Cyclotron Production of PET Radiometals in Liquid Targets: Aspects and Prospects.

The present review describes the methodological aspects and prospects of the production of Positron Emission Tomography (PET) radiometals in a liquid target using low-medium energy medical cyclotrons. The main objective of this review is to delineate and discuss the critical factors involved in the liquid target production of radiometals, including type of salt solution, solution composition, beam energy, beam current, the effect of irradiation duration (length of irradiation) and challenges posed by in-target chemistry in relation with irradiation parameters. We also summarize the optimal parameters for the production of various radiometals in liquid targets. Additionally, we discuss the future prospects of PET radiometals production in the liquid targets for academic research and clinical applications. Significant emphasis has been given to the production of 68Ga using liquid targets due to the growing demand for 68Ga labeled PSMA vectors, [68Ga]- Ga-DOTATATE, [68Ga]Ga-DOTANOC and some upcoming 68Ga labeled radiopharmaceuticals. Other PET radiometals included in the discussion are 86Y, 63Zn and 89Zr.

Zinc and copper complexes with azacrown ethers and their comparative stability in vitro and in vivo.

Copper-based radiopharmaceuticals are of high interest these days owing to the decay properties of copper radioisotopes. In contrast, labeled zinc compounds have been less studied for applications in nuclear medicine. In this study, the stability of labeled zinc and copper complexes with two azacrown ether ligands was investigated and compared. Then, the in vitro and in vivo stability of the studied zinc complexes was demonstrated, with the complexes showing promise for biomedical applications. In contrast, analogous copper complexes quickly dissociated in the presence of serum proteins. Furthermore, a simple method for the production of radiochemically pure 65Zn was proposed, and the opportunity for its use as a surrogate radionuclide for research into potential zinc-containing radiopharmaceuticals was demonstrated.

Green solid synthesis of polyaniline-silver oxide nanocomposite for the adsorptive removal of ionic divalent species of Zn/Co and their radioactive isotopes 65Zn/ 60Co.

A comparative study between two nanosorbents, nanopolyaniline (NPANI) and nanopolyaniline coated with nanosilver oxide (NPANI-NAg2O) is explored to dispose the divalent species of Zn/Co from water and radioactive isotopes 65Zn/60Co from radioactive wastewater using batch and column techniques. NPANI-NAg2O nanocomposite was synthesized via solid-solid reaction. Characterization was achieved using FT-IR, TGA, XRD, SEM, HR-TEM, and surface area analysis. The images of SEM and HR-TEM confirmed the success of the modification process and the particle size was found in the range 28.78-68.28 nm (NPANI) and 25.74-85.71 nm (NPANI-NAg2O), respectively. Solution pH, contact time, solid dosage, and ionic concentration of the metals were studied as fundamental factors. The obtained results indicated that the optimum conditions to dispose Zn/Co divalent species using NPANI were pH 7 and 30-33 min, while NPANI-NAg2O exhibited the optimum conditions at pH 7 and 20-30 min. The maximum removal capacities were 100.1 and 139.75 mg/g for Zn(II) and 57.93 and 112.1 mg/g for Co(II) using NPANI and NPANI-NAg2O, respectively. Graphical abstract ᅟ.

Comparing single-feeding and multi-feeding approaches for experimentally assessing trophic transfer of metals in fish.

Diet is an important pathway for metal uptake in marine organisms, and assimilation efficiency is one of the most relevant parameters to quantify trophic transfer of metals along aquatic food webs. The most commonly used method to estimate this parameter is pulse-chase feeding using radiolabeled food. This approach is, however, based on several assumptions that are not always tested in an experimental context. The present study aimed to validate the approach by assessing single-feeding and multiple-feeding approaches, using a model species (the turbot Scophthalmus maximus). Using the kinetic data obtained from the single-feeding experiment, the reconstruction of a multi-feeding experiment was tested for consistency with data provided by an actual multi-feeding performed under the same experimental conditions. The results validated the single-feeding approach. Environ Toxicol Chem 2017;36:1227-1234. © 2016 SETAC.

First PET Imaging Studies With 63Zn-Zinc Citrate in Healthy Human Participants and Patients With Alzheimer Disease.

