Taking cyclotron 68Ga production to the next level: Expeditious solid target production of 68Ga for preparation of radiotracers.

INTRODUCTION: Gallium-68 is an important radionuclide for positron emission tomography (PET) with steadily increasing applications of 68Ga-based radiopharmaceuticals for clinical use. Current 68Ga sources are primarily 68Ge/68Ga-generators, along with successful attempts of 68Ga production using a cyclotron. This study evaluated cyclotron 68Ga production and automated separation using expeditiously manufactured solid targets, demonstrates an order of magnitude improvement in yield compared to 68Ge/68Ga generators, and presents a convenient alternative to existing cyclotron production processes. A comparison of radiolabeling and preclinical PET imaging was performed with both cyclotron and generator produced 68Ga. METHODS: 100 mg enriched 68Zn (99.3% 68Zn, 0.48% 67Zn, 0.1% 66Zn) pellets pressed on silver discs were bombarded for 20-75 min using 12.5 MeV proton beam energies and 10-30 µA currents. 68Ga was separated using an automated TRASIS AllinOne synthesizer employing AG 50W-X8 and UTEVA resins. Post-separation recovery of the 68Zn by electrolysis yielded 76.7 ± 4.3%. Radionuclidic purity of cyclotron-produced 68Ga was investigated with gamma spectroscopy using a HPGe-detector. Radiolabeling was investigated using the macrocyclic chelator DOTA and the bombesin-derived peptide NOTA-BBN2. PET imaging was performed using [68Ga]Ga-NOTA-BBN2 in a PC3 xenograft model. RESULTS: 600 µA·min fresh and recycled quadruplet 68Zn target irradiations (n = 8) at 12.5 MeV and 30 µA yielded 13.9 ± 1.0 GBq 68Ga; 2200 µA·min irradiations (n = 3) yielded 37.5 ± 1.9 GBq 68Ga. HPGe analysis showed EOB 0.0074% and 0.0084% of total activity of 66Ga and 67Ga, respectively. Metal impurities were 0.06 ± 0.03 µg/GBq Zn, 0.13 ± 0.007 µg/GBq Fe, and 0.02 ± 0.01 µg/GBq Al for cyclotron 68Ga. Cyclotron and 68Ge/68Ga generator 68Ga respective DOTA and NOTA-BBN2 labeling incorporations were 99.4 ± 0.0% and 99.3 ± 0.2%, and 90.4 ± 1.5% and 93.0 ± 3.6% determined by radio-thin layer chromatography (radio-TLC). Preclinical PET imaging comparison between generator and cyclotron produced 68Ga showed identical radiotracer tumor uptake and biodistribution profiles in PC3 tumor bearing mice. CONCLUSIONS: Cyclotron 68Ga production provides highly scalable production with equivalent or superior quality 68Ga to a 68Ge/68Ga generator, while providing identical biodistribution and tumor uptake profiles. Our described targetry is simpler and more cost-effective than existing liquid and solid targetry, enabling a turnkey production system for multi-facility distribution of cyclotron produced 68Ga. The manufacturing simplicity described has potential applications for producing other radiometals such as 44Sc. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: Our cost-effective method of solid target 68Ga production can enhance 68Ga production capabilities to meet the high demand for 68Ga-radiopharmaceuticals for research and clinical use.

66Ga: A Novelty or a Valuable Preclinical Screening Tool for the Design of Targeted Radiopharmaceuticals?

Emerging interest in extending the plasma half-life of small molecule radioligands warrants a consideration of the appropriate radionuclide for PET imaging at longer time points (>8 h). Among candidate positron-emitting radionuclides, 66Ga (t1/2 = 9.5 h, ß+ = 57%) has suitable nuclear and chemical properties for the labeling and PET imaging of radioligands of this profile. We investigated the value of 66Ga to preclinical screening and the evaluation of albumin-binding PSMA-targeting small molecules. 66Ga was produced by irradiation of a natZn target. 66Ga3+ ions were separated from Zn2+ ions by an optimized UTEVA anion exchange column that retained 99.99987% of Zn2+ ions and allowed 90.2 ± 2.8% recovery of 66Ga3+. Three ligands were radiolabeled in 46.4 ± 20.5%; radiochemical yield and >90% radiochemical purity. Molar activity was 632 ± 380 MBq/µmol. Uptake in the tumor and kidneys at 1, 3, 6, and 24 h p.i. was determined by µPET/CT imaging and more completely predicted the distribution kinetics than uptake of the [68Ga]Ga-labeled ligands did. Although there are multiple challenges to the use of 66Ga for clinical PET imaging, it can be a valuable research tool for ligand screening and preclinical imaging beyond 24 h.

