169673-06-7Relevant academic research and scientific papers
Novel NK1R‐Targeted68Ga‐/177Lu‐Radioconjugates with Potential Application against Glioblastoma Multiforme: Preliminary Exploration of Structure–Activity Relationships
Gniazdowska, Ewa,Halik, Pawe? K.,Ko?miński, Przemys?aw,Kosińska, Katarzyna,Lipiński, Piotr F. J.,Matalińska, Joanna,Misicka, Aleksandra
, (2022/01/24)
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 with68Ga and177Lu. 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. The177Lu‐radioconjugates exhibited the binding characteristics towards NK1R similar or better than that of the177Lu‐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.
Identification of L-Tryptophan Derivatives with Potent and Selective Antagonist Activity at the NK1 Receptor
MacLeod, Angus M.,Merchant, Kevin J.,Brookfield, Frederic,Kelleher, Fintan,Stevenson, Graeme,et al.
, p. 1269 - 1274 (2007/10/02)
As part of a program of screening the Merck sample collection, N-ethyl-L-tryptophan benzyl ester was identified as a weak antagonist at the substance P (NK1) receptor.Structure-activity studies showed that the indole ring system could be replaced by 3,4-dichlorophenyl, α- or β-naphthyl, or benzthiophene with retention or only small loss of affinity.It was found that acylation of the tryptophan nitrogen gave compounds with higher affinity than N-ethyl or other basic amines.Optimization of substitution on the benzyl ester led to the identification of the 3,5-bis(trifluoromethyl) benzyl ester of N-acetyl-L-tryptophan 26 as a potent and selective substance P receptor antagonist.Compound 26 blocked substance P induced dermal extravasation in vivo and was the most potant compound from this structurally novel class of antagonists which further adds to the diversity of small molecules that bind to the (NK1) receptor.
