ArticleNuclear medicine and biology2015
Evaluation of DOTA-chelated neurotensin analogs with spacer-enhanced biological performance for neurotensin-receptor-1-positive tumor targeting.
Article in Nuclear medicine and biology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 26 citations in OpenAlex.
- Development of a Neurotensin-DerivedCancers · 2022Article
- Examination of Charge Modifications of an Endolysosomal Trapping Inhibitor in an Antagonistic NTSR1-Targeted Construct for Colon Cancer.Bioconjugate chemistry · 2022Article
- Examination of the impact molecular charge has on NTSR1-targeted agents incorporated with cysteine protease inhibitors.European journal of medicinal chemistry · 2022Article
- Preclinical PET Imaging of NTSR-1-Positive Tumors withCancer biotherapy & radiopharmaceuticals · 2021Article
- Development of Radiogallium-Labeled Peptides for Platelet-Derived Growth Factor ReceptorMolecules (Basel, Switzerland) · 2020Article
- Optimizing the Profile of [International journal of molecular sciences · 2020Article
- Key-Protease Inhibition Regimens Promote Tumor Targeting of Neurotensin Radioligands.Pharmaceutics · 2020Article
- Enhanced tumor retention of NTSR1-targeted agents by employing a hydrophilic cysteine cathepsin inhibitor.European journal of medicinal chemistry · 2019Article
- Modifications at Arg and Ile Give Neurotensin(8-13) Derivatives with High Stability and Retained NTSACS medicinal chemistry letters · 2019Article
- Increasing time on target: utilization of inhibitors of cysteine cathepsins to enhance the tumor retention of receptor-targeted agents.Chemical communications (Cambridge, England) · 2018Article
- Review
- New Insights in the Design of Bioactive Peptides and Chelating Agents for Imaging and Therapy in Oncology.Molecules (Basel, Switzerland) · 2017Review
- Investigation of the Biological Impact of Charge Distribution on a NTR1-Targeted Peptide.Bioconjugate chemistry · 2016Article
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
introductionNeurotensin receptor 1 (NTR1) is overexpressed in many cancer types. Neurotensin (NT), a 13 amino acid peptide, is the native ligand for NTR1 and exhibits high (nM) affinity to the receptor. Many laboratories have been investigating the development of diagnostic and therapeutic radiopharmaceuticals for NTR1-positive cancers based on the NT peptide. To improve the biological performance for targeting NTR1, we proposed NT analogs with a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelation system and different lengths of spacers.
methodsWe synthesized four NTR1-targeted conjugates with spacer lengths from 0 to 9 atoms (null (N0), β-Ala-OH (N1), 5-Ava-OH (N2), and 8-Aoc-OH (N3)) between the DOTA and the pharmacophore. In vitro competitive binding, internalization and efflux studies were performed on all four NT analogs. Based on these findings, metabolism studies were carried out on our best performing conjugate, (177)Lu-N1. Lastly, in vivo biodistribution and SPECT/CT imaging studies were performed using (177)Lu-N1 in an HT-29 xenograft mouse model.
resultsAs shown in the competitive binding assays, the NT analogs with different spacers (N1, N2 and N3) exhibited lower IC50 values than the NT analog without a spacer (N0). Furthermore, N1 revealed higher retention in HT-29 cells with more rapid internalization and slower efflux than the other NT analogs. In vivo biodistribution and SPECT/CT imaging studies of (177)Lu-N1 demonstrated excellent accumulation (3.1 ± 0.4%ID/g) in the NTR1-positive tumors at 4h post-administration.
conclusionsThe DOTA chelation system demonstrated some modest steric inhibition of the pharmacophore. However, the insertion of a 4-atom hydrocarbon spacer group restored optimal binding affinity of the analog. The in vivo assays indicated that (177)Lu-N1 could be used for imaging and radiotherapy of NTR1-positive tumors.
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