{"doi":"10.1021/jacs.4c11254","title":"Phosphonate-Based Aza-Macrocycle Ligands for Low-Temperature, Stable Chelation of Medicinally Relevant Rare Earth Radiometals and Radiofluorination","abstract":"Radioisotopes of fluorine ( 18 F), scandium ( 43/44 Sc, 47 Sc), lutetium ( 177 Lu), and yttrium ( 86 Y, 90 Y) have decay properties ideally suited for targeted nuclear imaging and therapy with small biologics, such as peptides and antibody fragments. However, a single-molecule strategy to introduce these radionuclides into radiopharmaceuticals under mild conditions to afford inert in vivo complexes is critically lacking. Here, we introduce H 4 L2 and H 4 L3, two small-cavity macrocyclic chelator structural isomers bearing a single phosphonate functional group. Potentiometry and spectrophotometry were employed to determine H 4 L2 and H 4 L3′s ability to form a single [M(L)] − species with metals of different sizes (Sc 3+, Lu 3+, and Y 3+ ) under physiologically relevant conditions. NMR spectroscopy and density functional theory (DFT) calculations suggest modulation of H 4 L2 and H 4 L3′s inner-sphere hydration across the Sc 3+ /Lu 3+ /Y 3+ series. Radiochemical labeling experiments with 18 F, 44 Sc, 177 Lu, and 86 Y reveal that H 4 L2 selectively chelates radioscandium at room temperature with high apparent molar activity (AMA, 462 mCi/μmol), while radiofluorination remains inaccessible. In contrast, H 4 L3 enables room temperature radiochelation 44 Sc, 177 Lu, and 86 Y (AMA: 96–275 mCi/μmol) and incorporates 18 F via the Sc– 18 F methodology to form [ 18 F][ScF(L3)] 2– . In vivo biodistribution analysis at 1 h postinjection confirms the broad utility of H 4 L3: all four radiochemical complexes clear off-target organs and remain >98% intact in urine metabolite analyses. The scope of room temperature radiochemical labeling, paired with facile 18 F incorporation, to afford in vivo compatible complexes exceeds the clinical gold standard chelator DOTA and previously reported acyclic chelators, rendering H 4 L3 promising for prospective radiopharmaceutical applications.","journal":"Journal of the American Chemical Society","year":2024,"id":426262,"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":18,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9522,"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":1087200,"name":"Dariusz Śmiłowicz","orcid":null,"position":1,"is_corresponding":false},{"id":700952,"name":"K. Becker","orcid":"0000-0002-7382-7354","position":2,"is_corresponding":false},{"id":402471,"name":"Eduardo Aluicio‐Sarduy","orcid":"0000-0002-7889-9162","position":3,"is_corresponding":false},{"id":1225146,"name":"Cormac A. A. Kelderman","orcid":"0000-0003-1940-2555","position":4,"is_corresponding":false},{"id":792348,"name":"Angus J. Koller","orcid":"0000-0002-3000-8201","position":5,"is_corresponding":false},{"id":1225727,"name":"Owen M. Glaser","orcid":null,"position":6,"is_corresponding":false},{"id":1225728,"name":"Axia Marlin","orcid":null,"position":7,"is_corresponding":false},{"id":1019569,"name":"Shin Hye Ahn","orcid":"0000-0003-4700-4861","position":8,"is_corresponding":false},{"id":1225729,"name":"Margarita N. Kretowicz","orcid":null,"position":9,"is_corresponding":false},{"id":244590,"name":"Jonathan W. Engle","orcid":"0000-0002-3399-7228","position":10,"is_corresponding":false},{"id":327011,"name":"Eszter Boros","orcid":"0000-0002-4186-6586","position":11,"is_corresponding":false},{"id":1087202,"name":"Jennifer N. Whetter","orcid":null,"position":0,"is_corresponding":true}],"reference_count":29,"raw_metadata":null,"created_at":"2026-07-19T01:58:37.924718Z","pmid":"39570707","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":[]}