Abnormalities in zinc homeostasis are indicated in many human diseases, including Alzheimer disease (AD). 63Zn-zinc citrate was developed as a positron emission tomography (PET) imaging probe of zinc transport and used in a first-in-human study in 6 healthy elderly individuals and 6 patients with clinically confirmed AD. Dynamic PET imaging of the brain was performed for 30 minutes following intravenous administration of 63Zn-zinc citrate (∼330 MBq). Subsequently, body PET images were acquired. Urine and venous blood were analyzed to give information on urinary excretion and pharmacokinetics. Regional cerebral 63Zn clearances were compared with 11C-Pittsburgh Compound B (11C-PiB) and 18F-fluorodeoxyglucose (18F-FDG) imaging data. 63Zn-zinc citrate was well tolerated in human participants with no adverse events monitored. Tissues of highest uptake were liver, pancreas, and kidney, with moderate uptake being seen in intestines, prostate (in males), thyroid, spleen, stomach, pituitary, and salivary glands. Moderate brain uptake was observed, and regional dependencies were observed in 63Zn clearance kinetics in relationship with regions of high amyloid-ß plaque burden (11C-PiB) and 18F-FDG hypometabolism. In conclusion, zinc transport was successfully imaged in human participants using the PET probe 63Zn-zinc citrate. Primary sites of uptake in the digestive system accent the role of zinc in gastrointestinal function. Preliminary information on zinc kinetics in patients with AD evidenced regional differences in clearance rates in correspondence with regional amyloid-ß pathology, warranting further imaging studies of zinc homeostasis in patients with AD.

Synthesis, characterization and in vivo evaluation of [(62)Zn]-benzo-δ-sultam complex as a possible pet imaging agent.

OBJECTIVE: The development of a new tracer based on the cyclic sulfonamides (sultams) was investigated. METHODS: 3-(Methoxy-phenyl-methyl)-1,6-dimethyl-1H benzo[c][1,2] thiazine 2,2-dioxide (benzo-δ-sultam) was synthesized and characterized by elemental analysis, FT-IR spectroscopy and single crystal X-ray structure determination. The prepared cyclic sulfonamide was labeled with non-commercial (62)Zn radioisotope for fast in vivo targeting and Coincidence imaging purposes (radiochemical purity 97 % ITLC, 96 % HPLC, specific activity 20-23 GBq/mmol). In vivo biodistribution of the final complex was investigated in Sprague Dawley(®) rats bearing fibro sarcoma tumor after 2, 4 and 8 h post injection and compared with free Zn(+2) cation. RESULTS: Using instant paper chromatography method, the physicochemical properties of labeled compounds were found sufficiently stable in organic phases, e.g. a human serum, to be reliably used in bioapplications. CONCLUSIONS: The complex exhibited a rapid as well as high tumor uptake (tumor to blood ratio 4.38 and tumor to muscle ratio 9.63) resulting in an efficient tumor targeting agent.

Performance of a 6²Zn/6²Cu microgenerator in kit-based synthesis and delivery of [6²Cu]Cu-ETS for PET perfusion imaging.

The performance of a commercially produced (62)Zn/(62)Cu microgenerator system, and an associated kit-based radiopharmaceutical synthesis method, was evaluated for clinical site production of [(62)Cu]Cu-ETS (ethylglyoxal bis(thiosemicarbazonato)copper(II)), an investigational agent for PET perfusion imaging. Using 37 generators, containing 1.84±0.23 GBq (62)Zn at 9:00 AM on the day of clinical use, a total of 45 patient doses of [(62)Cu]Cu-ETS (672±172 MBq) were delivered without difficulty. (62)Cu elution yields were high (approximately 90%), accompanied by extremely low (62)Zn breakthrough (<0.001%). Radiopharmaceutical preparation, from the start-of-elution to time-of-injection, consumed less than five minutes. The (62)Zn/(62)Cu microgenerator was a dependable source of short-lived positron-emitting (62)Cu, and the kit-based synthesis proved to be rapid, robust, and highly reliable for "on-demand" delivery of [(62)Cu]Cu-ETS for PET perfusion imaging.

