Separation of 44mSc/44gSc Nuclear Isomers Based on After-Effects.

44gSc presents a particular interest for application in nuclear medicine for positron emission tomography (PET) due to its favorable nuclear decay properties (t1/2 = 3.97 h, Emax = 1.47 MeV, branching ratio 94.3% ß+). Its nuclear isomer 44mSc (t1/2 = 58.61 h) decays by isomeric transition (IT) into 44gSc, accompanied by ≈12% of conversion electron emission, which can cause a partial release of the daughter 44gSc from the chelate complex. A 13 MeV cyclotron at TRIUMF was used to produce both 44mSc and 44gSc via the natCa(p,n)44m,gSc reaction. A 44mSc/44gSc generator was designed by using a Strata C-18E cartridge. After several tested systems, a successful separation method was developed using DOTATOC as a chelator, a Strata C-18E cartridge as a generator column, and an elution solution of 0.1 M NH4-α-HIB. The yield of the generator with the daughter 44gSc release was equal to 9.8 ± 1.0% (or ≈80% per portion of conversion). This result shows the important role of after-effects in the design of radionuclide generators. Nuclear cross-section calculations were applied using the TALYS code to allow for the determination of the most promising alternative routes for 44mSc production, which will enable the development of a full-scale 44mSc/44gSc radionuclide generator based on after-effects.

Production and radiochemistry of antimony-120m: Efforts toward Auger electron therapy with 119Sb.

Targeted Meitner-Auger Therapy (TMAT) has potential for personalized treatment thanks to its subcellular dosimetric selectivity, which is distinct from the dosimetry of ß- and α particle emission based Targeted Radionuclide Therapy (TRT). To date, most clinical and preclinical TMAT studies have used commercially available radionuclides. These studies showed promising results despite using radionuclides with theoretically suboptimal photon to electron ratios, decay kinetics, and electron emission spectra. Studies using radionuclides whose decay characteristics are considered more optimal are therefore important for evaluation of the full potential of Meitner-Auger therapy; 119Sb is among the best such candidates. In the present work, we develop radiochemical purification of 120Sb from irradiated natural tin targets for TMAT studies with 119Sb.

An alternative radiochemical separation strategy for isolation of Ac and Ra isotopes from high energy proton irradiated thorium targets for further application in Targeted Alpha Therapy (TAT).

Targeted Alpha Therapy (TAT) has shown very high potential for the treatment of cancers that were not responsive to other therapy options (e.g., ß- therapy and chemotherapy). The main constraint to the widespread use of TAT in clinics is the limited availability of alpha-emitting radionuclides. One of the most promising candidates for TAT is 225Ac (t1/2 = 9.92 days), which can be used directly in combination with selective biomolecules (e.g., antibodies, peptides, etc.) or be a generator source of 213Bi (t1/2 = 45.6 min), another shorter-lived TAT radionuclide. Several strategies are currently under investigation to increase the supply of 225Ac. One of the most attractive options is the irradiation of natural thorium-232 targets with high-energy protons (≥100 MeV). However, there are several challenges associated with this production method including the development of an efficient radiochemical purification method. During irradiation of natural thorium with proton energy above 100 MeV, several Ra isotopes (223,224,225Ra) are produced. 223Ra (t1/2 = 11.43 days) is used for the treatment of bone metastases and can also be used as a generator source for 211Pb. Additionally, 225Ra (t1/2 = 14.9 days) can be a valuable source of isotopically pure 225Ac. In the present work, we address the radiochemical separation aspects of isolating Ac and Ra isotopes from irradiated thorium targets.

Potent candidates for Targeted Auger Therapy: Production and radiochemical considerations.

Targeted Auger Therapy represents great potential for the therapy of diseases which require a high degree of selectivity on the cellular level (e.g. for therapy of metastatic cancers). Due to their high Linear Energy Transfer (LET), Auger emitters, combined with selective biological systems which enable delivery of radionuclides close to the DNA of the targeting cell, can be extremely selective and powerful treatment tools. There are two main aspects associated with the development of efficient radiopharmaceuticals based on Auger Emitters: a) the availability of suitable Auger-emitting radionuclides for therapy and b) the design of targeting vectors which can deliver Auger emitters into/close to the nucleus. In the present review, we address the first aspect by defining important parameters for the selection of radionuclides for application to Targeted Auger Therapy and form a categorized list of the most promising radionuclides, their possible production routes, and their use in the synthesis of radiopharmaceuticals.

Perturbed Angular Correlation as a Tool to Study Precursors for Radiopharmaceuticals.

