Accelerator-Based Production of Scandium Radioisotopes for Applications in Prostate Cancer: Toward Building a Pipeline for Rapid Development of Novel Theranostics.

In the field of nuclear medicine, the ß+ -emitting 43Sc and ß- -emitting 47Sc are promising candidates in cancer diagnosis and targeted radionuclide therapy (TRT) due to their favorable decay schema and shared pharmacokinetics as a true theranostic pair. Additionally, scandium is a group-3 transition metal (like 177Lu) and exhibits affinity for DOTA-based chelators, which have been studied in depth, making the barrier to implementation lower for 43/47Sc than for other proposed true theranostics. Before 43/47Sc can see widespread pre-clinical evaluation, however, an accessible production methodology must be established and each isotope's radiolabeling and animal imaging capabilities studied with a widely utilized tracer. As such, a simple means of converting an 18 MeV biomedical cyclotron to support solid targets and produce 43Sc via the 42Ca(d,n)43Sc reaction has been devised, exhibiting reasonable yields. The NatTi(γ,p)47Sc reaction is also investigated along with the successful implementation of chemical separation and purification methods for 43/47Sc. The conjugation of 43/47Sc with PSMA-617 at specific activities of up to 8.94 MBq/nmol and the subsequent imaging of LNCaP-ENZaR tumor xenografts in mouse models with both 43/47Sc-PSMA-617 are also presented.

Preclinical Evaluation of Novel 64Cu-Labeled Gastrin-Releasing Peptide Receptor Bioconjugates for PET Imaging of Prostate Cancer.

We report herein the preclinical evaluation of new [64Cu]Cu-gastrin-releasing peptide receptor (GRPR)-targeting tracers, employing the potent peptide antagonist DPhe-Gln-Trp-Ala-VaI-Gly-His-Sta-Leu-NH2 conjugated to NOTA (in 1) or NODAGA (in 2) chelators via a 6-aminohexanoic acid linker. The Cu-1/2 metalated peptides were synthesized by reacting 1/2 with CuCl2 and were characterized by LC-ESI-MS and HR-ESI-MS. Cu-1/2 exhibited high GRPR-binding affinities with IC50 values <3 nM, as measured in a competition assay using the GRPR-expressing human PC-3 prostate cancer cell line and [125I]I-Tyr4-BBN as the competing ligand. Tracers [64Cu]Cu-1/2 were prepared in quantitative radiochemical yield (by radio-HPLC), and their identities were confirmed by coelution with their Cu-1/2 standards via comparative HPLC studies. Lipophilicity was measured in 1-octanol/PBS (pH 7.4), and the negative log D7.4 values (≤-1) confirmed the anticipated hydrophilic character for [64Cu]Cu-1/2. Both tracers demonstrated excellent in vitro stability, with ≥98% remaining intact through 24 h at physiological conditions (PBS, pH 7.4, 37 °C). Biodistribution in PC-3 tumor-bearing mice demonstrated good tumor uptake (%ID/g at 4 h: 4.34 ± 0.71 for [64Cu]Cu-1, 3.92 ± 1.03 for [64Cu]Cu-2) and rapid renal clearance (≥87% ID at 4 h). Tumor uptake was receptor-mediated, as verified by parallel GRPR-blocking studies. Small-animal PET/CT imaging studies validated the biodistribution data. These preclinical data support that the [64Cu]Cu-1/2 tracers show promise for further development as diagnostic PET imaging agents of GRPR-expressing tumors.

Photonuclear production of 47Ca for 47Ca/47Sc generator from natural CaCO3 targets.

This work investigated the indirect production of 47Sc from natural Ca targets via 48Ca(γ,n)47Ca→47Sc + ß- + ν‾e with incident electron energies of 30, 35, and 40 MeV. The 47Ca production yields were simulated using the PHITS Monte Carlo simulation code and compared to experimental data. The simulated production rates for all three irradiations are in good agreement with experimental data within uncertainties. As a demonstration of the 47Ca/47Sc generator system, one of the irradiated CaCO3 targets was dissolved in nitric acid, and 47Sc was isolated from the target material using commercially available Eichrom DGA resin. The 47Sc was allowed to grow in, and the purification process was repeated with promising 47Sc and Ca recovery yields.

Production and purification of 43Sc and 47Sc from enriched [46Ti]TiO2 and [50Ti]TiO2 targets.

The radioscandium isotopes, 43Sc and 47Sc, compose a promising elementally matched theranostic pair that can be used for the development of imaging and therapeutic radiopharmaceuticals with identical structures. This study aimed to investigate the production of high radionuclidic purity 43Sc from enriched [46Ti]TiO2 targets and 47Sc from enriched [50Ti]TiO2 targets and establish a target recycling technique. Enriched [46Ti]TiO2 targets were irradiated with 18 MeV protons, and enriched [50Ti]TiO2 targets were bombarded with 24 MeV protons. 43Sc and 47Sc were purified using ion chromatography attaining recovery yields of 91.7 ± 7.4% and 89.9 ± 3.9%, respectively. The average radionuclidic purity for 43Sc was 98.8 ± 0.3% and for 47Sc 91.5 ± 0.6%, while the average recovery of enriched titanium target material was 96 ± 4.0%. The highest apparent molar activity for [43Sc]Sc-DOTA was 23.2 GBq/µmol and 3.39 GBq/µmol for [47Sc]Sc-DOTA. This work demonstrates the feasibility of using enriched recycled [46Ti]TiO2 and [50Ti]TiO2 targets to produce high purity 43Sc and 47Sc as an elementally matched theranostic isotope pair.

Efficient electro/photocatalytic water reduction using a [NiII(N2Py3)]2+ complex.

The pyridine-rich complex [NiII(LN2Py3)(MeCN)](ClO4)2 (1) acts as an efficient electro- and photocatalyst in the generation of H2 from water. Observed TONs reach 1050 for electrocatalysis and a remarkable 3500 for photocatalysis. Experimental and DFT data support the ligand-reduced [NiIL˙] as the catalytically active species, contrasting with the [CoIL] observed for cobalt catalysts.