Johannes Platzek

Equilibria and formation kinetics of some cyclen derivative complexes of lanthanides

Abstract The kinetics of the formation reactions between the lanthanide(III) ions Ce 3+ , Eu 3+ and Yb 3+ and four cyclen derivative ligands, DO3A-B, DO3A-ME, DO2A and DO2A-2B, were studied by spectrophotometry and a stopped-flow method at 25°C in 1.0 M KCl solutions. The reactions were found to be of first order, which was interpreted in terms of the formation of a diprotonated intermediate, Ln(H 2 L) + . The formation of products occurs via deprotonation and rearrangement of the intermediate, characterised by the rate constant, k r . The rate law obtained, k r = k OH [OH − ], is similar to those obtained for the formation reactions of DOTA and DOTA derivative complexes. The rate constants, k OH , decrease with decrease in the number of charged carboxylate functional groups in the ligands; the lowest rates were found for the formation of the DO2A complexes. The formation rates increase significantly from Ce 3+ to Yb 3+ . The direct proportionality between the formation rates and [H + ] −1 was interpreted by assuming the equilibrium formation of a monoprotonated intermediate, Ln(HL), which undergoes deprotonation in a slow, rate-determining step. The validity of general base catalysis was detected in the formation reactions, which supports the assumption of the rate-controlling role of deprotonation of the monoprotonated intermediate. The protonation constants of the ligands DO3A-ME and DO2A-2B and the stability constants of their complexes were also determined. The ligand DO2A forms the usual complexes Ln(DO2A) + and the unusual species Ln(DO2A) 2 xa0− . In the complexes Ln(DO2A) 2 xa0− , the two ligands exhibit different coordination modes which were demonstrated by 1 H NMR spectroscopy.

EQUILIBRIUM AND KINETIC STUDIES ON COMPLEXES OF 10-2,3-DIHYDROXY-(1-HYDROXYMETHYL)-PROPYL-1,4,7,10-TETRAAZACYCLODODECANE-1,4,7-TRIACETATE

Complexation properties of the ligand 10-[2,3-dihydroxy-(1-hydroxymethyl)-propyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetatic acid (DO3A-B) were studied and compared with those of 10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (HP-DO3A) and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). The protonation constants of DO3A-B (KiH) and the stability constants (K) of the complexes formed with Ca2+, Sr2+, Ba2+, Zn2+, Cu2+, Fe3+, Ce3+, Nd3+, Eu3+, Gd3+, Dy3+, Tm3+ and Lu3+ were determined in different media (I = 0.1 M; 25°C). The first protonation constants (log K1H) in Me4NCl, KCl and NaCl were found to be 11.75, 11.27 and 9.46, respectively, indicating the formation of Na+ and weaker K+ complexes. The complexes of lanthanides, alkaline earths and Zn2+ form slowly and the complexation equilibria could be studied by means of an out-of-cell technique. The stabilities of the complexes Ln(DO3A-B) increase from La to Eu while the log K values are practically constant for the heavier lanthanides. The stability constants of the DO3A-B complexes of Ce, Gd and Lu are 1–2 orders of magnitude lower than those of the HP-DO3A complexes. The coordinated alcoholic hydroxy groups dissociate at relatively low pH. The dissociation constant (Kd) obtained pH-metrically for Gd(DO3A-B) (pKd=9.48) is about 100 times higher than that for Gd(HP-DO3A) (pKd=11.36), indicating the higher basicity of the alcoholic oxygen in HP-DO3A, which may contribute to the larger stability constants of the complexes formed with HP-DO3A. The kinetic stability of the complexes Gd(DO3A-B) and Gd(HP-DO3A) were studied by spectrophotometry in the pH range 3.2–5.3 by following the exchange reactions between the complexes and Eu3+. The rates of the exchange reactions proved to be linearly proportional to the H+ concentration. This was interpreted in terms of the rate-determining role of the rearrangement and dissociation of the monoprotonated complexes. The rate constants obtained for the proton-assisted dissociation of Gd(DO3A-B) and Gd(HP-DO3A) were (2.8 ± 0.1) × 10−5 and (2.6 ± 0.1) × 10−4 M−1 s−1, respectively.

Gadolinium neutron capture therapy (GdNCT) of melanoma cells and solid tumors with the magnetic resonance imaging contrast agent gadobutrol

RATIONALE AND OBJECTIVESnThe therapeutic gain of neutron capture therapy with a neutral macrocyclic gadolinium (Gd) complex (Gadobutrol) was evaluated through in vitro and in vivo studies in a beam of low-energy neutrons.nnnMETHODSnNeutron irradiation for both the in vitro and in vivo studies was performed in a beam of low-energy neutrons produced by the research reactor of the Hahn-Meitner-Institut, Berlin. Malignant melanoma cells of human origin were irradiated in the presence or absence of Gadobutrol. In vivo irradiation was performed on tumor-bearing nude mice. The tumor site was irradiated subsequent to intratumoral injection of Gadobutrol and compared with irradiation in the absence of the Gd complex.nnnRESULTSnIn vitro studies showed a Gd-dependent delay of cell proliferation as a consequence of neutron irradiation. In animals, intratumoral administration of the Gd complex at a dose of 1.2 mmol Gd/kg before neutron irradiation results in a significant delay in tumor growth with respect to the control groups.nnnCONCLUSIONSnIn vitro and in vivo studies showed a therapeutic benefit with the neutral Gd complex and suggest Gd-containing magnetic resonance contrast media are potential candidates for neutron capture therapy. The Gd dose used in the irradiation experiments was four times the presently accepted high dose in clinical magnetic resonance imaging.

Biotransformation of Finerenone, a Novel Nonsteroidal Mineralocorticoid Receptor Antagonist, in Dogs, Rats, and Humans, In Vivo and In Vitro

Mass balance and biotransformation of finerenone, a nonsteroidal mineralocorticoid receptor antagonist, were investigated in four healthy male volunteers following a single oral administration of 10 mg (78 μCi) of [14C]finerenone and compared with data from studies in dogs and rats. The total recovery of the administered radioactivity was 101% in humans, 94.7% in dogs, and 95.2% in rats. In humans, radioactivity was mainly excreted renally (80%); in rats, it was primarily the biliary/fecal route (76%); and in dogs, excretion was more balanced. Finerenone was extensively metabolized in all species by oxidative biotransformation, with minor amounts of unchanged drug in excreta (humans: 1%; dogs, rats: <9%). In vitro studies suggested cytochrome P450 3A4 was the predominant enzyme involved in finerenone metabolism in humans. Primary metabolic transformation involved aromatization of the dihydronaphthyridine moiety of metabolite M1 as a major clearance pathway with a second oxidative pathway leading to M4. These were both prone to further oxidative biotransformation reactions. Naphthyridine metabolites (M1–M3) were the dominant metabolites identified in human plasma, with no on-target pharmacological activity. In dog plasma, finerenone and metabolite M2 constituted the major components; finerenone accounted almost exclusively for drug-related material in rat plasma. For metabolites M1–M3, axial chirality was observed, represented by two atropisomers (e.g., M1a and M1b). Analysis of plasma and excreta showed one atropisomer (a-series, >79%) of each metabolite predominated in all three species. In summary, the present study demonstrates that finerenone is cleared by oxidative biotransformation, mainly via naphthyridine derivatives.