Claire Deville

Erbium-165 (¹⁶⁵Er) is an Auger electron emitter with 7.2 electrons per decay and very few other emissions, making it an interesting candidate for Auger electron therapy. We present here a procedure for producing ¹⁶⁵Er by the ^natHo(p,n)¹⁶⁵Er nuclear reaction on a 16.5 MeV medical cyclotron. The target was prepared by pressing a Ho₂O₃:Al 1:1 (w/w) powder mixture on a Ag disc with a cylindrical depression in the center. With a 0.1 mm Nb foil in front, degrading the energy to 15 MeV, and water cooling at the back of the Ag disc, the target could withstand irradiation at currents up to 45 µA without showing any signs of damage. The beam tolerance of the target was also estimated by calculating the temperature and heat dissipation in the target via the numerical solution of the heat transport equations. For a 180 mg target, the production yield was 12.3 ± 1.9 MBq/µAh. The separation of two neighboring lanthanides is challenging, which led us to study the distribution coefficients for Er and Ho on commercially available LN2 resin for both HNO₃ and HCl eluents. Based on these values, we propose a purification procedure involving two successive LN2 columns for separating the ¹⁶⁵Er from Ho and Al, followed by a small TK221 column to concentrate the final eluate. No radionuclidic impurities were detected, and the chemical impurities found in the final formulation were traces of Ho, Er, Ca, Pb, and Fe. For three different chelators (DOTA, DTPA, and CHX-A″-DTPA), the effective molar activity of the final formulation was measured. The stability of the three complexes formed was also assessed upon incubation in mouse serum for 28 h.

With the emission of both Auger and conversion electrons (AE and CE) together with some x-rays and a few low intensity gamma-rays, palladium-103 (103Pd, T1/2 17 d) and its daughter rhodium-103m (103mRh, T1/2 56 min) are interesting radionuclides for applications in targeted radionuclide therapy. 103Pd’s x-ray emissions have been applied in brachytherapy implants, but the unavailability of non-carrier-added (n.c.a.) 103Pd has limited the development of 103Pd-radiolabeled compounds that exploit its AE and CE emissions. Through a collaboration between UWM and DTU, we have developed a procedure to produce n.c.a. 103Pd from Rh foils and electroplated Rh targets on graphite backings. The targets were irradiated on 16 MeV cyclotrons at 20-40 µA with a production yield of 1.6-2.2 MBq/µAh. Rh dissolution was performed in HCl by applying alternating current. The commercially available AG-1X8, TK200, normal DGA, and branched DGA resins were tested for 103Pd purification from the Rh bulk target material. The DGA resins were found to be the most convenient with high separation factors and quantitative 103Pd elution in HCl solutions. The Rh could be recycled and used for electroplating new targets. Recycled Rh targets improved the molar activity of the 103Pd produced. After two branched DGA columns, 87.2 ± 6.3 % of 103Pd activity was recovered. ICP-OES analysis of the purified batches showed the presence of only few remaining impurities: 1.2 ± 0.3 nmol Pd, 0.4 ± 0.3 nmol Rh and traces of Al, Fe, and Zn. Finally, n.c.a. 103Pd radiolabeling was demonstrated with the TETA chelator in acetate buffered solutions.

Increasing interest in ⁶⁷Cu for targeted radionuclide therapy necessitates development of robust and validated analytical methods to ensure compliance with regulatory standards for clinical translation. We validated methods based on inductively coupled plasma optical emission spectroscopy (ICP-OES) and high-purity germanium (HPGe) γ-spectrometry. For ICP-OES, criteria were met for most elements, with Al and Ca, suffering matrix effects. Apparent molar activity calculated by ICP-OES was congruent with DOTA-titration-based effective molar activity when Al and Ca were excluded. HPGe γ-spectrometry was shown to enable accurate discrimination and quantification of co-produced radionuclides (⁶⁷Ga, ⁶⁶Ga, ^69mZn) from ⁶⁷Cu at 99.5% radionuclidic purity.

