Toward 68Ga and 64Cu Positron Emission Tomography Probes: Is H2dedpa-N,N'-pram the Missing Link for dedpa Conjugation?

H2dedpa-N,N'-pram (H2L1), a new chelator derived from the hexadentate ligand 1,2-bis[[(6-carboxypyridin-2-yl)methyl]amino]ethane (H2dedpa), which incorporates 3-propylamine chains anchored to the secondary amines of the ethylenediamine core of the latter, has emerged as a very promising scaffold for preparing 68Ga- and 64Cu-based positron emission tomography probes. This new platform is cost-effective and easy to prepare, and the two pendant primary amines make it versatile for the preparation of bifunctional chelators by conjugation and/or click chemistry. Reported herein, we have also included the related H2dedpa-N,N'-prpta (H2L2) platform as a simple structural model for its conjugated systems. X-ray crystallography confirmed that the N4O2 coordination sphere provided by the dedpa2- core is maintained at both Ga(III) and Cu(II). The complex formation equilibria were deeply investigated by a thorough multitechnique approach with potentiometric, NMR spectrometric, and UV-vis spectrophotometric titrations, revealing effective chelation. The thermodynamic stability of the Ga(III) complexes at physiological relevant conditions is slightly higher than that of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), the common and clinically approved chelator used in the clinic [pGa = 19.5 (dedpa-N,N'-pram) and 20.8 (dedpa-N,N'-prpta) versus 18.5 (DOTA) at identical conditions], and significantly higher for the Cu(II) complexes [pCu = 21.96 (dedpa-N,N'-pram) and 22.8 (dedpa-N,N'-prpta) versus 16.2 (DOTA)], which are even more stable than that of the parent ligand dedpa2- (pCu = 18.5) and that of 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) (pCu = 18.5). This high stability found for Cu(II) complexes is related to the conversion of the secondary amines of the ethylenediamine core of dedpa2- into tertiary amines, whereby the architecture of the new H2L1 chelator is doubly optimal in the case of this metal ion: high accessibility of the primary amine groups and their incorporation via the secondary amines, which contributes to a significant increase in the stability of the metal complex. Quantitative labeling of both chelators with both radionuclides ([68Ga]Ga3+ and [64Cu]Cu2+) was observed within 15 min at room temperature with concentrations as low as 10-5 M. Furthermore, serum stability studies confirmed a high radiochemical in vitro stability of all systems and therefore confirmed H2L1 as a promising and versatile chelator for further radiopharmaceutical in vivo studies.

Integrative Self-Sorting of Bipyridinium/Diazapyrenium-Based Ligands into Pseudo[1]rotaxanes.

We present here the design and synthesis of a series of multicomponent supramolecular architectures, structures formed by the PdII /PtII -directed integrative social self-sorting in aqueous media of pairs of complementary N-monoalkyl-4,4'-bipyridinium/2,7-diazapyrenium-based ligands. Out of the different potential outcomes of the processes, we have found out how the designed systems selectively enhance the production of pseudo[1]rotaxanes, hermaphroditic host-guest aggregates that maximize the strength of the occurring π-π, C-H⋅⋅⋅π, and hydrophobic interactions, as well as the number of those interactions per receptor. It is also demonstrated how both integrative social and narcissistic PdII -directed self-sorting can occur orthogonally and concomitantly for this type of ditopic ligands.

Synthesis of non-symmetric viologen-containing ditopic ligands and their Pd(ii)/Pt(ii)-directed self-assembly.

We present here an efficient method for the preparation of non-symmetric viologen-containing ditopic ligands, as well as the Pd(ii)/Pt(ii)-directed self-assembly of some of these into metallacyclic receptors. The designed synthetic route, that implies the sequential alkylation and the Zincke reaction of activated bipyridinium salts, allowed us to substantially improve the yield in the preparation of three previously reported ligands. The versatility and efficiency of the method have also been tested for the preparation of four new viologen-containing ligands with very different structural features. Furthermore, the self-assembly of the new ligands around Pd(ii) and Pt(ii) centers has been tested, yielding mononuclear rectangular-shaped metallacycles of different dimensions and electronic characteristics.

