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| Home > Publications database > Preparation and preclinical evaluation of novel 18F-labeled FAP ligands |
| Conference Presentation (After Call) | FZJ-2024-03433 |
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2023
Abstract: Objectives: Fibroblast activation protein (FAP) is a membraneboundprolyl endopeptidase that is almost exclusively expressed bycancer-associated fibroblasts (CAFs), making it a promising target forpositron emission tomography (PET) imaging of different solid tumors.The aim of this study was the preparation and preclinical evaluation ofthree novel radiofluorinated candidate probes for FAP imaging usingradiolabeling protocols developed in our institute.Methods: [18F]AlF-FAPI-42 ([18F]1) was prepared by chelation of[18F]F– using FAPI-42 precursor (62 nmol) and AlCl3 (30 nmol) inDMSO/50 mM NaOAc buffer (pH 4) mixture (1.4 mL/0.4 mL) at 110 °Cfor 10 min. 7-[18F]F-1-Me-2-aza-IA-FAPI ([18F]2) was obtained byconjugation of appropriately modified AMC1110 with 7-[18F]F-1-Me-2-aza-IA. The latter was prepared from the respective N,N,N-trimethylammoniumtriflate precursor using (on-cartridge) radiofluorination.6-[18F]F-UAMC1110 ([18F]4) was produced from the respective Me3Snsubstrate (10 μmol) using an optimized protocol for Cu-mediatedradiofluorination, while 6-[18F]FSO2-AMC1110 ([18F]3) was preparedby using of an improved procedure for 18F/19F SuFEx isotopic exchangefrom 3 (45 nmol). All tracers were purified by HPLC or SPE. The tracercandidates were evaluated by in vivo μPET (120 min emission scanswith a Siemens Focus 220 small animal PET scanner) in immunodeficientSCID mice subcutaneously inoculated with wild type and FAP+transfected HT-1080 cells. The most promising candidate wasadditionally evaluated in a subcutaneous rat model based on the ratpancreatic tumor cell line DSL-6A/C1, which is characterized by apronounced tumor stroma with a high density of cancer-associatedfibroblasts (CAFs). [18F]AlF-FAPI-42 was applied as the reference FAPspecificPET-tracer in all biological experiments.Results: PET probes were prepared as injectable solutions inactivity yields of 25–57% and with molar activities of 28–170 GBq/μmol. The in vivo PET measurements demonstrated no accumulation inFAP+-HT-1080 tissue for both [18F]2 and [18F]3, reflecting insufficient ofin vivo stability of [18F]3, and the missing FAP selectivity for [18F]2. Incontrast, [18F]4 demonstrated high accumulation in FAP+ tissue andhigh stability in tumor. Uptake of the latter tracer and [18F]1 in FAP+-HT-1080 tumors were comparable and at least twice as high as in wildtype tumors. [18F]4 also enabled a clean delineation of DSL-6A/C1tumors with a target-to-background ratio of about 5, which remainedstable for at least 120 min. In the same model, [18F]1-PET allowedvisualization of tumors with a target-to-background ratio of 10 at40 min p.i., which increased to 15 at 120 min p.i. The higher tumor-tobackgroundratio of [18F]1 was due to lower background activity ratherthan higher tumor uptake. Both [18F]4 and [18F]1 accumulated in galland urinary bladder. [18F]4 showed a particularly strong hepatobiliaryexcretion, resulting in high amounts of radioactivity in the intestinaltract.Conclusions Three novel PET-probes were successfully producedusing emerging radiofluorination methods. Among them [18F]4represents a promising candidate for visualization of FAP-positivetumors. However, it is not superior to [18F]1 because of its higherbackground activity and stronger hepatobiliary excretion.
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