Brachytherapy (BT) is routinely used in the treatment of various cancers. Current BT relies on the placement of large sources of radioactivity at the tumor site, requiring applicators that may cause local traumas and lesions. Further, they suffer from inflexibility in where they can be placed and some sources reside permanently in the body, causing potential long-term discomfort. These issues can be circumvented through injectable sources, prepared as biodegradable materials containing radionuclides that form solid seeds after administration. The level of radioactivity contained in such seeds must be sufficient to achieve substantial local irradiation. In this report, we investigate two different strategies for biodegradable BT seeds. The first strategy entails injectable seeds based on 103Pd-labeled palladium-gold alloy nanoparticles ([103Pd]PdAuNPs). These were prepared by combining [103Pd]PdH2Cl4 and AuHCl4, followed by lipophilic surface coating and dispersed in lactose octaisobutyrate and ethanol (LOIB:EtOH), in overall radiochemical yield (RCY) of 83%. With the second strategy, [103Pd]Pd-SSIB was prepared by conjugating the [16]aneS4 chelator with lipophilic sucrose septaisobutyrate (SSIB) followed by complexation with [103Pd]PdH2Cl4 (RCY = 99%) and mixed with LOIB:EtOH. [103Pd]Pd-SSIB was likewise formulated as injectable liquid forming seeds by mixing with LOIB. Both formulations reached activities of 1.0–1.5 GBq/mL and negligible release of radioactivity after injection of 100 µL (100–150 MBq) into aqueous buffer or mouse serum of less than 1% over one month. Both strategies for forming injectable BT seeds containing high 103Pd activity resulted in high radiolabeling yields, high activity per seed, and high activity retention. We consider both strategies suitable for BT, with the preferable strategy using a [16]aneS4 chelator due to its higher biodegradability.

Controlled bottom-up synthesis of amorphous coordination polymers with tailored metal coordination is a research field in its infancy. In this study, synthesis control was achieved to selectively prepare one-dimensional (1D) crystalline and amorphous zinc(II)-based coordination polymers and a dimeric molecular compound, all with similar coordination geometry as evidenced by X-ray diffraction and total scattering studies. The compounds were obtained by bottom up self-assembly of Zn(II) with terephthalate (tph²⁻) as linker and the enantiopure chelating ligand S-(1,2)-bis(1H-benzimidazol-2-yl)ethanol (L). The solvent and the coordination ability of the precursor zinc salt anion control the crystalline products formed by slow diffusion at room temperature: perchlorate allows isolation of the phase pure crystalline 1D polymer {[Zn(tph)(L)]·H₂O·3DMF}_n (1·H₂O·3DMF, DMF = N,N-dimethylformamide). In contrast, zinc chloride leads to the formation of either a mixture of polymeric 1·H₂O·3DMF and a dimeric molecular species [Zn₂Cl₂(tph)(L)₂]·4DMF (2·4DMF), or to the phase pure dimer 2·4DMF, depending on the Zn(II) : tphH₂ stoichiometry. A modified synthesis using zinc nitrate and fast precipitation by base addition results in an amorphous analogue of the 1D polymer (3). Chains of 1·H₂O·3DMF pack into a non-porous crystalline material with a surface area of just 6 m² g⁻¹, while the outer surface area of amorphous polymer 3 is a factor of eight larger. Hence, the amorphous compound provides larger metal site accessibility for potential surface chemical reactions, while maintaining the coordination geometry of the metal sites. The temperature response of crystalline polymer 1·H₂O·3DMF was studied using multi-temperature single crystal X-ray diffraction (100–300 K). The a = b axes display normal positive thermal expansion, while the c axis remains constant with increasing temperature due to partial relaxation of the terephthalate linkers and slightly changed geometry within the individual polymer chains.

