t-Bu2SiF-Derivatized D2-Receptor Ligands: The First SiFA-Containing Small Molecule Radiotracers for Target-Specific PET-Imaging

Abstract

The synthesis, radiolabeling and in vitro evaluation of new silicon-fluoride acceptor (SiFA) derivatized D2-receptor ligands is reported. The SiFA-technology simplifies the introduction of fluorine-18 into target specific biomolecules for Positron-Emission-Tomography (PET). However, one of the remaining challenges, especially for small molecules such as receptor-ligands, is the bulkiness of the SiFA-moiety. We therefore synthesized four Fallypride SiFA-conjugates derivatized either directly at the benzoic acid ring system (SiFA-DMFP, SiFA-FP, SiFA-DDMFP) or at the butyl-side chain (SiFA-M-FP) and tested their receptor affinities. We found D2-receptor affinities for all compounds in the nanomolar range (Ki(SiFA-DMFP) = 13.6 nM, Ki(SiFA-FP) = 33.0 nM, Ki(SiFA-DDMFP) = 62.7 nM and Ki(SiFA-M-FP) = 4.21 nM). The radiofluorination showed highest yields when 10 nmol of the precursors were reacted with [18F]fluoride/TBAHCO3 in acetonitrile. After a reversed phased cartridge purification the desired products could be isolated as an injectable solution after only 10 min synthesis time with radiochemical yields (RCY) of more than 40% in the case of SiFA-DMFP resulting in specific activities >41 GBq/µmol (>1,100 Ci/mmol). Furthermore, the radiolabeled products were shown to be stable in the injectable solutions, as well as in human plasma, for at least 90 min.

Silicon-[18F]Fluorine Radiochemistry: Basics, Applications and Challenges

“…This high lipophilicity can result in a dramatically altered in vivo biodistribution of the labeled substances, especially in the case of small molecules. Thus, examples for small molecules containing organo-silicon building blocks for the introduction of 18 F are rare, but some approaches have been described recently [46][47][48].…”

Synthesis of new 18F-radiolabeled silicon-based nitroimidazole compounds

“…With a half-life of 110 min and a low-energy positron of 640 KeV, 18 F can yield PET images with high resolution. 18 F is often incorporated into organic molecules by electrophilic or nucleophilic reactions forming a carbon-[ 18 F]fluorine bond. Thus, the development of PET followed the need of new techniques for incorporation of radionuclides into biologically active molecules, such as the use of silicon as a fluorine-accepting agent.…”

“…An alternative method to conventional 18 F-labeling consists of the creation of Si-18 F, B-18 F and Al-18 F bonds 1-3 instead of a C-18 F bond. Herein, we report on the synthesis of organofluorosilane compounds.…”

“…In particular, positron emission tomography (PET) is a powerful non-invasive molecular-imaging technique providing physiological and biological information about the distribution of radiolabeled molecules by 180°coincidence detection of two simultaneously-emitted photons from positron-electron annihilation. 18 F is among the most widely used positron emitters due to its almost ideal physical properties. With a half-life of 110 min and a low-energy positron of 640 KeV, 18 F can yield PET images with high resolution.…”

“…18 F is among the most widely used positron emitters due to its almost ideal physical properties. With a half-life of 110 min and a low-energy positron of 640 KeV, 18 F can yield PET images with high resolution. 18 F is often incorporated into organic molecules by electrophilic or nucleophilic reactions forming a carbon-[ 18 F]fluorine bond.…”