{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T04:48:54Z","timestamp":1782449334761,"version":"3.54.5"},"reference-count":128,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T00:00:00Z","timestamp":1781568000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Fibroblast activation protein (FAP) has emerged as a promising target for the development of cancer radiotheranostics due to its selective overexpression in cancer-associated fibroblasts (CAFs) within the tumor stroma. Affinity and selectivity refer to the binding affinities of FAP inhibitors toward FAP and related family members, whereas the accumulation of radiolabeled-FAP inhibitors varies by tumor type. Although monomeric FAP inhibitors (FAPIs) have shown extraordinary utility in diagnostic imaging, their clinical application in radiotherapy has been limited by short tumor retention times and heterogeneous uptake. To address these challenges, homomultimeric FAPI ligands\u2014featuring two or more identical FAP-targeting motifs\u2014have been developed with the aim of enhancing binding avidity and prolonging tumor residence. This review comprehensively examines the evolution of homomultimeric FAPI ligands, from molecular design and preclinical validation to early clinical implementation. We highlight how dimeric and higher-order multimeric constructs improve tumor retention and therapeutic efficacy compared to monomers, while also discussing the impact of linker chemistry, valency, and scaffold architecture on pharmacokinetics and targeting efficiency. Preclinical studies demonstrate that optimized dimers and trimers achieve superior tumor-to-background ratios and sustained tumor uptake, whereas excessive multimerization can lead to steric hindrance and reduced efficacy. Clinical data from pioneering studies using agents such as [177Lu]Lu-DOTAGA.(SA.FAPi)2 and [177Lu]Lu-DOTAGA.Glu.(FAPi)2 confirm prolonged tumor retention, encouraging therapeutic responses and a favorable safety profile in advanced cancers. However, translational challenges remain, including the need for better preclinical models that reflect stromal FAP heterogeneity, optimized radiometal\u2013chelator pairs, and standardized dosing protocols for comparative clinical trials. Overall, homomultimeric FAPI ligands represent a significant advance in FAP-targeted theranostics, offering a robust platform for personalized cancer management.<\/jats:p>","DOI":"10.3390\/molecules31122124","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T01:58:38Z","timestamp":1781661518000},"page":"2124","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Homomultimeric FAP Inhibitor-Based Radioligands for Cancer Theranostics: Design Principles, Structure\u2013Function Relationships, and Preclinical Performance"],"prefix":"10.3390","volume":"31","author":[{"given":"Zhiyang","family":"Wu","sequence":"first","affiliation":[{"name":"SCV Spezial-Chemikalien-Vertrieb GmbH, 10243 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleni","family":"Gourni","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, Inselspital, Bern University Hospital, CH-3010 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjana","family":"Ballal","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, All India Institute of Medical Sciences, New Delhi 110029, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pieter","family":"Van der Veken","sequence":"additional","affiliation":[{"name":"Laboratory of Medicinal Chemistry, Department of Pharmaceutical Sciences, University of Antwerp, 2610 Wilrijk, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Roesch","sequence":"additional","affiliation":[{"name":"Department of Chemistry\u2013TRIGA Site, Johannes Gutenberg-University Mainz, 55128 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"801","DOI":"10.2967\/jnumed.119.227967","article-title":"68Ga-FAPI PET\/CT: Tracer Uptake in 28 Different Kinds of Cancer","volume":"60","author":"Kratochwil","year":"2019","journal-title":"J. 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