Recent progress using the Staudinger ligation for radiolabeling applications

Abstract

The increasing application of positron emission tomography and single-photon emission computer tomography in radiopharmacy and nuclear medicine has stimulated the development of a multitude of novel and versatile bioorthogonal conjugation techniques. Currently, there is particular interest in radiolabeling biologically active, high molecular weight compounds like peptides, proteins, or antibodies, but also for the labeling of small organic compounds. An enormous challenge in radiolabeling these biologically active molecules is that the introduction of radiohalogens like fluorine-18 as well as various radiometals proceeds under harsh conditions, which could destroy the biomolecule. The Staudinger ligation is one of the most powerful bioorthogonal conjugation techniques. The reaction proceeds over wide temperature and pH ranges; an amide (peptide) bond is formed as the ligation unit, which minimizes distortion of the structure; no isomers are obtained; and the reaction proceeds without any metal catalyst. Due to this adaptability, this robust ligation type is a perfect candidate with a high potential for various applications in the field of radiopharmacy for the labeling of biomolecules under mild conditions. This review summarizes recent research concerning the implementation of the Staudinger ligation for radiolabeling applications.

Mechanistic Insight into the Catalytic Staudinger Ligation

“…The Staudinger ligation has been of paramount importance for examinations of various molecular and biomolecular systems . The first catalytic Staudinger ligation was described by Ashfeld et al in 2012 .…”

Strained Ammonium Precursors for Radiofluorinations

“…In 2011, Mamat et al used 1-(3-[ 18 F]fluoropropyl)piperazines as model compounds to prepare 18 F-radiotracers based on inhibitors to image cyclin-dependent kinases (CDK), [73] since the piperazine moiety is a basic structural element of these CDKinhibitors (Scheme 16). [74] They In 2013, this method was transferred, by the same group, to prepare two radiolabelling building blocks [ 18 F]AFP and [ 18 F]BFP for bioorthogonal 18 F-introduction, [75] which can be used for labelling purposes either with the traceless Staudinger Ligation [76] or using Cu-mediated or -free click reactions. [77,78] Based on the piperazine skeleton, the respective reference NMR analyses, MS and XRD confirmed the molecular structure of the formed spiro salts 60 a,b.…”

“…In 2013, this method was transferred, by the same group, to prepare two radiolabelling building blocks [ 18 F]AFP and [ 18 F]BFP for bioorthogonal 18 F‐introduction, [75] which can be used for labelling purposes either with the traceless Staudinger Ligation [76] or using Cu‐mediated or ‐free click reactions. [ 77 , 78 ] Based on the piperazine skeleton, the respective reference compounds AFP and BFP as well as the spiro precursors 60 a , b were synthesised by first introducing the azide or alkyne function into the piperazine moiety yielding 58 a , b (Scheme 17 ).…”

Strategic Evaluation of the Traceless Staudinger Ligation for Radiolabeling with the Tricarbonyl Core

“…The traceless Staudinger ligation belongs to the biorthogonal click conjugation reactions and is widely used, e.g., to connect small molecules to (bio)macromolecules like peptides, proteins, or carbohydrates, for cyclization processes to construct large sized lactams, or for the preparation of molecular rods [1][2][3][4][5]. In general, two variants of the traceless Staudinger ligation are described for (radio)labeling purposes [6,7]. Both approaches are shown in Scheme 1.…”

“…The second, indirect variant, uses an azide-functionalized molecule bearing the (radio)label and a biomolecule, which is connected to the phosphane unit. Due to the smooth reaction conditions, the insertion of any label, such as fluorescent dyes [8] or radionuclides like fluorine-18 [9], iodine-131, or radiometals [7], is also possible without the need for a catalyst in contrast to other Cu-catalyzed click reactions.…”