Recent Advances in the Development of Tetrazine Ligation Tools for Pretargeted Nuclear Imaging

Abstract

Tetrazine ligation has gained interest as a bio-orthogonal chemistry tool within the last decade. In nuclear medicine, tetrazine ligation is currently being explored for pretargeted approaches, which have the potential to revolutionize state-of-the-art theranostic strategies. Pretargeting has been shown to increase target-to-background ratios for radiopharmaceuticals based on nanomedicines, especially within early timeframes. This allows the use of radionuclides with short half-lives which are more suited for clinical applications. Pretargeting bears the potential to increase the therapeutic dose delivered to the target as well as reduce the respective dose to healthy tissue. Combined with the possibility to be applied for diagnostic imaging, pretargeting could be optimal for theranostic approaches. In this review, we highlight efforts that have been made to radiolabel tetrazines with an emphasis on imaging.

The inverse electron demand Diels–Alder cycloaddition with carbon‐11 and fluorine‐18: A gateway to pretargeted imaging across the blood–brain barrier

“…The above highlighted the poor stability of the tetrazine core under typical S N 2 nucleophilic substitution conditions with [ 18 F]fluoride, that is, prolonged heating under basic conditions, and thus represents the biggest challenge in radiolabelling tetrazines 19,32,46 . More recently, Bratteby et al 46 have reported a method for the radiolabelling of base sensitive tetrazines using polyanionic preconditioning agents for the quaternary ammonium ion exchange cartridges used for [ 18 F]fluoride trapping and weak bases as [ 18 F]fluoride eluents.…”

“…PET imaging of pathology in the brain has largely relied on the use of small lipid soluble ligands, which passively diffuse across the BBB or polar molecules that mimic endogenous molecules and exploit active transport systems to cross the BBB. Pretargeting has the potential to greatly expand the scope of PET imaging agents available for interrogation of diseases that affect the brain, and as described above, this has largely focussed on the IEDAA reaction between activated tetrazines and TCOs 2,19,58 . Pretargeting efforts in the oncology space are now reaching clinical trial stage in humans 59,60 ; however, we are still waiting to see similar successes with pretargeting in the brain.…”

“…32 The above highlighted the poor stability of the tetrazine core under typical S N 2 nucleophilic substitution conditions with [ 18 F]fluoride, that is, prolonged heating under basic conditions, and thus represents the biggest challenge in radiolabelling tetrazines. 19,32,46 More recently, Bratteby et al 46 have reported a method for the radiolabelling of base sensitive tetrazines using polyanionic preconditioning agents for the quaternary ammonium ion exchange cartridges used for [ 18 F]fluoride trapping and weak bases as [ 18 F]fluoride eluents. Under these conditions, radiolabelled tetrazines that were prepared in low RCY using 'standard' [ 18 F]fluoride preparation conditions were successfully radiolabelled in up to 23% RCY, offering a new route to 18 F-radiolabelled tetrazines that were previously inaccessible.…”

“…Pretargeting has the potential to greatly expand the scope of PET imaging agents available for interrogation of diseases that affect the brain, and as described above, this has largely focussed on the IEDAA reaction between activated tetrazines and TCOs. 2,19,58 Pretargeting efforts in the oncology space are now reaching clinical trial stage in humans 59,60 ; however, we are still waiting to see similar successes with pretargeting in the brain. There is an abundance of potential targets in the brain that have remained intractable or very challenging to develop radiotracers for using small-molecule based PET probes (e.g., alpha-synuclein, 61 Huntingtin 62,63 and AMPA receptors 64 ).…”

“…For pretargeting using the IDEAA reaction, this means linking the TCO to the pretargeting agent, whilst the tetrazine carries the radiolabel. There are many examples of radiolabelled tetrazines, which have been extensively reviewed by García-V azquez et al 19 ; however, this review focuses on tetrazines that have potential application within pretargeted PET imaging in the brain.…”