Self-assembly of Pd2L2 Metallacycles Owning Diversely Functionalized Racemic Ligands.

We present herein the efficient palladium(II)-directed self-assembly in water of a series of nine new diversely functionalized metallacycles, owning hydroxy/alkoxycarbonyl/azidoalkyl exo pendant groups attached to ditopic N-monoalkyl/aryl-4,4'-bipyridinium/2,7-diazapyrenium ligands. The highly convergent and versatile synthetic route for the ligands uses the Zincke reaction between (dinitrophenyl)bipyridinium/diazapyrenium salts and racemic amines as the key step. The stereochemical outcome of the self-assembly of the Pd2L2 species is discussed on the basis of density functional theory quantum-chemical calculations.

Complexation and Catenation in Aqueous Media Using a Self-Assembled Pd(II) Metallacyclic Receptor.

A M2L2 rectangular-shaped metallacycle, obtained by metal-directed self-assembly of a 2-(pyridin-4-ylmethyl)-2,7-diazapyrenium salt and [(en)Pd(NO3)2 (en=ethylenediamine), has been investigated as a molecular receptor for a wide range of aromatic substrates in water. Complexation and catenation of the receptor with selected mono- and polycyclic aromatic substrates produced 1:1 inclusion complexes and [2]catenanes in a highly efficient fashion, as determined by NMR and UV/Vis spectroscopic techniques, as well as single-crystal X-ray crystallography. Furthermore, the thermodynamic and kinetic features of the complexation processes have been analyzed for selected model guests.

Metal-directed self-assembly of constitutionally dynamic systems: control of the nuclearity of Pd(II)/Pt(II) metallacycles.

Self-assembly with the square-planar Pd(II) or Pt(II) (en)M(ONO2)2 (en = ethylenediamine) complexes of ditopic ligands incorporating both N,N'-dialkyl-4,4'-bipyridinium and N-monoalkyl-4,4'-bipyridinium or N-monoalkyl-2,7-diazapyrenium moieties leads to constitutionally dynamic systems responsive to the concentration of the components. At low concentrations, the metallamacrocyclic mononuclear [ML]5+ species is formed. In contrast, when the concentration is increased, a defined dinuclear [M2L2]10+ structure appears as a second species in equilibrium, becoming the major one at high concentrations. Besides concentration changes, the addition of an aromatic guest also allows the control of the system speciation, shifting the outcome of the metal-directed self-assembly towards the mononuclear metallacycle. This dynamic behavior enables the control of the nuclearity of the metallacycles assembled by external stimuli.

Self-Assembly of Pseudo[1]rotaxanes by Palladium(II)/Platinum(II)-Directed Integrative Social Self-Sorting: Is the Metal Required?

New results are presented on the multicomponent supramolecular synthesis of pseudo[1]rotaxanes, achieved by designing pairs of structurally matching N-monoalkyl-4,4'-bipyridinium/2,7-diazapyrenium-based ligands having complementary π-donor/acceptor features, and intended to self-assemble into the targeted supramolecules by following integrative self-sorting processes. In all the studied cases, it was found that the envisioned species, characterized by NMR spectroscopy and MS spectrometry, arise as the main products of the self-assembly in aqueous media by using palladium(II)/platinum(II) metal centers as the guiding force. Crucially, we have also found that by improving the π-donor/acceptor properties of the matching pairs of ligands (L4 and L5 ), the integrative self-sorting processes prevail even in the absence of metallic ions to afford the heterodimeric species with an association constant being 756±43 M-1 .

Amplification of a metallacyclic receptor out of a dynamic combinatorial library.

We present herein the Pt(ii)-directed self-assembly in water of a new conformationally flexible N-monoalkyl-4,4-bipyridinium-based ditopic ligand into a library of six different metallacyclic structures. This constitutionally dynamic library can be pushed to increase the production of one of the supramolecules in aqueous media, either by controlling the concentration of the building blocks or upon addition of an appropriate aromatic substrate.