68Ga 'vacuum elution approach' for direct radiolabelling of DOTA-conjugated and NODAGA-conjugated peptides.

BACKGROUND/OBJECTIVES: The Ge/Ga generator is of increasing interest for clinical PET. The arrival on the market of the pharmaceutical-grade generator, which provides an eluate with chemical and radiochemical purities in conformity with the European Pharmacopeia specifications, makes the direct labelling of vectors possible. The kit formulation strategies using single vial productions can improve the access of hospitals and imaging centres that are not equipped with costly automated synthesis modules to the Ga-radiopharmaceutical production. The manual radiosynthesis of Ga requires handling of a relatively high amount of radioactivity, resulting in a high radiation dose to the hand. Moreover, the elution of the Ga/Ge generator with 5 ml of HCl as recommended by the manufacturer leads to a low Ga concentration, which can decrease the efficiency of the labelling procedure. The aim of our approach is to circumvent these disadvantages and to offer an alternative to the hand elution and labelling for a routine production of Ga-radiopharmaceuticals. METHODS: A mixture of buffer and peptide was first transferred to an evacuated collection vial. Fixed volume of HCl was adapted to the inlet line of the generator. The elution was then performed by the action of vacuum and the labeling occurs at RT or 95°C. RESULTS AND CONCLUSION: The 'vacuum elution approach' developed in this work enables the elution of 95% of the available generator activity with 2.5 ml of eluent, the direct labelling of DOTA-conjugated and NODAGA-conjugated peptides with high radiochemical (>97% for all cases) and radionuclidic (100%) purities without exposure of the hand to radiation during the preparation steps.

Preparation of 68Ga-labelled DOTA-peptides using a manual labelling approach for small-animal PET imaging.

(68)Ga-DOTA-peptides are a promising PET radiotracers used in the detection of different tumours types due to their ability for binding specifically receptors overexpressed in these. Furthermore, (68)Ga can be produced by a (68)Ge/(68)Ga generator on site which is a very good alternative to cyclotron-based PET isotopes. Here, we describe a manual labelling approach for the synthesis of (68)Ga-labelled DOTA-peptides based on concentration and purification of the commercial (68)Ga/(68)Ga generator eluate using an anion exchange-cartridge. (68)Ga-DOTA-TATE was used to image a pheochromocytoma xenograft mouse model by a microPET/CT scanner. The method described provides satisfactory results, allowing the subsequent (68)Ga use to label DOTA-peptides. The simplicity of the method along with its implementation reduced cost, makes it useful in preclinical PET studies.

(68)Ge/ (68)Ga generators: past, present, and future.

In 1964, first (68)Ge/(68)Ga radionuclide generators were described. Although the generator design was by far not adequate to our today's level of chemical, radiopharmaceutical and medical expectations, it perfectly met the needs of molecular imaging of this period. (68)Ga-EDTA as directly eluted from the generators entered the field of functional diagnosis, in particular for brain imaging. A new type of generators became commercially available in the first years of the 21st century. Generator eluates based on hydrochloric acid provided "cationic" (68)Ga instead of "inert" (68)Ga-complexes and opened new pathways of Me(III) based radiopharmaceutical chemistry. The impressive success of utilizing (68)Ga- DOTA-octreotides and PET/CT instead of e.g., (111)In-DTPA-octreoscan and SPECT paved the way not only towards clinical acceptance of this particular tracer for imaging neuroendocrine tracers, but to the realisation of the great potential of the (68)Ge/(68)Ga generator for modern nuclear medicine in general. The last decade has seen a (68)Ga rush. Increasing applications of generator based (68)Ga radiopharmaceuticals (for diagnosis alone, but increasingly for treatment planning thanks to the inherent option as expressed by THERANOSTICS), now ask for further developments - towards the optimization of (68)Ge/(68)Ga generators both from chemical and regulatory points of view. Dedicated chelators may be required to broaden the feasibility of (68)Ga labeling of more sensitive targeting vectors and generator chemistry may be adopted to those chelators - or vice versa. This review describes the development and the current status of (68)Ge/(68)Ga radionuclide generators.

