52g/55Mn-Labelled CDTA-based trimeric complexes as novel bimodal PET/MR probes with high relaxivity.

trans-1,2-Diaminocyclohexane-N,N,N',N'-tetraacetic acid (CDTA) labelled with a mixture of paramagnetic 55Mn(ii) and ß+-emitting 52gMn(ii) offers access to bimodal Positron Emission Tomography/Magnetic Resonance (PET/MR) tracers. To enhance the number of NMR-active nuclei and simultaneously improve the longitudinal relaxivity r1, a complex composed of three CDTA units was designed. Accordingly, a functionalised tris-CDTA-1,3,5-tris-triazolobenzene was prepared and labelled with c.a. and n.c.a. 52gMn. Relaxivity measurements of the 55Mn-complex showed an enhancement of r1 of 144% in comparison to the Mn-CDTA monomer. Moreover, the trimer was equipped with an additional linker functionality suitable for conjugation with biomolecules, enabling interaction with specific molecular targets.

Novel CDTA-based, Bifunctional Chelators for Stable and Inert MnII Complexation: Synthesis and Physicochemical Characterization.

In the search for MnII MR and PET/MR imaging agents with optimal balance between thermodynamic stability, kinetic inertness, and relaxivity, two novel bifunctional MnII chelators (BFMnCs) based on CDTA (trans-1,2-diaminocyclohexane-N,N,N',N'-tetraacetic acid) were synthesized. A six-step synthesis, involving the buildup of a functionalized trans-1,2-diaminocyclohexane core, provided CuAAC-reactive 6a and 6b bearing an alkyne or azide substituent on the cyclohexane ring, respectively (CuAAC = CuI-catalyzed azide-alkyne 1,3-dipolar cycloaddition). Thermodynamic, kinetic, and relaxometric studies were performed with 4-HET-CDTA (8a) as a "model chelator," synthesized in two steps from 6a. The protonation constants revealed that 8a is slightly less basic than CDTA and forms a MnII complex of marginally lower thermodynamic stability (log KMnL = 13.80 vs 14.32, respectively), while the conditional stability constant is almost identical for both chelates (pMn = 8.62 vs 8.68, respectively). Kinetic assessment of the CuII-mediated transmetalation of [Mn(4-HET-CDTA)]2- showed that proton-assisted complex dissociation is slightly slower than for [Mn(CDTA)]2- (k1 = 297 vs 400 M-1 s-1, respectively). Importantly, the dissociation half-life near physiological conditions (pH 7.4, 25 °C) underlined that [Mn(4-HET-CDTA)]2- is ∼35% more inert (t1/2 = 16.2 vs 12.1 h, respectively). Those findings may be accounted for by a combination of reduced basicity and increased rigidity of the ligand. Analysis of the 17O NMR and 1H NMRD data attributed the high relaxivity of [Mn(4-HET-CDTA)]2- (r1 = 4.56 mM-1 s-1 vs 3.65 mM-1 s-1 for [Mn(CDTA)]2-; 20 MHz, 25 °C) to slower rotational dynamics (τR298 = 105 ps). Additionally, the fast water exchange of the complex correlates well with the value reported for [Mn(CDTA)]2- (kex298 = 17.6 × 107 vs 14.0 × 107 s-1, respectively). Given the exquisite compromise between thermodynamic stability, kinetic inertness, and relaxivity achieved by [Mn(4-HET-CDTA)]2-, appropriately designed CuAAC-conjugates of 6a/6b are promising precursors for the preparation of targeted, bioresponsive, or high relaxivity manganese-based PET/MR tracers (52g/55 MnII) and MR contrast agents (MnII).

Radiolabelling with isotopic mixtures of (52g/55)Mn(II) as a straight route to stable manganese complexes for bimodal PET/MR imaging.

Radiolabelling using isotopic mixtures of (52g/55)Mn(ii) offers fast and easy access to new small molecule PET/MR tracers, composed of chemically identical reporting units. trans-1,2-Diaminocyclohexane-N,N,N',N'-tetraacetic acid (CDTA) was radiolabelled with carrier-added (52g)Mn(ii) in >99% radiochemical yield, producing the first manganese-based bimodal PET/MR probe. The Mn-CDTA chelate was shown to be very stable to air oxidation and sufficiently inert to decomplexation in blood serum. These data sparked our interest in functionalized CDTA ligands for the design of optimized PET/MR tracers.

Gadolinium DOTA chelates featuring alkyne groups directly grafted on the tetraaza macrocyclic ring: synthesis, relaxation properties, "click" reaction, and high-relaxivity micelles.

This paper reports on the synthesis and relaxivity properties of tetraacetic DOTA-type chelating agents featuring one or two alkyne groups directly grafted on the tetraaza macrocyclic ring and available for "click" reactions with azide-bearing substrates. The racemic DOTAma ligand bearing one alkyne group was obtained by a bisaminal template route. The same approach was used to prepare ligand DOTAda substituted by two alkyne groups located on two adjacent carbon atoms. The S,S enantiomer of DOTAda was also prepared by a "crab-like" condensation. This ligand is the first example of a DOTA derivative featuring two reactive functions adjacent to each other on the macrocyclic ring. A triacetic monoalkyne ligand (DO3ma) was also synthesized for comparison purposes. NMR studies indicate that the Yb(III) chelates of DOTAma and DOTAda adopt two conformations in solutions in which the tetraaza ring is rigidified. The hydration state of the Eu(III) chelates was determined by luminescence spectroscopy, and the water exchange time of the Gd(III) complexes was measured by (17)O NMR. Ring substitution accelerates the water exchange. These data were used to interpret nuclear magnetic relaxation dispersion curves of the Gd(III) chelates. Two long aliphatic chains have been added to DOTAda by a "click" procedure to form the (C18)(2)DOTAda ligand. The corresponding Gd(III) complex forms micelles of unusually high relaxivity presumably because of the close proximity of the aliphatic chains on the macrocyclic ring that ensures a rigid double anchoring into the micelles.