Publications Repository - Helmholtz-Zentrum Dresden-Rossendorf

Objectives: Various kinds of tumour entities are characterised by increased activity of transglutaminase 2 (TGase 2), which contributes to enhanced invasive potential of the tumour cells and their resistance to chemo- and radiotherapy. Therefore, this enzyme represents an interesting target for the development of PET tracers for functional imaging of tumours. Among the TGase 2 inhibitors described in the literature, Nε-acryloyllysine 1 [1] seems to be most suitable for radiotracer development as this compound exhibits both strong inhibitory potential and selectivity towards human TGase 2. Extensive structure-activity relationship studies by our group revealed some potent fluorinated analogues of 1, of which compounds 2 and 4 were identified as potential candidates for PET tracer development due to their great inhibitory potencies and promising pharmacokinetic properties.
Methods: Reference compounds 2 and 4 as well as the precursor 3 were synthesised in a modular synthetic route. For the radiosynthesis of [¹⁸F]2, thienyl and anisyl iodonium salts were envisaged as precursors for prosthetic labelling groups, which were synthesised starting from iodophenylacetates. The fluorination reactions using [18F]F- were performed under various conditions to maximise the radiochemical yield (RCY).
Results: Although a wide range of conditions for radiolabelling of the phenylacetic acid-derived iodonium salts were applied, no incorporation of [¹⁸F]F- could be observed. To identify possible reasons for this, the two other regioisomeric phenylacetic acid-derived iodonium salts were synthesised and subjected to labelling with [¹⁸F]F-. As a result of these efforts, the CH acidity of the benzylic methylene group was supposed to have a detrimental effect on the labelling reaction. In contrast to this, labelling of precursor 3 was successful with RCYs (non-isolated crude product) of up to 15%. Due to the difficult separation of 3 and [¹⁸F]4, the nitro group was reduced to the respective amino group by tin(II) chloride prior to purification by RP-HPLC.
Conclusions: After identifying fluorinated N^ε-acryloyllysines as potential PET tracer candidates, strategies for their radiosynthesis were developed. While attempts for the incorporation of fluorine-18 at the non-activated phenylacetic acid moiety revealed inherent structural limitations, labelling at the 2-nitropyridine-derived precursor led to a promising PET tracer candidate.
References:
[1] J. Wityak et al. ACS Med. Chem. Lett. 2012, 3, 1024-1028