Silapiperidine-Silicon-Fluoride Acceptors (Pip-SiFA) for 18 F-Radiolabelling

Abstract

Silicon fluoride acceptors (SiFAs) are a promising radiopharmaceutical motif that promote mild and rapid 18 F-labeling via isotope exchange (SiFEx). Nevertheless, their use in biologically active small molecules is complicated by their poor pharmacokinetic properties that stem from their high lipophilicity and large steric profiles. In an effort to overcome these limitations, we report here the synthesis and properties of fluorosilapiperidines (Pip-SiFAs), which retain SiFEx efficiency on an endocyclic Si center that approaches more pharmocologically compatible motifs.Positron emission tomography (PET) is a non-invasive imagingtechnique that is used to diagnose a range of human disorders, including various cancers 1 , as well as diseases of the central nervous system and the cardiovascular system. 2,3 PET relies on the radioactive decay of positron-emitting isotopes, among which fluorine-18 ( 18 F) is preferred for its optimal half-life (109.8 min) and the low energy of its emitted β + -particles (E(β + )= 0.635 MeV) that provide high-resolution images. Nevertheless, strict time constraints imposed by the rate of radioactive decay require rapid radiosynthesis with minimal time lost to isotope incorporation or tracer purification in order to ensure radiochemical yields (RCY) of clinical relevance.The most common methods for 18 F-labelling employ C-F bond formation via nucleophilic substitution at aliphatic (SN2) or aromatic (SNAr) carbon centers (Figure 1A). 4,5 These reactions typically necessitate elevated temperatures, a large excess of non-radioactive precursor, and often require protecting groups due to poor chemoselectivity. In addition, these protocols generally require purification of the tracer by high performance liquid chromatography (HPLC), leading to losses of RCY due to