From FAP biology to theranostic precision – insights from the dose escalation study

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Ziel/Aim: The main objective of this study was to explore the impact of the administered mass of five radiotracers on their overall pharmacokinetic performance, shedding light on crucial factors influencing their efficacy. Methodik/Methods: DOTA.SA.FAPi, DATA 5m .SA.FAPi, DOTAGA.(SA.FAPi) 2 , DOTAGA.Glu.(FAPi) 2 and DO3A.Glu.(FAPi) 2 were labelled with gallium-68. In a dose-escalation study using PC3 xenografts, the administered mass ranged from 10 to 1500 pmol of all tested radiotracers, followed by biodistribution and PET/CT imaging at 1 h p.i..The selectivity towards FAP, PREP, and DDP4, along with their stability in vivo, was examined by biodistribution and metabolite analysis, respectively. FAP expression in various murine organs was confirmed by qPCR. Circulating FAP presence in the plasma of PC3 xenografts, healthy mice and healthy human volunteers was determined by ELISA. Ergebnisse/Results: The administered mass of radiotracers significantly influenced blood retention and tumor uptake. Increasing the mass from 10 pmol to the optimal dose reduced blood uptake by a factor of 5 to 8, with optimal masses ranging from 350 to 600 pmol resulting in tumor uptake between 12% and 19% IA/g. For example, with [ 68 Ga]Ga-DOTAGA.Glu.(FAPi) 2 , blood uptake dropped from 25.8±3.2% IA/g at 10 pmol to 3.2±0.5% IA/g at 600 pmol, while tumor uptake increased from 12.5±1.7% IA/g to 16.5±2.3% IA/g. Higher doses ranging between 1000 and 1500 pmol significantly altered pharmacokinetics of all the tested radiotracers. The 68 Ga-labeled radiotracers were found to be selective towards FAP and demonstrated stability in vivo. The organs with the highest FAP expression were found to be bones, tumor, pancreas, salivary glands and bone marrow. Circulating FAP was detected in the plasma of PC3 xenografts, healthy mice (100-116 µg/mL), and healthy human volunteers (112-180 µg/mL). Schlussfolgerungen/Conclusions: Our extensive dose escalation study of monomeric and dimeric FAP radiotracers, revealed the critical importance of administering the correct mass for their effectiveness. Despite FAP's presence in the bloodstream, achieving optimal injected mass correlates directly with improved in vivo performance. Publication History Article published online: 12 March 2025 © 2025. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

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