Selective accumulation of [6²Zn]-labeled glycoconjugated porphyrins as multi-functional positron emission tomography tracers in cancer cells.

Positron-emission tomography (PET) can be used to visualize active stage cancer. Fluorine-18 ([(18)F])-labeled 2-([(18)F])2-deoxy-2-fluoroglucose (([(18)F])-FDG), which accumulates in glucose-dependent tissues, is a good cancer-targeting tracer. However, ([(18)F])-FDG is obscured in glucose-dependent normal tissues. In this study, we assessed the cancer-selective accumulation of zinc-labeled glycoconjugated 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin (ZnGlc1-4), both in vitro and in vivo. Experiments using both normal and cancer cells confirmed the relationship between cancer cell-selective accumulation and the substitution numbers and orientations of glycoconjugated porphyrins. ZnGlctrans-2 accumulated at greater levels in cancer cells compared with other glycoconjugated porphyrins. PET imaging showed that ZnGlctrans-2 accumulated in tumor.

Evaluation of in vivo detection properties of 22Na, 65Zn, 86Rb, 109Cd and 137Cs in plant tissues using real-time radioisotope imaging system.

In plant research, radioisotope imaging provides useful information about physiological activities in various tissues and elemental transport between plant organs. To expand the usage of imaging techniques, a new system was developed to visualize beta particles, x-rays and gamma-rays emitted from plant bodies. This real-time radioisotope imaging system (RRIS) visualizes radioactivity after conversion into light with a CsI(Tl) scintillator plate. Herein, the RRIS detection properties of the gamma-ray emitters (22)Na, (65)Zn, (86)Rb, (109)Cd and (137)Cs were evaluated in comparison with those of radioluminography (RLG) using an imaging plate. The lower quantitative detection limit (Bq mm(-2)) during a 15 min period ranged from 0.1 to 4, depending on the nuclide, similar to that of RLG. When the quantitative ability to detect radiation from various Arabidopsis tissues was analyzed, the quantitative capability in silique and the thick internode tended to be low. In an EGS5 simulation, beta particles were the greatest contributors to RRIS imaging of (22)Na, (86)Rb and (137)Cs, and low-energy x-rays contributed significantly to (65)Zn and (109)Cd detection. Thus, both self-absorption and air space between the sample and scintillator surface could impair quantitative RRIS imaging. Despite these issues, RRIS is suggested for quantitative time-course measurements of radionuclide motion within plants.

Use of 65Zn as a tracer for the assessment of purification in the 68Ga-DOTANOC synthesis.

In the last years (68)Ga has got into the focus of researchers and clinicians especially for radio-labeling of biomolecules; an important characteristic of this positron emitting isotope is its availability via the (68)Ge/(68)Ga generator system: the long-lived (68)Ge (t1/2=270.8 d) produces the short-lived (68)Ga (t1/2=67.63 min) which decays to stable (68)Zn. (68)Ge breakthrough compromises (68)Ga radionuclidic purity, while (68)Zn might affect the specific activity of the radiopharmaceutical. In this paper we investigated the weight of these impurities in (68)Ga-DOTANOC synthesis. (65)Zn (t1/2=244.26d; decay mode: EC 98.3%, ß(+) 1.7%) was used as a radiotracer of stable (68)Zn; samples of the purification columns, wastes and product were recovered and measured with a calibrated HPGe gamma-ray spectrometry system. The results showed that (68)Zn competes with (68)Ga in labeling DOTANOC with a (95±2)% labeling yield; they also proved the effectiveness of the STRATA X-C cationic post-processing of the generator eluate in lowering the amount of this impurity to less than 1%. Moreover this approach, along with the purification of the final product through a STRATA X cartridge, effectively removes (68)Ge breakthrough providing a (68)Ga-DOTANOC radionuclidic purity of (99.9999986±0.0000006)%, superior to 99.9% required by the Pharmacopoeia Monograph on (68)Ga Edotreotide injection.

The consistency of the data for neutron fission averaged cross-sections of threshold reactions: a study on the cross-section of 46Ti(n,p)46Sc, 47Ti(n,p)47Sc, 48Ti(n,p)48Sc and 64Zn(n,p)64Cu reactions.

