Synthesis and Evaluation of a Novel 64Cu- and 67Ga-Labeled Neurokinin 1 Receptor Antagonist for in Vivo Targeting of NK1R-Positive Tumor Xenografts.
Bioconjug Chem
; 29(4): 1319-1326, 2018 04 18.
Article
em En
| MEDLINE
| ID: mdl-29466853
ABSTRACT
Neurokinin 1 receptor (NK1R) is expressed in gliomas and neuroendocrine malignancies and represents a promising target for molecular imaging and targeted radionuclide therapy. The goal of this study was to synthesize and evaluate a novel NK1R ligand (NK1R-NOTA) for targeting NK1R-expressing tumors. Using a carboxymethyl moiety linked to L-733060 as a starting reagent, NK1R-NOTA was synthesized in a three-step reaction and then labeled with 64Cu (or 67Ga for in vitro studies) in the presence of CH3COONH4 buffer. The radioligand affinity and cellular uptake were evaluated with NK1R-transduced HEK293 cells (HEK293-NK1R) and NK1R nontransduced HEK293 cells (HEK293-WT) and their xenografts. Radiolabeled NK1R-NOTA was obtained with a radiochemical purity of >95% and specific activities of >7.0 GBq/µmol for 64Cu and >5.0 GBq/µmol for 67Ga. Both 64Cu- and 67Ga-labeled NK1R-NOTA demonstrated high levels of uptake in HEK293-NK1R cells, whereas co-incubation with an excess of NK1R ligand L-733060 reduced the level of uptake by 90%. Positron emission tomography (PET) imaging showed that [64Cu]NK1R-NOTA had a accumulated rapidly in HEK293-NK1R xenografts and a 10-fold lower level of uptake in HEK293-WT xenografts. Radioactivity was cleared by gastrointestinal tract and urinary systems. Biodistribution studies confirmed that the tumor-to-organ ratios were ≥5 for all studied organs at 1 h p.i., except kidneys, liver, and intestine, and that the tumor-to-intestine and tumor-to-kidney ratios were also improved 4 and 20 h post-injection. [64Cu]NK1R-NOTA is a promising ligand for PET imaging of NK1R-expressing tumor xenografts. Delayed imaging with [64Cu]NK1R-NOTA improves image contrast because of the continuous clearance of radioactivity from normal organs.
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Radioisótopos de Cobre
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Receptores da Neurocinina-1
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Antagonistas dos Receptores de Neurocinina-1
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Radioisótopos de Gálio
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Compostos Heterocíclicos
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Neoplasias
Limite:
Animals
Idioma:
En
Revista:
Bioconjug Chem
Assunto da revista:
BIOQUIMICA
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Estados Unidos