Overview and perspectives on automation strategies in (68)Ga radiopharmaceutical preparations.

The renaissance of (68)Ga radiopharmacy has led to great advances in automation technology. The availability of a highly efficient, reliable, long-lived (68)Ge/(68)Ga generator system along with a well-established coordination chemistry based on bifunctional chelating agents have been the bases of this development in (68)Ga radiopharmacy. Syntheses of (68)Ga peptides were originally performed by manual or semiautomated systems, but increasing clinical demand, radioprotection, and regulatory issues have driven extensive automation of their production process. Several automated systems, based on different post-processing of the (68)Ga generator eluate, on different engineering, and on fixed tubing or disposable cassette approaches, have been developed and are discussed in this chapter. Since automatic systems for preparation of radiopharmaceuticals should comply with qualification and validation protocols established by regulations such as current Good Manufacturing Practices (cGMP) and local regulations, some regulatory issues and the more relevant qualification protocols are also discussed.

Post-processing via cation exchange cartridges: versatile options.

New (68)Ge/(68)Ga radionuclide generators provide the positron emitter (68)Ga (T½ = 67.7 min) as an easily available and relatively inexpensive source of a PET nuclide for labeling of interesting targeting vectors. However, currently available "ionic" (68)Ge/(68)Ga radionuclide generators are not necessarily optimized for the routine synthesis of (68)Ga-labeled radiopharmaceuticals in a clinical environment. Post-processing of (68)Ge/(68)Ga generators using cation exchange resins provides chemically and radiochemically pure (68)Ga with 97±2% within less than 4 min, with (68)Ge almost completely removed, and ready for online labeling. This simple, fast, and efficient technology can be extended for new applications. The options are (a) to transfer (68)Ga from the cation exchange resin onto an anion exchange resin, to remove acetone, and to further purify the (68)Ga, (b) to obtain (68)Ga in pure non-aqueous solution via (68)Ga(acac)(3) as a synthon for syntheses in organic solvents, and (c) to create an option toward instantaneous determination of (68)Ge breakthrough, what may be required prior to the release of (68)Ga radiopharmaceutical preparations.

(68)Ga generator integrated system: elution-purification-concentration integration.

A (68)Ge/(68)Ga generator combined with an automated (68)Ga eluate purification-concentration unit [radioisotope generator integrated system (RADIGIS)], specially designed for (68)Ga processing (RADIGIS-(68)Ga), was developed. The high-stability sorbents of a nanocrystalline structure Zr-Ti ceramic matrix were used for immobilizing the (68)Ge, and the (68)Ga was eluted from the sorbent column with 3.5 mL 0.05-0.1 M HCl solution following an optimized (68)Ga-elution schedule. The (68)Ge breakthrough <10(-3)% and no (68)Ge zone spreading/drift found in PET imaging of the (68)Ga generator column prove the excellent performance of the sorbents. (68)Ga eluate was purified on a small column of salt-form ion exchange resin using an aqueous alcohol solution mixture of hydrochloric and ascorbic acids, and halide salts. An alkali solution was used for stripping (68)Ga from the ion exchange resin column to obtain a purified (68)Ga solution, which is conditioned with acidic solution to obtain a final (68)Ga product in either 0.75 mL 0.5 M NaCl solution of pH 3-4 or 0.5 M sodium acetate or citrate solution of pH 5. The (68)Ge content in purified (68)Ga solution was <10(-6)%. An insignificant metallic contamination including (68)Zn found in the (68)Ga solution and its alkalinity-acidity were evaluated with respect to (68)Ga radiolabeling efficacy for DOTATATE and DOTATOC ligands. Quality control protocols were also developed to evaluate the quality of (68)Ga solution.

Purification and labeling strategies for (68)Ga from (68)Ge/ (68)Ga generator eluate.

