Universität zu Köln

Bertram, Jan ORCID: 0000-0003-2199-2128 (2025). Sulfamoyl [18F]Fluorides: Novel Radiosynthesis Methods and Evaluation of their Potential for PET Imaging. PhD thesis, Universität zu Köln.

PDF Dissertation_Jan_Bertram_Veroeffentlichung_2025.pdf Download (27MB)

Abstract

Positron emission tomography (PET) enables the non-invasive visualization of physiological and pathological processes using radiotracers labeled with β+-emitting radionuclides. Among these, fluorine-18 is the most widely used due to its favorable decay properties. However, conventional C–18F bond-forming strategies often require harsh reaction conditions incompatible with sensitive biomolecules. Sulfur(VI) fluoride exchange (SuFEx) click chemistry has therefore emerged as an attractive alternative for mild radiofluorination. Although isotopic exchange labeling of fluorosulfates is operationally simple, their limited in vivo stability has restricted clinical translation. This work investigated sulfamoyl [18F]fluorides (SAFs) as a more stable class of fluorosulfuryl-based PET building blocks through three interconnected subprojects. First, a chromatography-free synthesis of the fluorosulfurylating reagent desmethyl SuFEx-IT was developed without the use of SO2F2. The scalable protocol afforded the reagent in high overall yield from inexpensive starting materials and enabled the efficient synthesis of diverse fluorosulfates and SAFs. Second, a base-free SuFEx isotopic exchange protocol was adapted for SAF precursors. Efficient 18F incorporation was achieved within minutes at temperatures as low as 40 °C using nanomolar precursor amounts. Selected [18F]SAFs exhibited excellent stability over a broad pH range and in human serum. In vivo studies demonstrated minimal defluorination of protected tryptophan-derived SAFs, while dihydrotryptophan analogs showed further improved metabolic stability. Third, a no-carrier-added radiosynthetic strategy based on imidazolium and dimethylaminopyridinium salt precursors was developed for aliphatic [18F]SAFs. Radiochemical conversions above 90% were achieved under mild conditions across a broad substrate scope and the method was successfully automated. In vivo evaluation confirmed negligible defluorination and demonstrated that an aliphatic [18F]SAF-based artificial amino acid provided superior tumor-to-background contrast compared with [18F]FET in an orthotopic glioblastoma model. Overall, this work establishes [18F]SAFs as hydrolytically and metabolically stable, synthetically accessible building blocks for PET radiochemistry and highlights their potential for the development of next-generation molecular imaging agents.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Bertram, Jan jdbertram@outlook.de https://orcid.org/0000-0003-2199-2128 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-806548
Date:	2025
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Außeruniversitäre Forschungseinrichtungen > Forschungszentrum Jülich
Subjects:	Chemistry and allied sciences
Uncontrolled Keywords:	Keywords Language radiochemistry UNSPECIFIED PET tracer UNSPECIFIED fluorine-18 UNSPECIFIED SuFEx UNSPECIFIED radiolabeling strategies UNSPECIFIED
Date of oral exam:	23 October 2025
Referee:	Name Academic Title Neumaier, Bernd Prof. Dr. Griesbeck, Axel Prof. Dr.
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/80654