Despite promising anti-cancer properties in vitro, all titanium-based pharmaceuticals have failed in vivo. Likewise, no target-specific positron emission tomography (PET) tracer based on the radionuclide ⁴⁵Ti has been developed, notwithstanding its excellent PET imaging properties. In this contribution, we present liquid–liquid extraction (LLE) in flow-based recovery and the purification of ⁴⁵Ti, computer-aided design, and the synthesis of a salan-^natTi/⁴⁵Ti-chelidamic acid (CA)-prostate-specific membrane antigen (PSMA) ligand containing the Glu-urea-Lys pharmacophore. The compound showed compromised serum stability, however, no visible PET signal from the PC3+ tumor was seen, while the ex vivo biodistribution measured the tumor accumulation at 1.1% ID/g. The in vivo instability was rationalized in terms of competitive citrate binding followed by Fe(III) transchelation. The strategy to improve the in vivo stability by implementing a unimolecular ligand design is presented.

Lanthanum-135 (¹³⁵La) is a favorable Auger electron emitter with a high Auger electron yield and low gamma emission, making it promising for Auger electron radiotherapy. However, successful application requires reliable and scalable ¹³⁵La production. Up to now, metallic natural barium (^natBa) is a commonly used target material, but this material is sensitive to moisture and oxidation. BaCO₃ has also been tested, due to its higher chemical stability. However, BaCO₃ has poor thermal conductivity, limiting the applicable current and making high yield production challenging. In this study, we pressed a mixture of enriched [¹³⁵Ba]BaCO₃ and fine aluminum (Al) powder to provide a stable target with improved thermal conductivity compared to pure BaCO₃. After 4 h of irradiation with a 16.5 MeV proton beam at 20 μA current, 1.62 ± 0.18 GBq was produced from a 200 mg [¹³⁵Ba]BaCO₃:Al (1:2, w/w) target. This corresponded to a saturation yield of 11.91 ± 1.31 GBq (or 596 ± 66 MBq/μA). A purification procedure involving initial precipitation, followed by a single composite column containing a layer of TK200 resin and a second layer of branched DGA resin was developed, with 97.1 ± 3.6 % decay corrected ¹³⁵La recovery. [¹³⁵La]LaCl₃ was obtained in an effective molar activity of 79.6 ± 25.3 MBq/nmol (DOTA titration), 104.0 ± 40.4 MBq/nmol (DTPA titration) and 186.5 ± 83.8 MBq/nmol (CHX-A″-DTPA titration), and a radionuclidic purity (RNP) of >99.9 % at end of purification, hereby demonstrating a purity suitable for radiopharmaceutical use.

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.

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.