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      Comparative Study with 89Y-foil and 89Y-pressed Targets for the Production of 89Zr †

      , ,
      Applied Sciences
      MDPI AG

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          Abstract

          Zirconium-89 (89Zr, t1/2 = 3.27 days) owns great potential in nuclear medicine, being extensively used in the labelling of antibodies and nanoparticules. 89Zr can be produced by cyclotron via an 89Y(p,n)89Zr reaction while using an 89Y-foil target. In this study, we investigated for the first time the use of 89Y-pressed target for the preparation of 89Zr-oxalate via a (p,n) reaction. We performed comparative studies with an 89Y-foil target mounted on custom-made target supports. A new automated cassette-based purification module was used to facilitate the purification and the fractionation of 89Zr-oxalate. The effective molar activity (EMA) was calculated for both approaches via titration with deferoxamine (DFO). The radionuclidic purity was determined by gamma-ray spectroscopy and the metal impurities were quantified by ICP-MS on the resulting 89Zr-oxalate solution. The cassette-based purification process leading to fractionation is simple, efficient, and provides very high EMA of 89Zr-oxalate. The total recovered activity was 81 ± 4% for both approaches. The highest EMA was found at 13.3 MeV and 25 μA for 0.25-mm thick 89Y-foil. Similar and optimal production yields were obtained at 15 MeV and 40 μA while using 0.50-mm thick 89Y-foil and pressed targets. Metallic impurities concentration was below the general limit of 10 ppm for heavy metals in the US and Ph.Eur for both 89Y-foil and pressed targets. Overall, these results show that the irradiation of 89Y-pressed targets is a very effective process, offering an alternative method for 89Zr production.

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          Standardized methods for the production of high specific-activity zirconium-89.

          Zirconium-89 is an attractive metallo-radionuclide for use in immuno-PET due to favorable decay characteristics. Standardized methods for the routine production and isolation of high-purity and high-specific-activity (89)Zr using a small cyclotron are reported. Optimized cyclotron conditions reveal high average yields of 1.52+/-0.11 mCi/muA.h at a proton beam energy of 15 MeV and current of 15 muA using a solid, commercially available (89)Y-foil target (0.1 mm, 100% natural abundance). (89)Zr was isolated in high radionuclidic and radiochemical purity (>99.99%) as [(89)Zr]Zr-oxalate by using a solid-phase hydroxamate resin with >99.5% recovery of the radioactivity. The effective specific-activity of (89)Zr was found to be in the range 5.28-13.43 mCi/microg (470-1195 Ci/mmol) of zirconium. New methods for the facile production of [(89)Zr]Zr-chloride are reported. Radiolabeling studies using the trihydroxamate ligand desferrioxamine B (DFO) gave 100% radiochemical yields in 7 days. Small-animal positron emission tomography (PET) imaging studies have demonstrated that free (89)Zr(IV) ions administered as [(89)Zr]Zr-chloride accumulate in the liver, whilst [(89)Zr]Zr-DFO is excreted rapidly via the kidneys within <20 min. These results have important implication for the analysis of immuno-PET imaging of (89)Zr-labeled monoclonal antibodies. The detailed methods described can be easily translated to other radiochemistry facilities and will facilitate the use of (89)Zr in both basic science and clinical investigations.
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            Radiation dosimetry of 89Zr-labeled chimeric monoclonal antibody U36 as used for immuno-PET in head and neck cancer patients.

            Immuno-PET is an appealing concept in the detection of tumors and planning of antibody-based therapy. For this purpose, the long-lived positron emitter (89)Zr (half-life, 78.4 h) recently became available. The aim of the present first-in-humans (89)Zr immuno-PET study was to assess safety, biodistribution, radiation dose, and quantification of the (89)Zr-labeled chimeric monoclonal antibody (cmAb) U36 in patients with head and neck squamous cell carcinoma (HNSCC). In addition, the performance of immuno-PET for detecting lymph node metastases was evaluated, as described previously. Twenty HNSCC patients, scheduled to undergo surgical tumor resection, received 75 MBq of (89)Zr-cmAb U36 (10 mg). Immuno-PET scans were acquired at 1, 24, 72, or 144 h after injection. The biodistribution of the radioimmunoconjugate was evaluated by ex vivo radioactivity measurement in blood and in biopsies from the surgical specimen obtained at 168 h after injection. Uptake levels and residence times in blood, tumors, and organs of interest were derived from quantitative immuno-PET studies, and absorbed doses were calculated using OLINDA/EXM 1.0. The red marrow dose was calculated using the residence time for blood. (89)Zr-cmAb U36 was well tolerated by all subjects. PET quantification of blood-pool activity in the left ventricle of the heart showed a good agreement with sampled blood activity (difference equals 0.2% +/- 16.9% [mean +/- SD]) except for heavy-weight patients (>100 kg). A good agreement was also found for the assessment of mAb uptake in primary tumors (mean deviation, -8.4% +/- 34.5%). The mean absorbed red marrow dose was 0.07 +/- 0.02 mSv/MBq and 0.09 +/- 0.01 mSv/MBq in men and women, respectively. The normal organ with the highest absorbed dose was the liver (mean dose, 1.25 +/- 0.27 mSv/MBq in men and 1.35 +/- 0.21 mSv/MBq in women), thereafter followed by kidneys, thyroid, lungs, and spleen. The mean effective dose was 0.53 +/- 0.03 mSv/MBq in men and 0.66 +/- 0.03 mSv/MBq in women. Measured excretion via the urinary tract was less than 3% during the first 72 h. (89)Zr immuno-PET can be safely used to quantitatively assess biodistribution, uptake, organ residence times, and radiation dose, justifying its further clinical exploitation in the detection of tumors and planning of mAb-based therapy.
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              PET tracers based on Zirconium-89.

              Positron emission tomography (PET) imaging with radiolabeled monoclonal antibodies has always been a dynamic area in molecular imaging. With decay half-life (3.3 d) well matched to the circulation half-lives of antibodies (usually on the order of days), (89)Zr has been extensively studied over the last decade. This review article will give a brief overview on (89)Zr isotope production, the radiochemistry generally used for (89)Zr-labeling, and the PET tracers that have been developed using (89)Zr. To date, (89)Zr-based PET imaging has been investigated for a wide variety of cancer-related targets, which include human epidermal growth factor receptor 2, epidermal growth factor receptor, prostate-specific membrane antigen, splice variant v6 of CD44, vascular endothelial growth factor, carbonic anhydrase IX, insulin-like growth factor 1 receptor, among others. With well-developed radiochemistry, commercial availability of chelating agents for (89)Zr labeling, increasingly widely available isotope supply, as well as successful proof-of-principle in pilot human studies, it is expected that PET imaging with (89)Zr-based tracers will be a constantly evolving and highly vibrant field in the near future.
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                Author and article information

                Journal
                ASPCC7
                Applied Sciences
                Applied Sciences
                MDPI AG
                2076-3417
                September 2018
                September 07 2018
                : 8
                : 9
                : 1579
                Article
                10.3390/app8091579
                2dc2611b-cebb-4508-9ab3-5ff1e59c8f0a
                © 2018

                https://creativecommons.org/licenses/by/4.0/

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