The consistency of the published values for fission averaged cross-sections of threshold reactions induced in a nuclear reactor is analyzed. The influence of the literature data involved in the determination of these cross-sections is discussed. Renormalizations based on cross-sections value for the standard reactions, isotopic abundances of the precursors and radiation emission probabilities of the radionuclide under study and the monitor, are applied to the evaluation of the cross-sections for the reactions: (46)Ti(n,p)(46)Sc; (47)Ti(n,p)(47)Sc; (48)Ti(n,p)(48)Sc; and (64)Zn(n,p)(64)Cu.

Effective production of 65Zn with a PET cyclotron.

Cyclotrons dedicated to the production of PET radiopharmaceuticals for clinical use can be a resource also for research in other fields of science. In the present study we assessed the feasibility of (65)Zn production via the (65)Cu(p,n)(65)Zn reaction using a 16.5 MeV GE-PETtrace biomedical cyclotron. The radioisotope (65)Zn (t(1/2)=244.26 zd; decay mode: EC 98.3%, ß(+) 1.7%) has a wide range of applications, especially in botany and agriculture; its long half life allows storage and delivery to research centers without a cyclotron on site. Natural copper foils (thickness: 100 µm; purity: >99.9%) were irradiated in a solid target station developed in our institution. The EXFOR and IAEA cross sections databases were carefully studied to optimize the irradiation setup in order to maximize the yield of the radionuclide of interest and minimize the production of isotopic impurities. We performed production runs at 20 µA for 30 min. Activity was measured using a calibrated HPGe gamma ray detector and an ionization chamber radionuclide activity meter. These measures showed the presence of two main contaminants: (63)Zn (t(1/2)=38.47 min) and (64)Cu (t(1/2)=12.7h); we produced (65)Zn with a saturation yield of (1.06 ± 0.07) GBq/µA (E(p)=12.65→10.48 MeV). The irradiated target was dissolved in 1 ml of 6N HNO(3) at the temperature of 90°C and then purified through anion exchange chromatography with BIO RAD AG 1×8 resin. The radionuclidic purity of the final solution of (65)Zn in HCl 0.005 N, expressed in activity, resulted superior to (99.921 ± 0.003) %.

Standardization of 65Zn by sum-peak method.

A commercial solution of (65)Zn was standardized by the sum peak-method using a planar HPGe detector. The activity results were compared with measurements made with a well type 4πγ ionization chamber, which is traceable to BIPM.RI (II)-K2.Zn-65 key-comparison performed in 2002. The sum-peak value was 42.79 kBq/g and the ionization chamber value was 42.74 kBq/g both at the reference date. The uncertainty obtained in the sum peak standardization was 0.25% (k=1), and in the ionization chamber was 0.85% (k=1). The results showed that sum-peak method can be used in (65)Zn standardization and this method is easier, simpler and more practical than others methods.

Studies on stabilities of some human chorionic gonadotropin complexes with ß-emitting radionuclides.

Human chorionic gonadotropin (hCG) is a peptide hormone, whose one of the structural subunits is identical to that of thyroid-stimulating hormone (TSH). As a consequence, the receptors of TSH also act as receptor for hCG hormone. Keeping in mind this interesting property of hCG we have studied the complex formation ability of various no-carrier-added ß-emitting isotopes of (61)Cu (3.3 h), (62)Zn (9.2 h), (90)Nb (14.60 h) and (99)Mo (66.02 h) with hCG molecule. Stability of the hCG-M (M=metal ions) complexes was investigated by dialysis with respect to triple distilled water and ringer lactate solution, which has the same composition as extracellular fluid.

The use of radioactive zinc oxide nanoparticles in determination of their tissue concentrations following intravenous administration in mice.

