Orthogonal synthesis of a heterodimeric ligand for the development of the GdIII–GaIII ditopic complex as a potential pH-sensitive MRI/PET probe

Abstract

A heterodimeric polyaminocarboxylate ligand based on a DO3A-sulfonamide linked to AAZTA (6-amino-6-methylperhydro-1,4-diazepinetetracarboxylic acid) was synthesised via an orthogonal pathway in order to differentiate the two chelating cages and allow the formation of a Gd(III)-Ga(III) heteroditopic complex. The goal is to create a smart MRI/PET probe with pH dependent relaxivity and with the bimodal imaging approach that enables direct quantification of the stimulus, in this case pH. A (1)H NMR relaxometric study of the Gd-Ga heteroditopic complex addressed the pH modulation of the relaxivity and thus its possible use as an MRI pH sensitive probe.

Current advances in ligand design for inorganic positron emission tomography tracers 68Ga, 64Cu, 89Zr and 44Sc

“…92 The multimodal probe was constructed by conjugating a protected AAZTA chelate through an arylsulfonamide bridge to a protected DO3A moiety. 92 The multimodal probe was constructed by conjugating a protected AAZTA chelate through an arylsulfonamide bridge to a protected DO3A moiety.…”

Convenient Synthesis of 68Ga‐Labeled Gadolinium(III) Complexes: Towards Bimodal Responsive Probes for Functional Imaging with PET/MRI

“…Our approach neither involves conjugation of already formed Gd III com-plexes, nor requires stepwise precursor deprotection. [19] Instead, the extraordinary Ga III affinity of TRAP promotes formation of the desired multitopic complexes by virtue of selective transmetalation, enabling simultaneous PET and MRI recording based on truly identical pharmacokinetics and, therefore, quantitative assessment of MRI probe concentration from PET data. Due to temperature dependency of their relaxivity, complexes 3 a and 5 already constitute a pair of fully functional (i.e., temperature-responsive) PET/MRI probes, although the effect is too small for mapping temperature in vivo.…”

“…[14] However, the latter approach has the inherent drawback that the resulting pairs of MRI and PET probes are chemically not equivalent, which can result in different pharmacokinetics. To date, we are aware of only one example for a chemically homogeneous small-molecule PET/MRI probe, a 18 F-labeled, pH-sensitive, Gd III -based MRI CA and its nonradioactive (i.e., 19 Fcontaining) counterpart described by Caravan and co-workers. [8] We aimed at a general concept for labeling of gadoliniumcontaining CA with 68 Ga, because this generator-produced PET nuclide combines locally unrestricted availability with comparably low investment expenses and, hence, is widely expected to become a key resource of PET radiopharmacy soon.…”

“…[17][18][19] Although none of these studies covered actual radiolabeling, it was nevertheless clearly demonstrated that the primary challenge consists in specific placement of each ion at a defined site. For instance, synthesis of a [Gd III DOTA]/[Ga III AAZTA] (6-amino-6-methylperhydro-1,4-diazepine tetraacetic acid) system required rather cumbersome, selective deprotection of the orthogonally protected, conjugated chelators during stepwise complexation; [19] instead, our simple and straightforward approach exploits the pronounced Ga III selectivity of triazacyclononanetriphosphinate (TRAP). [20][21][22][23][24][25] Functionalization of the previously described TRAP-A C H T U N G T R E N N U N G (HMDA) 3 intermediate [21] with three DOTA units led to TRAP(HMDA-DOTA) 3 showed that using the minimally required amount of three equivalents resulted in formation of a mixture of di-, tri-, and tetragadoliniumA C H T U N G T R E N N U N G (III) complexes.…”

Copper complexes as a source of redox active MRI contrast agents

“…However, the synthesis of new, smart imaging agents for measuring biochemical processes (e.g. pH and pO 2 ) requires that the contrast agent has added capability (Angelovski et al 2008;Iwaki et al 2012;Viger et al 2013;Vologdin et al 2013) A method of introducing added capability is to modify the ligand that chelates the lanthanoid centre (Angelovski et al 2008;Iwaki et al 2012;Vologdin et al 2013). Alternatively, it is possible to encapsulate a gadolinium species into a polymer matrix which degrades in response to the biological environment (Viger et al 2013).…”