The high in vivo stability of 2,2-dihydroxymethyl-3-[ 18 F]fluoropropyl-2-nitroimidazole ([ 18 F]DiFA) prompted us to evaluate neopentyl as a scaffold to prepare a radiotheranostic system with radioiodine and astatine. Three DiFA analogues with one, two, or without a hydroxyl group were synthesized. While all 125 I-labeled compounds remained stable against nucleophilic substitution, only a 125 I-labeled neopentyl glycol was stable against cytochrome P450 (CYP)-mediated metabolism and showed high stability against in vivo deiodination. 211 At-labeled neopentyl glycol also remained stable against both nucleophilic substitution and CYP-mediated metabolism. 211 At-labeled neopentyl glycol showed the biodistribution profiles similar to those of its radioiodinated counterpart in contrast to the 125 I/ 211 At-labeled benzoate pair. The urine analyses confirmed that 211 Atlabeled neopentyl glycol was excreted in the urine as a glucuronide conjugate with the absence of free [ 211 At]At − . These findings indicate that neopentyl glycol would constitute a promising scaffold to prepare a radiotheranostic system with radioiodine and 211 At.

Copper-64 ( 64 Cu)-labeled antibody fragments such as Fab are useful for molecular imaging (immuno-PET) and radioimmunotherapy. However, these fragments cause high and persistent localization of radioactivity in the kidneys after injection. To solve this problem, this study assessed the applicability of a molecular design to 64 Cu, which reduces renal radioactivity levels by liberating a urinary excretory radiometabolite from antibody fragments at the renal brush border membrane (BBM). Since 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) forms a stable complex with Cu, NOTA-conjugated Met-Val-Lys-maleimide (NOTA-MVK-Mal), which is a radio-gallium labeling agent for antibody fragments, was evaluated for applicability to 64 Cu. The MVK linkage was recognized by the BBM enzymes to liberate [ 64 Cu]Cu-NOTA-Met although the recognition of the MVK sequence for the [ 64 Cu]Cu-NOTA-MVK derivative was reduced compared with that of its [ 67 Ga]Ga-counterpart, probably due to the difference in the charge of the metal-NOTA complexes. When injected into mice, [ 64 Cu]Cu-NOTA-MVK-Fab resulted in similar renal radioactivity levels to the 67 Ga-labeled counterpart. In addition, [ 64 Cu]Cu-NOTA-MVK-Fab resulted in lower renal radioactivity levels than those from 64 Cu-labeled Fab using a conventional method, without a reduction in the tumor radioactivity levels. These findings indicate that our approach to reducing renal radioactivity levels by liberating a radiolabeled compound from antibody fragments at the renal BBM for urinary excretion is applicable to 64 Cu-labeled antibody fragments and useful for immuno-PET and radioimmunotherapy.

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DNA damage in the irradiated cells. The present investigation was carried out to evaluate the radiobiological effect of 223 Ra in 3 different prostate cell models (PC-3, U-2OS metastatic lines, and normal RWPE) by assays of clonogenic survival and DNA damage. Clonogenic cell survival curves were analyzed for different cell lines after irradiation with 225 kVp X-rays from 0 to 8 Gy (dose rate 0.594 Gy/ min), external a-particles (241 Americium) from 0 to 2 Gy (dose rate 1.579 Gy/ min) and 223 Ra from 0 to 0.5 Gy (dose rate 1.389 mGy/min). The results showed a superior efficacy of 223 Ra in comparison with the external a source in all cell lines but with a cell type dependency. The Relative Biological Effectiveness (RBE) for 50% survival for RWPE is 6.07 and 7.97, for external aparticles and 223 Ra respectively. For U-2OS is 6.36 and 8.9 and finally for PC-3 the values are 3.63 and 7.47. Lastly, the induction and repair of DNA damage by different radiation qualities was analyzed by immunofluorescence (53BP1) for doses up to 2 Gy and recovery times of 1, 4, 24 and 96h. For all irradiation setups there is a linear relationship between the number of foci and the absorbed dose. The level of induction and the shape of the kinetics curves are radiation-and cell-specific with the highest induction of foci observed after X-ray irradiation, the lowest after external a irradiation, and 223 Ra being slightly higher than external a particles. In terms of repair, foci induced by external a source or 223 Ra are repaired approximately 3.5 times slower than the X-ray induced breaks in the same cell line. These observations support the higher propensity for complex DNA-damage induced by heavy particles as reported in the literature. Interestingly, exposure to 223 Ra severely affects the nuclear structure with a significant number of giant nuclei, and a large fraction of cells undergoing mitotic catastrophe, features not seem to the same extent with external beam irradiation. In conclusion, our results suggest that response to Radium-223 is cell-specific and that better effectiveness does not solely depend on the DNA damage complexity. Reference:

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