The increasing uses of zinc oxide nanoparticles (ZnONPs) in coatings, paints, personal care products and many other products increase the possibility of the body's exposure to ZnONPs. Accurate and quantitative profiling on the tissue distribution and body clearance of ZnONPs, which is an important factor to clarify the acute and chronic safety concerns of ZnONPs, is interfered by the abundance of the body's endogenous zinc moiety. In this report, radioactive zinc oxide nanoparticles (R-ZnONPs) generated from neutron activation were employed for the in vivo bio-distribution studies using mice as the animal model. Gamma-ray emitting radioactive R-ZnONPs were produced from neutron activation. Zeta potentials of the ZnONPs before and after the neutron irradiation remained about the same, and R-ZnONPs largely remained its original nano-particulate form after neutron irradiation. After intravenous administration into ICR mice, R-ZnONPs exhibited a primary retention in lung (43.6% injected dose (ID)/g tissue wet weight) for the first hour and began to be translocated to intestinal tract for feces excretion at a later stage. This type of labeling free and radioactive nanoparticles retains the surface property and can be a convenient protocol for studying bio-distribution of nanoparticles in pristine chemical form.

Radioactivity-synchronized fluorescence enhancement using a radionuclide fluorescence-quenched dye.

We demonstrate the first evidence of radioactivity-synchronized fluorescence quenching of a near-infrared light-emitting dye by a radionuclide, (64)Cu, and subsequent fluorescence enhancement upon (64)Cu decay to the daughter isotopes (64)Ni and (64)Zn. The dynamic switch from high radioactivity and low fluorescence to low radioactivity and high fluorescence is potentially useful for developing complementary multimodal imaging and detection platforms for chemical, environmental, and biomedical applications as well as for unraveling the mechanisms of metal-induced dynamic fluorescence changes.

New best estimates for radionuclide solid-liquid distribution coefficients in soils. Part 3: miscellany of radionuclides (Cd, Co, Ni, Zn, I, Se, Sb, Pu, Am, and others).

New best estimates for the solid-liquid distribution coefficient (K(d)) for a set of radionuclides are proposed, based on a selective data search and subsequent calculation of geometric means. The K(d) best estimates are calculated for soils grouped according to the texture and organic matter content. For a limited number of radionuclides this is extended to consider soil cofactors affecting soil-radionuclide interaction, such as pH, organic matter content, and radionuclide chemical speciation. Correlations between main soil properties and radionuclide K(d) are examined to complete the information derived from the best estimates with a rough prediction of K(d) based on soil parameters. Although there are still gaps for many radionuclides, new data from recent studies improve the calculation of K(d) best estimates for a number of radionuclides, such as selenium, antimony, and iodine.

Use of activated carbon in removal of some radioisotopes from their waste solutions.

Removal of some radioisotopes namely (152+154)Eu and (65)Zn from radioactive solutions by activated carbon using both batch and column techniques has been performed. Experimental studies were conducted to evaluate and optimize the various process variables, i.e., equilibrium time, carbon dose, solution pH. Sorption data have been interpreted in terms of both Freündlich and Langmuir isotherms. The fixed-bed results indicate the high capacity of the activated carbon for the removal of europium and zinc ions. The data suggest the possible use of activated carbon for the removal of these cations from radioactive waste solutions.

Modeling the metal center of Cys4 zinc proteins.

We present here a 67Zn solid-state NMR investigation of several model complexes of zinc coordinated by four sulfurs. The lineshapes were obtained at a variety of magnetic fields from 11.7 T (500 MHz for 1H) to 21.15 T (900 MHz for 1H) and at ambient temperature down to 10 K. The quadrupole coupling constants, Cq's, ranged from 3.25 to 16.7 MHz throughout the series, while the average bond distances only spanned 2.34-2.36 A. Reasonable agreement with experiment was achieved in the molecular orbital calculations using DFT methods and the local density approximation to predict electric field gradients.

Excitation function measurements and integral yields estimation for natZnp,x reactions at low energies.

Excitation functions have been measured for a number of proton-induced nuclear reactions on natural zinc in the energy range from 27.5 MeV down to their threshold energy, using the activation method on stacked foils. Excitation functions and thick target yield for the reactions leading to the formation of (67)Ga,(66)Ga,(68)Ga,(62)Zn and (65)Zn are presented and compared with earlier reported experimental data. The experimental cross-sections and the production yields are tabulated; the excitation functions and the thick target yield curves are plotted in graphs.