Gallium(III) complexes of DOTA and DOTA-monoamide: kinetic and thermodynamic studies

Given the practical advantages of the (68)Ga isotope in positron emission tomography applications, gallium complexes are gaining increasing importance in biomedical imaging. However, the strong tendency of Ga(3+) to hydrolyze and the slow formation and very high stability of macrocyclic complexes altogether render Ga(3+) coordination chemistry difficult and explain why stability and kinetic data on Ga(3+) complexes are rather scarce. Here we report solution and solid-state studies of Ga(3+) complexes formed with the macrocyclic ligand 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, (DOTA)(4-), and its mono(n-butylamide) derivative, (DO3AM(Bu))(3-). Thermodynamic stability constants, log K(GaDOTA) = 26.05 and log K(GaDO3AM(Bu)) = 24.64, were determined by out-of-cell pH-potentiometric titrations. Due to the very slow formation and dissociation of the complexes, equilibration times of up to ～4 weeks were necessary. The kinetics of complex dissociation were followed by (71)Ga NMR under both acidic and alkaline conditions. The GaDOTA complex is significantly more inert (τ(1/2) ～12.2 d at pH = 0 and τ(1/2) ～6.2 h at pH = 10) than the GaDO3AM(Bu) analogue (τ(1/2) ～2.7 d at pH = 0 and τ(1/2) ～0.7 h at pH = 10). Nevertheless, the kinetic inertness of both chelates is extremely high and approves the application of Ga(3+) complexes of such DOTA-like ligands in molecular imaging. The solid-state structure of the GaDOTA complex, crystallized from a strongly acidic solution (pH < 1), evidenced a diprotonated form with protons localized on the free carboxylate pendants.     

Synthesis of aminomethylazetidines regioselective reactions of mesyloxymethylazetidinones with nucleophiles II

Two efficient methods have been developed for the synthesis of variously substituted 2‐aminomethylazetidine derivatives 5 by regioselective nucleophilic substitution of 4‐mesyloxymethylazetidin‐2‐ones 3 followed by reduction or by reduction of the appropriate 4‐oxo‐azetidine‐2‐carboxamides 7 . A novel ring transformation of 4‐oxoazetidine‐2‐carboxamides 7 into tetrahydroquinolines 16 by reaction with lithium aluminium hydride/aluminium trichloride has been investigated.     

Synthesis of 8,9‐dialkoxybenzodiazepines and 7,8‐dialkoxyisoquinolines

o‐Aroylarylacetone type 1,5‐diketone derivatives (5, 6) were synthesised from arylacetones (1) protected as 1,3‐dioxolanes (4) through directed ortho lithiation followed by acylation with aroyl chlorides. 8,9‐Dialkoxy‐2,3‐benzodiazepines 9 were obtained by cyclisation of diketones 6 with hydrazine. The reaction of diketones 6 with ammonia gave 7,8‐dialkoxyisoquinolines 11. Reaction of ketals 5 with hydrazine hydrochloride and hydroxylamine hydrochloride afforded N‐amino‐7,8‐dialkoxyisoquinolinium chlorides (10) and 7,8‐dialkoxyisoquinolinium oxides (12), respectively.     

Equilibrium and formation/dissociation kinetics of some Ln(III)PCTA complexes

The protonation constants () of 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-3,6,9-triacetic acid (PCTA) and stability constants of complexes formed between this pyridine-containing macrocycle and several different metal ions have been determined in 1.0 M KCl at 25 degrees C and compared to previous literature values. The first protonation constant was found to be 0.5-0.6 log units higher than the value reported previously, and a total of five protonation steps were detected (log = 11.36, 7.35, 3.83, 2.12, and 1.29). The stability constants of complexes formed between PCTA and Mg2+, Ca2+, Cu2+, and Zn2+ were also somewhat higher than those previously reported, but this difference could be largely attributed to the higher first protonation constant of the ligand. Stability constants of complexes formed between PCTA and the Ln3+ series of ions and Y3+ were determined by using an "out-of-cell" potentiometric method. These values ranged from log K = 18.15 for Ce(PCTA) to log K = 20.63 for Yb(PCTA), increasing along the Ln series in proportion to decreasing Ln3+ cation size. The rates of complex formation for Ce(PCTA), Eu(PCTA), Y(PCTA), and Yb(PCTA) were followed by conventional UV-vis spectroscopy in the pH range 3.5-4.4. First-order rate constants (saturation kinetics) obtained for different ligand-to-metal ion ratios were consistent with the rapid formation of a diprotonated intermediate, Ln(H(2)PCTA)(2+). The stabilities of the intermediates as determined from the kinetic data were 2.81, 3.12, 2.97, and 2.69 log K units for Ce(H(2)PCTA), Eu(H(2)PCTA), Y(H(2)PCTA), and Yb(H(2)PCTA), respectively. Rearrangement of these intermediates to the fully chelated complexes was the rate-determining step, and the rate constant (k(r)) for this process was found to be inversely proportional to the proton concentration. The formation rates (k(OH)) increased with a decrease in the lanthanide ion size [9.68 x 10(7), 1.74 x 10(8), 1.13 x 10(8), and 1.11 x 10(9) M(-1) s(-1) for Ce(PCTA), Eu(PCTA), Y(PCTA), and Yb(PCTA), respectively]. These data indicate that the Ln(PCTA) complexes exhibit the fastest formation rates among all lanthanide macrocyclic ligand complexes studied to date. The acid-catalyzed dissociation rates (k1) varied with the cation from 9.61 x 10(-4), 5.08 x 10(-4), 1.07 x 10(-3), and 2.80 x 10(-4) M(-1) s(-1) for Ce(PCTA), Eu(PCTA), Y(PCTA), and Yb(PCTA), respectively.     

Versatile synthesis of oxindole-1,3-dicarboxamides

A new, high-yielding synthesis of oxindole-1,3-dicarboxamides was elaborated starting from 1-phenoxycarbonyl-3-ethoxycarbonyl-2-oxindole and 1,3-diphenoxycarbonyl-2-oxindole. This method permits also the preparation of N,N,N′-tri- and N,N,N′,N′-tetrasubstituted oxidole-1,3-dicarboxamides, families of compounds that are unknown in the literature. The scope and limitations of the methodology have also been investigated, and a remarkable selectivity has been observed among the amines used in the amidation steps.     

Point Configurations in <Emphasis Type="Italic">d</Emphasis>-Space without Large Subsets in Convex Position

In this paper we give a lower bound for the Erd\H os–Szekeres number in higher dimensions. Namely, in two different ways we construct, for every $n>d\ge 2$, a configuration of $n$ points in general position in $\R^d$ containing at most $c_d(\log n)^{d-1}$ points in convex position. (Points in $\R^d$ are in convex position if none of them lies in the convex hull of the others.)