$^{18}$F-labeling of small molecules and peptides

Rickmeier, H. Jens; Ritter, Tobias (Thesis advisor); Bolm, Carsten (Thesis advisor)

Aachen (2019)
Dissertation / PhD Thesis

Dissertation, RWTH Aachen University, 2019


As of 2018, the Food and Drug Administration (FDA) has approved just ten positron-emission-tomography (PET)-tracers, of which six have been developed in the last seven years. The overall low quantity of approved PET-tracers can be partly attributed to the lack of general methods to access potential tracers. The half-life of commonly used radionuclides is below two hours; therefore, the radionuclide should be introduced in the last step of the synthesis. The high density of functional groups on advanced molecular structures can lower the reactivity of fluoride, and can deactivate reagents and catalysts. New methods are required that tolerate high structural complexity and thereby permit access to new tracers. The group of Ritter has developed the highly functional group tolerant ruthenium-mediated radio-deoxyfluorination of phenols. The first chapter of this thesis describes an improved procedure for the ruthenium-mediated radio-deoxyfluorination, which has allowed us to obtain the otherwise inaccessible [18F]atorvastatin. Under basic conditions, selective complexation to the 4-hydroxyphenyl substituent over other aryl substituents in hydroxy-atorvastatin was achieved. The use of protic polar solvents enabled almost quantitative elution of [18F]fluoride from the anion exchange cartridge without the need for inversion. These improvements of the method allowed us to isolate [18F]atorvastatin in 20% radiochemical yield and we could show that it is stable in human and rat serum. Peptides are a favorable platform for the development of PET-tracers, because they can show very selective binding and rapid clearance from the bloodstream. Additionally, rapid synthesis of derivatives by solid phase peptide synthesis (SPPS) enables for the fast screening of a structural library. Over the last decade, many methods for polypeptide labeling with [18F]fluoride have been developed, however, all require the introduction of a prosthetic group that changes the properties of the peptide. The second part of this thesis reports a method that provides access to peptides containing 4-[18F]fluoro-phenylalanine side chains by radio-deoxyfluorination of a tyrosine residue bearing a traceless transition metal activating group. By merely exchanging one hydrogen or hydroxyl substituent of the native peptide structure with fluorine-18, the steric properties of the peptide are barely altered and thus its biological functions are likely preserved. The presented method tolerates all 20 canonical amino acids, allows the labeling on the C- terminus, N- terminus or within the peptide, and enables the labeling precursor to be easily accessed by SPPS using a novel ruthenium-containing amino acid building block.