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We hypothesized that adjusting the administered radiotracer dose one could enhance the tumor-to-background ratios.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In a dose-escalation study with PC3 xenografts, all radiotracers were administered at doses between 10 and 1500 pmol, followed by biodistribution and PET\/CT imaging. Their selectivity towards FAP, PREP, and DDP4, along with their stability in vivo, was assessed by biodistribution and metabolite analysis, respectively. Organ FAP expression was quantified using qPCR, and circulating FAP (sFAP) levels were measured in mouse and human blood samples via ELISA. Proof-of-principle human studies were also conducted.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Increasing the dose from 10 to 600 pmol significantly reduced blood uptake and enhanced tumor uptake, optimizing their in vivo performance. All radiotracers showed peak efficacy at 350\u2013600 pmol, with altered pharmacokinetics beyond 600 pmol. Biodistribution studies validated the in vivo selectivity of all radiotracers towards FAP, even in the presence of PREP and DPP4 inhibitors, while they demonstrated remarkable stability in vivo. FAP expression was confirmed in various organs, with sFAP quantified in both healthy mice and humans. Human studies with [\n                      <jats:sup>68<\/jats:sup>\n                      Ga]Ga-DOTA.SA.FAPI revealed reduced off-target uptake (e.g., pancreas, salivary glands, heart), aligning with the preclinical findings.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The study highlights the crucial need for precise FAPI-radiotracer dosing, optimizing PET imaging, reducing radiation exposure, and enhancing treatment by accounting for FAP biology and sFAP\u2019s influence on pharmacokinetics.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00259-025-07141-1","type":"journal-article","created":{"date-parts":[[2025,2,25]],"date-time":"2025-02-25T22:03:23Z","timestamp":1740521003000},"page":"3238-3251","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Improved FAPI-radiopharmaceutical pharmacokinetics from the perspectives of a dose escalation study"],"prefix":"10.1007","volume":"52","author":[{"given":"Adrianna","family":"Bilinska","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjana","family":"Ballal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chandrasekhar","family":"Bal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tilman","family":"L\u00e4ppchen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eirinaios","family":"Pilatis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Men\u00e9ndez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Euy Sung","family":"Moon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcel","family":"Martin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"R\u00f6sch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Axel","family":"Rominger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2198-382X","authenticated-orcid":false,"given":"Eleni","family":"Gourni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,2,26]]},"reference":[{"key":"7141_CR1","doi-asserted-by":"publisher","unstructured":"Chandekar KR, Prashanth A, Vinjamuri S, Kumar R. 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