Syntheses of High‐Valent fac‐[^99mTcO₃]⁺ Complexes and [3+2] Cycloadditions with Alkenes in Water as a Direct Labelling Strategy

Abstract

Reported herein is a new concept for the labelling of biomolecules with small [(99m)TcO(3)](+) complexes through a [3+2] cycloaddition with alkenes for radiopharmaceutical applications. We developed convenient reactions for the synthesis of small, water stable fac-[TcO(3)(tacn-R)](+) complexes ((99)Tc and (99m)Tc, tacn = 1,4,7-triazacyclononane, R = H, -CH(2)-C(6)H(5), -CH(2)-C(6)H(4)COOH). With alkenes, these high valent [(99m)TcO(3)](+) complexes undergo [3+2] cycloaddition with formation of the corresponding Tc(V)-glycolato complexes. The (99m)Tc(V) and (99m)Tc(VII) complexes are stable at 37 degrees C in water and in the presence of serum proteins. Therefore, new opportunities in technetium chemistry are enabled with a high potential for medicinal and biological applications. In contrast to classical labelling, the presented strategy is ligand and not metal-centred.

Water-stable fac-{TcO3}+ Complexes – A New Field of Technetium Chemistry

“…Since, after the reaction, the resin can easily be filtered after a heterogeneous reaction, which allows for removal of excess reagents. In the presence of such polymers and a very strong tripodal ligand such as tacn, the corresponding trioxo complex was formed in moderate yield after 1 hour at 95°C as the only product from [31] rhenium analog) confirms its identity. In this particular case the compound is the 'cold' standard ( Figure 5).…”

“…Investigations with a variety of alkenyl-substrates showed that the reaction mechanism is strongly associatively driven and that the rates are highly dependent on the substrate used, but nearly independent of the solvent. [31] Further kinetic studies of the [ 99 TcO 3 (tacn-R)] + (R = H, bz, bz-COOH) system under pseudo-firstorder conditions showed that complexes of monosubstituted tacn-derivatives undergo a faster (3+2)-cycloaddition reaction than in the case with unsubstituted tacn. [31] This observation seems to be of critical importance when taking into account that the rate of the (3+2)-cycloaddition could be tuned by the properties of one or possibly more substituents on the tacn ligand.…”

“…[31] The phosphine was conjugated to a solid-phase support (resin), since the resin can easily be filtered after a heterogeneous reaction, which allows for the removal of excess reagents. In the presence of such polymers and a very strong tripodal ligand such as tacn, the corresponding trioxo complex was formed in moderate yield after 1 h at 95 °C as the only product from [ The only suitable analytical method at these low concentrations is a HPLC system which is coupled to a UV-and a radiodetector.…”

“…31 The phosphine was conjugated to a solid phase support (resin). Since, after the reaction, the resin can easily be filtered after a heterogeneous reaction, which allows for removal of excess reagents.…”

“…[30] The small tridentate ligand 1,4,7-triazacyclonane and its derivatives form very stable mono oxo Tc +V complexes of the general type [TcO(glyc)(tacn-R)] + (glyc = ethylene glycol; tacn-R = 1,4,7-triazacyclononane or derivatives). [30,31] These deep blue complexes are water stable at neutral and basic pH, and only decompose slowly under acidic conditions, accompanied by a color change from deep blue to brown. It is believed that acidic conditions lead to the loss of the glycol ligand, which initiates further decomposition.…”