1,2‐Bis(benzimidazol‐2‐yl)ethanol (1) and its bis‐N‐methylated derivative (2) act as chiral tridentate facially coordinating ligands capable of binding metals right across the d‐series. Octahedral complexes of divalent and trivalent metal ions are synthesised and characterised by X‐ray crystallography. Only two of the three possible diastereomers are observed in complexes of the type [M(1,2)₂] and appear to be close in energy. In complexes of M^II ions, the alcohol function of the ligand stays protonated, but the proton is lost in complexes of M^III ions. Electronic and CD spectra are reported. Slow oxidation of the vanadium(III) complex leads to a mixed valence compound where one ligand has been oxidised.

The methylene group of the ligand 1,2-di(pyridin-2-yl)-ethanone oxime (dpeo) is slowly oxygenated by the O₂ in air under ambient conditions when [Cu(dpeo)₂](ClO₄)₂ is dissolved in ethanol or acetonitrile. An initial transient ketone product, 2-(hydroxyimino)-1,2-di(pyridine-2-yl)ethanone, (hidpe) was characterized in the heteroleptic copper(II) complex [Cu(bpca)(hidpe)](ClO₄). The co-ligand in this complex, N-(2′-pyridylcarbonyl)pyridine-2-carboximidate (bpca⁻), is derived from a copper-promoted Beckmann rearrangement of hidpe. In the presence of bromide only [Cu(bpca)Br] is isolated. When significant water is present in reaction mixtures copper complexes of dpeo, hidpe and bpca⁻ are not recovered and [Cu(pic)₂H₂O] is isolated. This occurs since two equivalents of picolinate are ultimately generated from one equivalent of oxidized and hydrolysed dpeo. The copper-dependent O₂ activation and consequent stoichiometric dpeo C–H oxidation is reminiscent of the previously observed catalysis of dpeo oxidation by Mn(II) [C. Deville, S. K. Padamati, J. Sundberg, V. McKee, W. R. Browne, C. J. McKenzie, Angew. Chem., Int. Ed., 2016, 55, 545–549]. By contrast dpeo oxidation is not observed during complexation reactions with other late transition metal(II) ions (M = Fe, Co, Ni, Zn) under aerobic conditions. In these cases bis and tris complexes of bidentate dpeo are isolated in good yields. It is interesting to note that dpeo is not oxidised by H₂O₂ in the absence of Cu or Mn, suggesting that metal-based oxidants capable of C–H activation are produced from the dpeo-Cu/Mn systems and specifically O₂. The metastable copper complexes [Cu(dpeo)₂](ClO₄)₂ and [Cu(bpca)(hidpe)](ClO₄), along with [NiX₂(dpeo)₂] (X = Cl, Br), [Ni(dpeo)₃](ClO₄)₂, [Co(dpeo)₃](ClO₄)₃ and the mixed valence complex [Fe^IIIFe^II ₂(dpeo-H)₃(dpeo)₃](PF₆)₄, have been structurally characterized.

A Mn^II complex, [Mn(dpeo)₂]²⁺ (dpeo=1,2‐di(pyridin‐2‐yl)ethanone oxime), activates O₂, with ensuing stepwise oxidation of the methylene group in the ligands providing an alkoxide and ultimately a ketone group. X‐ray crystal‐structure analysis of an intermediate homoleptic alkoxide Mn^III complex shows tridentate binding of the ligand via the two pyridyl groups and the newly installed alkoxide moiety, with the oxime group no longer coordinated. The structure of a Mn^II complex of the final ketone ligand, cis‐[MnBr₂(hidpe)₂] (hidpe=2‐(hydroxyimino)‐1,2‐di(pyridine‐2‐yl)ethanone) shows that bidentate oxime/pyridine coordination has been resumed. H₂¹⁸O and ¹⁸O₂ labeling experiments suggest that the inserted O atoms originate from two different O₂ molecules. The progress of the oxygenation was monitored through changes in the resonance‐enhanced Raman bands of the oxime unit.