TY - JOUR
T1 - Synthesis and Evaluation of a Novel 64Cu- and 67Ga-Labeled Neurokinin 1 Receptor Antagonist for in Vivo Targeting of NK1R-Positive Tumor Xenografts
AU - Zhang, Hanwen
AU - Kanduluru, Ananda Kumar
AU - Desai, Pooja
AU - Ahad, Afruja
AU - Carlin, Sean
AU - Tandon, Nidhi
AU - Weber, Wolfgang A.
AU - Low, Philip S.
N1 - Funding Information:
This project was funded in part by MSKCC IMRAS grants and National Institutes of Health (NIH) Grant P50-CA84638 (H.Z. and W.A.W.). Technical services from the MSK Core Facilities were supported by NIH Small-Animal Imaging Research Program Grant R24 CA83084, NIH/National Cancer Institute Cancer Center Support Grant P30 CA008748-48, and NIH Shared Instrumentation Grants 1 S10 RR020892-01 and 1 S10 OD016207-01.
Funding Information:
All animal experiments were performed under approved protocol 13-10-015, which is in accordance with the ethical standards of the Institutional Animal Care and Utilization Committee of MSKCC. This project was funded in part by MSKCC IMRAS grants and National Institutes of Health (NIH) Grant P50-CA84638 (H.Z. and W.A.W.). Technical services from the MSK Core Facilities were supported by NIH Small-Animal Imaging Research Program Grant R24 CA83084, NIH/National Cancer Institute Cancer Center Support Grant P30 CA008748-48, and NIH Shared Instrumentation Grants 1 S10 RR020892-01 and 1 S10 OD016207-01.
Publisher Copyright:
© 2018 American Chemical Society.
PY - 2018/4/18
Y1 - 2018/4/18
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85045553930&partnerID=8YFLogxK
U2 - 10.1021/acs.bioconjchem.8b00063
DO - 10.1021/acs.bioconjchem.8b00063
M3 - Article
C2 - 29466853
AN - SCOPUS:85045553930
SN - 1043-1802
VL - 29
SP - 1319
EP - 1326
JO - Bioconjugate Chemistry
JF - Bioconjugate Chemistry
IS - 4
ER -