{"doi":"10.1007/s11307-025-02046-9","title":"PSMA-1-DOTA Potentially for Effective Targeted Radioligand Therapy of Prostate Cancer","abstract":"Abstract Purpose While PSMA-targeted radioligand therapy (RLT) has shown remarkable efficacy for treating end-stage prostate cancer, the α-emitting RLT often results in severe salivary gland toxicity, limiting its use. Various strategies to mitigate this side effect have been attempted with limited success. Accordingly, this study introduced a new PSMA-targeting ligand with more favorable binding characteristics than the existing ligands. Procedures The binding affinity of PSMA-1-DOTA to PSMA was compared with that of PSMA-11 and PSMA I&T. Comparison of uptake in the salivary glands, kidneys and PC3pip tumor cells in the xenograft mouse models between [ 68 Ga]Ga-PSMA-1-DOTA, [ 68 Ga]Ga-PSMA-11 and [ 68 Ga]Ga-PSMA I&T was conducted with microPET/CT within the same week. The same mouse models were treated with [ 177 Lu]Lu-PSMA-1-DOTA or [ 177 Lu]Lu-PSMA-617. A compassionate use PET imaging study on a patient with metastatic castration-resistant prostate cancer was performed using [ 68 Ga]Ga-PSMA-1-DOTA. Results The binding affinity of PSMA-1-DOTA to PSMA was found to be approximately four times greater than other PSMA-targeted ligands. Imaging with microPET/CT revealed significantly lower kidney, uptake and little salivary and lacrimal gland uptake with [ 68 Ga]Ga-PSMA-1-DOTA compared to other PSMA-radioligands. Preclinical efficacy studies demonstrated that [ 177 Lu]Lu-PSMA-1-DOTA inhibited tumor growth comparable to that with [ 177 Lu]Lu-PSMA-617, suggesting its potential to enhance the therapeutic window of targeted RLT by avoiding damage to the salivary glands. The compassionate use PET imaging confirmed the reduced salivary gland uptake of [ 68 Ga]Ga-PSMA-1-DOTA in the patient, indicating its potential utility as a targeting agent for RLT with α- or β-emitting radionuclides in patients with PSMA-positive prostate cancer. Conclusion PSMA-1-DOTA shows reduced uptake in salivary glands while effectively targeting PSMA-expressing tumors, thus potentially avoiding the side effects of xerostomia, and possibly moving PSMA-targeted RLT to a more frontline therapy for prostate cancer rather than the current use as a last resort.","journal":"Molecular Imaging and Biology","year":2025,"id":546563,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9463,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1271123,"name":"Olga Sergeeva","orcid":"0000-0003-0819-1967","position":1,"is_corresponding":false},{"id":976060,"name":"Maxim Sergeev","orcid":null,"position":2,"is_corresponding":false},{"id":1095865,"name":"Lifang Zhang","orcid":"0000-0001-8950-2936","position":3,"is_corresponding":false},{"id":1438664,"name":"Zoey A. Lockwood","orcid":null,"position":4,"is_corresponding":false},{"id":1438665,"name":"Patrick Wojtylak","orcid":null,"position":5,"is_corresponding":false},{"id":1438666,"name":"Riley Sangster","orcid":null,"position":6,"is_corresponding":false},{"id":989565,"name":"David Reichert","orcid":"0000-0002-9593-6447","position":7,"is_corresponding":false},{"id":1438667,"name":"Marc S. Berridge","orcid":null,"position":8,"is_corresponding":false},{"id":447113,"name":"Wolfgang Weber","orcid":"0000-0002-7854-4345","position":9,"is_corresponding":false},{"id":975585,"name":"Zhenghong Lee","orcid":"0000-0002-2429-9911","position":10,"is_corresponding":false},{"id":297134,"name":"James P. Basilion","orcid":null,"position":11,"is_corresponding":false},{"id":296387,"name":"Xinning Wang","orcid":"0000-0001-7729-0534","position":0,"is_corresponding":true}],"reference_count":37,"raw_metadata":null,"created_at":"2026-07-19T02:53:32.285899Z","pmid":"40897948","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":[]}