Contribution to a conference proceedings/Journal Article

FZJ-2026-03768

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Synthesis and preliminary in vitro evaluation of an 18F-labeled covalent FAP inhibitor

Elsner, A.-L. ; Bier, D.FZJ* ; Schneider, D.FZJ* ; Zlatopolskiy, B. (Corresponding author)FZJ* ; Neumaier, B.FZJ*

2025
Elsevier Science Amsterdam [u.a.]

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Please use a persistent id in citations: doi:10.1016/j.nucmedbio.2025.109307

Abstract: Introduction: UAMC-1110-based radioligands exhibit high affinity and selectivity for the fibroblast activation protein (FAP), making them valuable probes for tumor imaging by positron emission tomography (PET). However, limited tumor retention diminishes their suitability as FAP-specific radiotherapeutics. This work aimed to develop a novel UAMC-1110 analog with a fluorophosphonic acid warhead, designed to improve tumor retention through formation of a covalent bond with the active site of FAP. To enable validation of covalent binding through the release of [18F]fluoride, an 18F-labeled isotopologue was prepared and evaluated for stability and FAP binding in vitro. Methods: The diphenylphosphonate-substituted radiolabeling precursor 1 was prepared through a nine-step convergent synthesis route and radiofluorinated using the “minimalist” protocol. To this end, [18F]fluoride was trapped on a QMA cartridge and eluted with a solution of Et4NHCO3 in MeOH. After evaporation of the solvent and addition of 1 in MeCN (100 μL), the radiolabeling reaction was performed under argon at 50 °C for 20 min (Figure 1). The product [18F]2 was purified by semi-preparative HPLC, trapped on a QMA cartridge and eluted with isotonic saline. Stability studies with [18F]2 were performed in various media over two hours, while covalent binding to FAP was assessed by measuring [18F]fluoride release in the presence of FAP. Results: 1 was obtained in a total yield of 14% over nine steps and the non-radiolabeled reference compound in a yield of 7% over ten steps. [18F]2 was prepared with radiochemical conversions of 57±14% (n=48) and isolated in radiochemical yields over 56–70 min of 45±16% (n=17), with molar activities of 30–77 GBq/μmol (145–396 MBq product activity, n=7). Incubation in H2O, phosphate-buffered saline (pH=7.4), acidic (pH=2–5) or weakly basic (pH=8–10) aqueous solutions and human blood plasma demonstrated high stability of [18F]2. In contrast, incubation of FAP with [18F]2 resulted in the release of [18F]fluoride, which could be suppressed by preincubation with UAMC-1110 or the non-radiolabeled reference compound. Conclusions: The novel UAMC-1110 analog with a fluorophosphonic acid warhead could represent a promising lead structure for the development of FAP-specific covalent binding radiotherapeutics.

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Contributing Institute(s):

1. Nuklearchemie (INM-5)

Research Program(s):

1. 5253 - Neuroimaging (POF4-525) (POF4-525)

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF < 5 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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