Paweł K., Koźmiński, Przemysław, Lipiński, Piotr F. J., Gniazdowska, Ewa, Misicka, Aleksandra
Format: Article
Language:English
Subjects:
Affinity
Binding
Binding sites
Blood plasma
Brain cancer
Conjugates
Glioblastoma
glioblastoma multiforme
L732,138
Lipophilic
Lutetium isotopes
Medical prognosis
neurokinin-1 receptor antagonist
Peptides
Pharmaceuticals
Radiation therapy
Radiochemistry
radioconjugates
Radioisotopes
radiopharmaceuticals
Stability analysis
Substance P
targeted radionuclide therapy
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Summary: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.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms23031214