One of the key components of radiopharmaceuticals for targeting imaging and therapy is a stable bifunctional chelating system to attach radionuclides to selective delivery systems. After-effects of radioactive decay can cause the release of a radioactive isotope from its chelation agent. Perturbed angular correlation (PAC) of γ-rays has become a unique technique to study the behavior of complexes formed between a chelating agent and radionuclide in vivo (in real time) over a relevant range of concentrations (10-12 M). In the present work, four radionuclides, 111In, 111mCd, and 152, 154Eu, were investigated with diethylenetriaminepentaacetic acid (DTPA) at different pH values to determine the stability constants of the complexes as well as the effects of post-decay processes, which play a major role in determining the suitability of these complexes for application as radiopharmaceuticals (e.g., in vivo generators). The study provides a convenient parameter for the characterization of radionuclide-chelator systems using the PAC method. PAC is proven to be a suitable tool to study novel chelators and radiopharmaceutical precursors attached to radiometals.

A novel combined countercurrent chromatography - inductively coupled plasma mass spectrometry method for the determination of ultra trace uranium and thorium in Roman lead.

The concentration of uranium and thorium in lead shields, which are used in underground particle physics research, should be monitored at sub-ppt levels. A combination of extraction chromatography and inductively coupled plasma mass spectrometry can resolve this analytical task. However, a multi-step complicated separation procedure and clean room are required. Besides, the recovery yields for U and Th do not exceed 80% and 60%, correspondingly. We propose an alternative approach. U and Th were pre-concentrated and separated from Pb by countercurrent chromatography, which is a support-free liquid-liquid chromatography. A series of two-phase extraction systems were tested. Under the optimized conditions, U and Th were extracted using a system 1 M HNO3/0.01 M tetraphenylmethylenediphosphine dioxide in chloroform and then eluted by 0.01 M aqueous solution of etidronic acid and determined by inductively coupled plasma mass spectrometry. The separation is performed in one chromatographic run, takes less than 1 h, and provides the quantitative recovery of U and Th. The limits of detection are 3 and 1 ppt for U and Th, correspondingly. The concentrations of U and Th in Roman lead, which was raised from the sea bottom, were lower than the limits of detection. It sounds unbelievable, nevertheless, the antique lead manufactured by Romans can indeed serve as a high-purity low-background material for the construction of Pb shields. Apart from the analysis of antique lead, the proposed approach can be easily extended to the determination of ultra trace impurities in different materials due to a very wide variety of two-phase extraction systems, which can be used in countercurrent chromatography.

Labeling and preliminary in vivo assessment of niobium-labeled radioactive species: A proof-of-concept study.

The application of radionuclide-labeled biomolecules such as monoclonal antibodies or antibody fragments for imaging purposes is called immunoscintigraphy. More specifically, when the nuclides used are positron emitters, such as zirconium-89, the technique is referred to as immuno-PET. Currently, there is an urgent need for radionuclides with a half-life which correlates well with the biological kinetics of the biomolecules under question and which can be attached to the proteins by robust labeling chemistry. (90)Nb is a promising candidate for in vivo immuno-PET, due its half-life of 14.6h and low ß(+) energy of Emean=0.35MeV per decay. (95)Nb on the other hand, is a convenient alternative for longer-term ex vivo biodistribution studies, due to its longer half-life of (t½=35days) and its convenient, lower-cost production (reactor-based production). In this proof-of-principle work, the monoclonal antibody bevacizumab (Avastin(®)) was labeled with (95/90)Nb and in vitro and in vivo stability was evaluated in normal Swiss mice and in tumor-bearing SCID mice. Initial ex vivo experiments with (95)Nb-bevacizumab showed adequate tumor uptake, however at the same time high uptake in the liver, spleen and kidneys was observed. In order to investigate whether this behavior is due to instability of (⁎)Nb-bevacizumab or to the creation of other (⁎)Nb species in vivo, we performed biodistribution studies of (95)Nb-oxalate, (95)Nb-chloride and (95)Nb-Df. These potential metabolite species did not show any specific uptake, apart from bone accumulation for (95)Nb-oxalate and (95)Nb-chloride, which, interestingly, may serve as an "indicator" for the release of (90)Nb from labeled biomolecules. Concerning the initial uptake of (95)Nb-bevacizumab in non-tumor tissue, biodistribution of a higher specific activity radiolabeled antibody sample did show only negligible uptake in the liver, spleen, kidneys or bones. In-vivo imaging of a tumor-bearing SCID mouse after injection with (90)Nb-bevacizumab was acquired on an experimental small-animal PET camera, and indeed showed localization of the radiotracer in the tumor area. It is the first time that such results are described in the literature, and indicates promise of application of (90)Nb-labeled antibodies for the purposes of immuno-PET.