{"doi":"10.2967/jnumed.125.270047","title":"<sup>18</sup> F-FPP-RGD <sub>2</sub> PET Imaging for Interrogating Target Engagement and Antifibrotic Activity of an Integrin Antagonist in a Mouse Model of Metabolic Dysfunction–Associated Steatohepatitis","abstract":"Patient outcomes in metabolic dysfunction–associated steatohepatitis (MASH) are associated with the presence and stage of liver fibrosis. Activated hepatic stellate cells are a key mediator of MASH fibrogenesis and show increased expression of integrin α<sub>v</sub>β<sub>3</sub>, making it a promising target for imaging and treatment of liver fibrosis. The ability to noninvasively measure target engagement of integrin inhibitors is key to understanding their chances of success in clinical development. <b>Methods:</b> Target engagement was assessed using PET imaging of an arginine–glycine–aspartic acid (RGD)–based integrin-binding tracer <sup>18</sup>F-FPP-RGD<sub>2</sub>. Mice were fed a choline-deficient, ʟ-amino acid–defined, high-fat diet (CDAHFD) or control diet for 2, 6, 10, or 14 wk to induce fibrosis (<i>n</i> = 6/time point). PET was conducted on subsequent days without and with an oral dose of integrin α<sub>v</sub>β<sub>3 </sub>antagonist IDL-2965 (10 mg/kg). The antifibrotic activity was evaluated in mice fed CDAHFD for 12 wk and treated with daily oral IDL-2965 (10 mg/kg) or vehicle in weeks 5–12. Integrin β<sub>3</sub> expression was evaluated in liver biopsies from patients with varying degrees of fibrosis. <b>Results:</b> Significantly higher liver uptake of the integrin-binding PET tracer was found in MASH mice than in age-matched controls and increased with the duration of CDAHFD up to 10 wk. At each stage of fibrotic progression, a single oral dose of IDL-2965 significantly reduced hepatic <sup>18</sup>F-FPP-RGD<sub>2</sub> uptake, consistent with strong IDL-2965 target engagement. In a separate study, therapeutic administration of IDL-2965 significantly reduced multiple measures of CDAHFD-induced liver fibrosis, including histologic fibrosis scores, Sirius Red–stained area, hydroxyproline content, Col1α1 messenger RNA expression, and plasma cytokeratin-18. In human liver biopsies, integrin β<sub>3</sub> expression increased with increasing fibrosis score. <b>Conclusion:</b> Increased expression of integrin α<sub>v</sub>β<sub>3</sub> and strong target engagement by IDL-2965 in the CDAHFD-induced MASH model can be detected in&nbsp;vivo using the integrin-binding PET tracer <sup>18</sup>F-FPP-RGD<sub>2</sub>. Consistent with strong target engagement, therapeutic administration of IDL-2965 significantly reduced multiple measures of CDAHFD-induced hepatic fibrosis.","journal":"Journal of Nuclear Medicine","year":2025,"id":574615,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9573,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"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":1065419,"name":"Caiyuan Zhang","orcid":null,"position":1,"is_corresponding":false},{"id":50899,"name":"Mozhdeh Sojoodi","orcid":"0000-0002-9946-5910","position":2,"is_corresponding":false},{"id":345135,"name":"Nicholas J. Rotile","orcid":"0000-0001-6568-9927","position":3,"is_corresponding":false},{"id":146372,"name":"Yu Lan","orcid":"0000-0003-0148-4871","position":4,"is_corresponding":false},{"id":807768,"name":"Stephen C. Barrett","orcid":"0000-0002-8764-2027","position":5,"is_corresponding":false},{"id":329739,"name":"Changning Wang","orcid":"0000-0002-2076-4193","position":6,"is_corresponding":false},{"id":1482687,"name":"Caralee Schaefer","orcid":null,"position":7,"is_corresponding":false},{"id":1482688,"name":"Karl Kossen","orcid":null,"position":8,"is_corresponding":false},{"id":1482689,"name":"Scott D. Seiwert","orcid":null,"position":9,"is_corresponding":false},{"id":50930,"name":"Kenneth K. Tanabe","orcid":"0000-0003-1920-3417","position":10,"is_corresponding":false},{"id":334441,"name":"Peter Caravan","orcid":"0000-0002-3179-6537","position":11,"is_corresponding":false},{"id":443973,"name":"Iris Y. Zhou","orcid":"0000-0002-4351-7398","position":0,"is_corresponding":true}],"reference_count":44,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:57:44.572630Z","pmid":"40935611","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":[]}