For successful labeling, (68)Ge/(68)Ga generator eluate has to be concentrated (from 10 mL or more to less than 1 mL) and to be purified of metallic impurities, especially Fe(III), and (68)Ge breakthrough. Anionic, cationic and fractional elution methods are well known. We describe two new methods: (1) a combined cationic-anionic purification and (2) an easy-to-use and reliable cationic purification with NaCl solution. Using the first method, (68)Ga from 10 mL generator eluate was collected on a SCX cartridge, then eluted with 1.0 mL 5.5 M HCl directly on an anion exchanger (30 mg AG1X8). After drying with a stream of helium, (68)Ga was eluted with 0.4 mL water into the reaction vial. We provide as an example labeling of BPAMD. Using the second method, (68)Ga from 10 mL generator eluate was collected on a SCX cartridge, then eluted with a hydrochloric solution of sodium chloride (0.5 mL 5 M NaCl, 12.5 µL 5.5 M HCl) into the reaction vial, containing 40 µg DOTATOC and 0.5 mL 1 M ammonium acetate buffer pH 4.5. After heating for 7 min at 90°C, the reaction was finished. Radiochemical purity was higher than 95% without further purification. No (68)Ge breakthrough was found in the final product.

(67)Ga and (68)Ga purification studies: preliminary results.

The positron emission tomography technique is very useful for diagnosis of several diseases. (68)Ga is a positron emitter with half-life of 67.7 min. As it is available from (68)Ge/(68)Ga generator systems, it is not necessary to have a nearby cyclotron. However, the eluate from commercial generators contains high levels of metallic impurities, which compete with (68)Ga in biomolecular labeling. Thus, a subsequent purification step is needed after generator elution. Here we present the results of two different methods developed for handmade purification of (68)Ga and (67)Ga for subsequent radiolabeling of biomolecules. Two purification methods were employed. The first one uses a cation exchange resin, and (68)Ga is eluted with a solution of acetone/acid. The second method of purification is performed by column chromatography solvent extraction, with (68)Ga recovery in deionized water. The best result was achieved with cationic resin AG50W-X8 (>400 mesh). However, the resin is not commercially available. The extraction chromatography column based on absorption of diisopropyl ether in XAD-16 is the most promising purification method. Although the levels of (68)Ga recovery and purification were smaller with the cationic resin method, its advantage is the (68)Ga recovery in deionized water.

Early experience with (68)Ga-DOTATATE preparation.

Neuroendocrine tumors (NETs) are a rare form of cancer. NETs frequently express cell membrane-specific peptide receptors, such as somatostatin receptors (SSTRs). Radiolabeled peptides bind to SSTR and provide in vivo histopathological information for diagnostic purposes. (68)Ga-DOTATATE has higher sensitivity for low-grade tumors and greater avidity to well-differentiated NETs than (18)F-FDG, being superior to (111)In-DTPA-octreotide and (18)F-DOPA in evaluation of well-differentiated metastatic NETs. The feasibility of (68)Ga-DOTATATE application in routine clinical practice for PET imaging of NETs was determined in a limited number of known cases (n = 6). (68)Ga-DOTATATE scan could detect all known sites of NETs and in one case previously unknown peritoneal metastasis. Early regulatory consideration is important for routine clinical use.

Measurement of protein synthesis: in vitro comparison of (68)Ga-DOTA-puromycin, [ (3)H]tyrosine, and 2-fluoro-[ (3)H]tyrosine.

