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UV/Vis of natural Bi(III)- and Pb(II)-L2 and Bi(III)- and Pb(II)-L3; radio-SEC of 133La-L2; radiolabeling kinetics

Octa- and specifically nonadentate ligands with a bispidine scaffold (3,7-diazabicyclo[3.3.1]nonane) are known to be efficiently coordinated to a range of metal ions of interest in radiopharmaceutical chemistry and lead to exceedingly stable and inert complexes. The nonadentate bispidine L2 (with a tridentate bipyridine acetate appended to N3 and a picolinate at N7) has been shown before to be an ideal chelator for 111In3+, 177Lu3+ and 225Ac3+, nuclides of interest for diagnosis and therapy, and a proof-of-principle study with an SSTR2-specific octreotate has shown potential for theranostic applications. We now have extended these studies in two directions. Firstly, we present the ligand derivative L3, where the bipyridine acetate is substituted with terpyridine, a softer donor for metal ions with a preference for more covalency. L3 did not fulfill the hopes because complexation is much less efficient: while for Bi3+ and Pb2+ the ligand is an excellent chelator with similar properties to L2, Lu3+ and La3+ show very slow and inefficient complexation with L3 in contrast to L2, and 225Ac3+ is not fully coordinated, even at an elevated temperature (92% radiochemical yield (RCY) at 80 °C, 60 min, [L3] = 10-4 M). These observations have led to a hypothesis for the complexation pathway that is in line with all experimental data and supported by a preliminary DFT analysis, which is of importance for the design of further optimized bispidine chelators. Secondly, the coordination chemistry of L2 has been extended to Bi3+, La3+ and Pb2+, including solid state and solution structural work, complex stabilities, radiolabeling and radiostability studies. All complexes of this ligand (La3+, Ac3+, Lu3+, Bi3+, In3+, Pb2+), including nuclides for targeted alpha therapy (TAT), single photon emission computed tomography (SPECT), and positron emission tomography (PET) are formed efficiently at physiological conditions, i.e., suitable for the labeling of delicate biological vectors such a

Bei diesem Datensatz handelt es sich um analytische Charakterisierungen (ESI-MS, HR-MS, MALDI-TOF-MS) und Radiomarkierungsuntersuchungen zum nonadentaten Bispidin-Chelator bzw. Bispidin-TATE Konjugat mit Lutetium-177, Indium-111 und/oder Actinium-225. 1H, 13 C NMR and crystallographic data stored by collaboration partner (Heidelberg University)

We report a nonadentate bispidine (3,7-diazabicyclo[3.3.1]nonane) that unveils the potential to bind theranostically relevant radionuclides, including indium-111, lutetium-177 and actinium-225 at mild labeling conditions. This radiopharmaceutical candidate allows the simultaneous application of imaging and treatment (radionuclide theranostics) without changing the type of bioconjugate, i.e. it allows the strong binding to an imaging and a therapeutic radionuclide by the same chelator. Since sophisticated coordination chemistry is required to achieve high thermodynamic and kinetic stability, it is not surprising that only a few chelators have been reported that are able to strongly bind several radionuclides to a satisfactory extent. Bispidine-derived ligands have proven to be ideal for di- and trivalent metal ions with generally fast complexation kinetics and high in vitro and in vivo stabilities. The presented (radio)complexes are formed under mild conditions (pH 6, <40°C) and exhibit thermodynamic stability and inertness in human serum comparable to the corresponding DOTA complexes. The bispidine-based complexing agent was conjugated to a peptide, targeting somatostatin type 2 receptors (SSTR2), overexpressed on neuroendocrine tumors. The 177Lu- and 225Ac-labeled conjugates were investigated, considering their binding to two different SSTR2 positive cell lines, including the human pancreatic carcinoid tumor (BON-SSTR2+) and the murine pheochromocytoma cell line (MPC). The biodistribution and accumulation pattern in MPC tumor-bearing mice was also evaluated. The LuIII and AcIII complexes studied show how ligand structures can be optimized in general by extending the denticity and varying the donor set in order to allow for fast complex formation and medically relevant inertness.

Pentadentate bispidine ligands (3,7-diazabicyclo[3.3.1]nonanes) are optimized for maximum complex stability and facile functionalization with respect to their coupling to biological vector molecules and/or fluorescence markers for PET (positron emission tomography) and multimodal imaging (i.e., PET and optical imaging). The pentadentate ligand with two tertiary amine donors, two p-methoxy substituted pyridines, and one unsubsituted pyridine group is shown to best fulfill important conditions for PET applications, i.e., fast complexation with CuII and high in vivo stability, and this was predicted from the solution chemistry, in particular the CuII/I redox potentials. Also, solvent partition experiments to model the lipophilicity of the CuII complexes indicate that the bis p-methoxy substituted ligand leads to cationic complexes with an appreciable lipophilicity. This is supported by the biodistribution experiments that show that the complex with the p-methoxy substituted ligand is excreted very quickly and primarily via the renal route and therefore is ideally suited for the development of PET tracers with ligands of this type coupled to biomolecules.

The cluster anion [Co3(CO)3(µ2-CO)3(µ3-C8H8)]– (2) reacts with fragments [(ring)M]+ and [(cod)M]+ to give the Co3M clusters (ring)MCo3(CO)3(µ3-CO)3(µ3-C8H8) {(ring)M = CpFe (3a), Cp*Fe (3b), CpRu (4a), (C4Me4)Co (5)} and (cod)MCo3(CO)3(µ3-CO)3(µ3-C8H8) {M = Rh (6), Ir (7)}, respectively. However, 2 does not form stable complexes with [(Ph3P)M]+ species (M = Cu, Ag, Au), which was explained on the basis of DFT calculations by the inefficient overlap between the cluster and fragment orbitals. The structures of 3b and 5 were determined by X-ray diffraction. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim