¹⁸F-Labeled Silicon-Based Fluoride Acceptors: Potential Opportunities for Novel Positron Emitting Radiopharmaceuticals

Abstract

Background. Over the recent years, radiopharmaceutical chemistry has experienced a wide variety of innovative pushes towards finding both novel and unconventional radiochemical methods to introduce fluorine-18 into radiotracers for positron emission tomography (PET). These “nonclassical” labeling methodologies based on silicon-, boron-, and aluminium-18F chemistry deviate from commonplace bonding of an [18F]fluorine atom (18F) to either an aliphatic or aromatic carbon atom. One method in particular, the silicon-fluoride-acceptor isotopic exchange (SiFA-IE) approach, invalidates a dogma in radiochemistry that has been widely accepted for many years: the inability to obtain radiopharmaceuticals of high specific activity (SA) via simple IE. Methodology. The most advantageous feature of IE labeling in general is that labeling precursor and labeled radiotracer are chemically identical, eliminating the need to separate the radiotracer from its precursor. SiFA-IE chemistry proceeds in dipolar aprotic solvents at room temperature and below, entirely avoiding the formation of radioactive side products during the IE. Scope of Review. A great plethora of different SiFA species have been reported in the literature ranging from small prosthetic groups and other compounds of low molecular weight to labeled peptides and most recently affibody molecules. Conclusions. The literature over the last years (from 2006 to 2014) shows unambiguously that SiFA-IE and other silicon-based fluoride acceptor strategies relying on 18F− leaving group substitutions have the potential to become a valuable addition to radiochemistry.

Methods to Increase the Metabolic Stability of 18F-Radiotracers

“…Contrary to carbon, a real pentagonal transition state including hypervalent silicon is formed and assists this substitution. The larger covalent radius of silicon compared to carbon contributes to this nucleophilic substitution [128], which led to the poor kinetic stability of Si-F-bond despite the high thermodynamic stability. Thus, a stabilization of Si-F bond to prevent a nucleophilic attack is only possible by raising the sterical bulkiness of the substituents.…”

“…A summary of applied SiFA building blocks taken from the review by Bernard-Gauthier et al ., 2014 [128]. …”

Click Chemistry and Radiochemistry: The First 10 Years

“…Much, although not all, of this work has focused on 18 F. 35–38 Indeed, a variety of radiosynthetic methods have been employed to create azide- and alkyne-bearing 18 F-labeled prosthetic groups (Figure 2A). 37,39,40 These tools and the CuAAC reaction have been harnessed with great success in the radiolabeling of a wide variety of vectors, including phosphonium ions, 41 peptides, 42–50 oligonucleotides, 39,47 and proteins. 27,47 This application of the CuAAC reaction is not without its flaws, however.…”

Metabolism of a Bioorthogonal PET Tracer Candidate [19F/18F]SiFA-Tetrazine in Mouse Liver Microsomes: Biotransformation Pathways and Defluorination Investigated by UHPLC-HRMS

“…SiFAs are a new class of compounds for radiopharmaceutical chemistry where they are used for synthesizing new diagnostic tracer candidates for PET. 9 SiFA chemistry is a radiofluorination strategy for fast and efficient radiolabeling of higher molecular weight constructs such as peptides, proteins, or nanoparticles that accumulate to tumors by enhanced permeability and retention (EPR) effect 10 , 11 or by targeted strategies. 12 − 14 Recently, a compound radiolabeled with SiFA chemistry, a somatostatin receptor-2 targeting peptide 18 F-SiFA lin -TATE, has entered clinical trials.…”