{"doi":"10.2967/jnumed.124.267469","title":"Synthesis of<sup>64</sup>Cu-,<sup>55</sup>Co-, and<sup>68</sup>Ga-Labeled Radiopharmaceuticals Targeting Neurotensin Receptor-1 for Theranostics: Adjusting In Vivo Distribution Using Multiamine Macrocycles","abstract":"The development of theranostic radiotracers relies on their binding to specific molecular markers of a particular disease and the use of corresponding radiopharmaceutical pairs thereafter. This study reports the use of multiamine macrocyclic moieties (MAs), as linkers or chelators, in tracers targeting the neurotensin receptor-1 (NTSR-1). The goal is to achieve elevated tumor uptake, minimal background interference, and prolonged tumor retention in NTSR-1–positive tumors. <b>Methods:</b> We synthesized a series of neurotensin antagonists bearing MA linkers and metal chelators. The MA unit is hypothesized to establish a strong interaction with the cell membrane, and the addition of a second chelator may enhance water solubility, consequently reducing liver uptake. Small-animal PET/CT imaging of [<sup>64</sup>Cu]Cu-DOTA-SR-3MA, [<sup>64</sup>Cu]Cu-NT-CB-NOTA, [<sup>68</sup>Ga]Ga-NT-CB-NOTA, [<sup>64</sup>Cu]Cu-NT-CB-DOTA, and [<sup>64</sup>Cu]Cu-NT-Sarcage was acquired at 1, 4, 24, and 48 h after injection using H1299 tumor models. [<sup>55</sup>Co]Co-NT-CB-NOTA was also tested in HT29 (high NTSR-1 expression) and Caco2 (low NTSR-1 expression) colorectal adenocarcinoma tumor models. Saturation binding assay and internalization of [<sup>55</sup>Co]Co-NT-CB-NOTA were used to test tracer specificity and internalization in HT29 cells. <b>Results:</b> In vivo PET imaging with [<sup>64</sup>Cu]Cu-NT-CB-NOTA, [<sup>68</sup>Ga]Ga-NT-CB-NOTA, and [<sup>55</sup>Co]Co-NT-CB-NOTA revealed high tumor uptake, high tumor-to-background contrast, and sustained tumor retention (≤48 h after injection) in NTSR-1–positive tumors. Tumor uptake of [<sup>64</sup>Cu]Cu-NT-CB-NOTA remained at 76.9% at 48 h after injection compared with uptake 1 h after injection in H1299 tumor models, and [<sup>55</sup>Co]Co-NT-CB-NOTA was retained at 60.2% at 24 h compared with uptake 1 h after injection in HT29 tumor models. [<sup>64</sup>Cu]Cu-NT-Sarcage also showed high tumor uptake with low background and high tumor retention 48 h after injection <b>Conclusion:</b> Tumor uptake and pharmacokinetic properties of NTSR-1–targeting radiopharmaceuticals were greatly improved when attached with different nitrogen-containing macrocyclic moieties. The study results suggest that NT-CB-NOTA labeled with either <sup>64</sup>Cu/<sup>67</sup>Cu, <sup>55</sup>Co/<sup>58m</sup>Co, or <sup>68</sup>Ga (effect of <sup>177</sup>Lu in tumor to be determined in future studies) and NT-Sarcage labeled with <sup>64</sup>Cu/<sup>67</sup>Cu or <sup>55</sup>Co/<sup>58m</sup>Co may be excellent diagnostic and therapeutic radiopharmaceuticals targeting NTSR-1–positive cancers. Also, the introduction of MA units to other ligands is warranted in future studies to test the generality of this approach.","journal":"Journal of Nuclear Medicine","year":2024,"id":442628,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9462,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":741869,"name":"Xinrui Ma","orcid":"0000-0002-7970-3387","position":1,"is_corresponding":false},{"id":848492,"name":"Wilson Lin","orcid":"0000-0003-4049-9355","position":2,"is_corresponding":false},{"id":653930,"name":"Tao Zhang","orcid":"0000-0002-0920-0151","position":3,"is_corresponding":false},{"id":400875,"name":"Weiling Zhao","orcid":null,"position":4,"is_corresponding":false},{"id":1246479,"name":"Liqin Pan","orcid":null,"position":5,"is_corresponding":false},{"id":1256387,"name":"Xiaomei Li","orcid":"0000-0001-6505-3363","position":6,"is_corresponding":false},{"id":244586,"name":"Todd E. Barnhart","orcid":"0000-0002-9981-2150","position":7,"is_corresponding":false},{"id":402471,"name":"Eduardo Aluicio‐Sarduy","orcid":"0000-0002-7889-9162","position":8,"is_corresponding":false},{"id":1125057,"name":"Huaifu Deng","orcid":null,"position":9,"is_corresponding":false},{"id":726823,"name":"Xuedan Wu","orcid":"0000-0001-5875-4233","position":10,"is_corresponding":false},{"id":1256388,"name":"K.P. Rakesh","orcid":"0000-0001-9317-8462","position":11,"is_corresponding":false},{"id":258567,"name":"Zibo Li","orcid":"0000-0002-1063-0298","position":12,"is_corresponding":false},{"id":244590,"name":"Jonathan W. Engle","orcid":"0000-0002-3399-7228","position":13,"is_corresponding":false},{"id":504470,"name":"Zhanhong Wu","orcid":"0000-0002-3528-5603","position":14,"is_corresponding":false},{"id":1230965,"name":"German Oscar Fonseca Cabrera","orcid":null,"position":0,"is_corresponding":true}],"reference_count":45,"raw_metadata":null,"created_at":"2026-07-19T02:01:20.107161Z","pmid":"38871388","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}