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In vitro studies included lipophilicity, protein binding, saturation binding, internalization and externalization using FAP\n                      <jats:sup>+<\/jats:sup>\n                      CAFs. In vivo evaluation in PC3-mice comprised biodistribution, metabolic stability, blood and organ clearance, PET\/SPECT\/CT imaging, and autoradiography. Therapeutic efficacy was assessed using fractionated radioligand therapy with [\n                      <jats:sup>177<\/jats:sup>\n                      Lu]Lu-DOTAGA.Glu\n                      <jats:sub>2<\/jats:sub>\n                      .(FAPI)\n                      <jats:sub>2<\/jats:sub>\n                      , as monotherapy or combined with everolimus.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      All radioligands showed\u2009&gt;\u200999% radiochemical purity, high FAP affinity (K\n                      <jats:sub>d<\/jats:sub>\n                      : 0.9\u20131.5 nM), hydrophilic profiles (LogD\n                      <jats:sub>octanol\/PBS<\/jats:sub>\n                      \u2264-3), and low protein binding (&lt;\u200910%). They exhibited high internalization and low externalization (~\u200920% for [\n                      <jats:sup>177<\/jats:sup>\n                      Lu]Lu-DOTAGA.Glu\n                      <jats:sub>2<\/jats:sub>\n                      .(FAPI)\n                      <jats:sub>2<\/jats:sub>\n                      and ~\u200935% for [\n                      <jats:sup>177<\/jats:sup>\n                      Lu]Lu-DOTAGA.PEG\n                      <jats:sub>2<\/jats:sub>\n                      .Glu.(FAPI)\n                      <jats:sub>2<\/jats:sub>\n                      ). The\n                      <jats:sup>68<\/jats:sup>\n                      Ga-labeled radiotracers displayed sustained tumor uptake up to 3\u00a0h p.i. (&gt;\u200914%I.A.\/g) with increasing tumor-to-organ ratios. For the\n                      <jats:sup>177<\/jats:sup>\n                      Lu-labeled analogues the initial uptake was comparable (~\u200915%I.A.\/g at 4\u00a0h p.i.), with [\n                      <jats:sup>177<\/jats:sup>\n                      Lu]Lu-DOTAGA.Glu\n                      <jats:sub>2<\/jats:sub>\n                      .(FAPI)\n                      <jats:sub>2<\/jats:sub>\n                      , showing even improved retention compared to [\n                      <jats:sup>177<\/jats:sup>\n                      Lu]Lu-DOTAGA.PEG\n                      <jats:sub>2<\/jats:sub>\n                      .Glu.(FAPI)\n                      <jats:sub>2<\/jats:sub>\n                      (4.2\u2009\u00b1\u20090.5 vs. 1.2\u2009\u00b1\u20090.02%I.A.\/g at 96\u00a0h). Blood clearance was rapid and biphasic, with faster kinetics for DOTAGA.Glu\n                      <jats:sub>2<\/jats:sub>\n                      .(FAPI)\n                      <jats:sub>2<\/jats:sub>\n                      . For the same compound, tumor half-life was significantly prolonged (44.5 vs. 19\u00a0h), resulting in 2-fold higher tumor exposure (AUC: 971\u2009\u00b1\u200974 vs. 542\u2009\u00b1\u200928%I.A.\u00d7h\/g). Imaging confirmed high tumor-to-background ratios, while autoradiography revealed heterogeneous intratumoral FAP distribution. Fractionated therapy significantly inhibited tumor growth and improved survival, further enhanced by everolimus.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      DOTAGA.Glu\n                      <jats:sub>2<\/jats:sub>\n                      .(FAPI)\n                      <jats:sub>2<\/jats:sub>\n                      demonstrates superior tumor retention, favorable pharmacokinetics, and enhanced therapeutic efficacy, supporting its potential for clinical translation.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00259-026-08078-9","type":"journal-article","created":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T00:03:21Z","timestamp":1784073801000},"page":"7093-7108","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Optimizing FAPI homodimers for theranostic applications: The impact of the linker design in DOTAGA.Glu2.(FAPI)2 and DOTAGA.PEG2.Glu.(FAPI)2"],"prefix":"10.1007","volume":"53","author":[{"given":"Naveen","family":"Kumar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrianna","family":"Bilinska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Men\u00e9ndez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Stephan","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":[[2026,7,15]]},"reference":[{"key":"8078_CR1","doi-asserted-by":"publisher","unstructured":"Koustoulidou S, Hoorens MWH, Dalm SU, Mahajan S, Debets R, Seimbille Y, et al. 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