AIM: Puromycin has played an important role in our understanding of the eukaryotic ribosome and protein synthesis. It has been known for more than 40 years that this antibiotic is a universal protein synthesis inhibitor that acts as a structural analog of an aminoacyl-transfer RNA (aa-tRNA) in eukaryotic ribosomes. Due to the role of enzymes and their synthesis in situations of need (DNA damage, e.g., after chemo- or radiation therapy), determination of protein synthesis is important for control of antitumor therapy, to enhance long-term survival of tumor patients, and to minimize side-effects of therapy. Multiple attempts to reach this goal have been made through the last decades, mostly using radiolabeled amino acids, with limited or unsatisfactory success. The aim of this study is to estimate the possibility of determining protein synthesis ratios by using (68)Ga-DOTA-puromycin ((68)Ga-DOTA-Pur), [(3)H]tyrosine, and 2-fluoro-[(3)H]tyrosine and to estimate the possibility of different pathways due to the fluorination of tyrosine. METHODS: DOTA-puromycin was synthesized using a puromycin-tethered controlled-pore glass (CPG) support by the usual protocol for automated DNA and RNA synthesis following our design. (68)Ga was obtained from a (68)Ge/(68)Ga generator as described previously by Zhernosekov et al. (J Nucl Med 48:1741-1748, 2007). The purified eluate was used for labeling of DOTA-puromycin at 95°C for 20 min. [(3)H]Tyrosine and 2-fluoro-[(3)H]tyrosine of the highest purity available were purchased from Moravek (Bera, USA) or Amersham Biosciences (Hammersmith, UK). In vitro uptake and protein incorporation as well as in vitro inhibition experiments using cycloheximide to inhibit protein synthesis were carried out for all three substances in DU145 prostate carcinoma cells (ATCC, USA). (68)Ga-DOTA-Pur was additionally used for µPET imaging of Walker carcinomas and AT1 tumors in rats. Dynamic scans were performed for 45 min after IV application (tail vein) of 20-25 MBq (68)Ga-DOTA-Pur. RESULTS: No significant differences in the behavior of [(3)H]tyrosine and 2-fluoro-[(3)H]tyrosine were observed. Uptake of both tyrosine derivatives was decreased by inhibition of protein synthesis, but only to a level of 45-55% of initial uptake, indicating no direct link between tyrosine uptake and protein synthesis. In contrast, (68)Ga-DOTA-Pur uptake was directly linked to ribosomal activity and, therefore, to protein synthesis. (68)Ga-DOTA-Pur µPET imaging in rats revealed high tumor-to-background ratios and clearly defined regions of interest in the investigated tumors. SUMMARY: Whereas the metabolic pathway of (68)Ga-DOTA-Pur is directly connected with the process of protein synthesis and shows high tumor uptake during µPET imaging, neither [(3)H]tyrosine nor 2-fluoro-[(3)H]tyrosine can be considered useful for determination of protein synthesis.

Feasibility and availability of 68Ga-labelled peptides.

(68)Ga has attracted tremendous interest as a radionuclide for PET based on its suitable half-life of 68 min, high positron emission yield and ready availability from (68)Ge/(68)Ga generators, making it independent of cyclotron production. (68)Ga-labelled DOTA-conjugated somatostatin analogues, including DOTA-TOC, DOTA-TATE and DOTA-NOC, have driven the development of technologies to provide such radiopharmaceuticals for clinical applications mainly in the diagnosis of somatostatin receptor-expressing tumours. We summarize the issues determining the feasibility and availability of (68)Ga-labelled peptides, including generator technology, (68)Ga generator eluate postprocessing methods, radiolabelling, automation and peptide developments, and also quality assurance and regulatory aspects. (68)Ge/(68)Ga generators based on SnO(2), TiO(2) or organic matrices are today routinely supplied to nuclear medicine departments, and a variety of automated systems for postprocessing and radiolabelling have been developed. New developments include improved chelators for (68)Ga that could open new ways to utilize this technology. Challenges and limitations in the on-site preparation and use of (68)Ga-labelled peptides outside the marketing authorization track are also discussed.

A methodical 68Ga-labelling study of DO2A-(butyl-L-tyrosine)2 with cation-exchanger post-processed 68Ga: practical aspects of radiolabelling.

Positron emission tomography (PET) with (68)Ga is a fast-growing field in molecular imaging, both in research and in clinical routine. The availability of (68)Ga via the (68)Ge/(68)Ga radionuclide generator facilitates the development and production of radiopharmaceuticals independent of a cyclotron. The presented work shows a complete (68) Ga labelling study exemplified on [(68)Ga]DO2A-(butyl-L-tyrosine)(2), a potential tumour tracer for PET. A methodical sequence is followed to optimize the (68)Ga-labelling reaction. Practical aspects are described and the different parameters contributing to the labelling yield are demonstrated. The influence of temperature, time, amount of labelling precursor and pH value on the radiochemical yields is demonstrated. A conventional heating method is compared with microwave irradiation as an alternative labelling method. Finally, purification of (68)Ga-labelled compounds via solid-phase extraction and quality control is shown. The procedure described in this manuscript may serve as a guideline for optimizing (68)Ga labelling reactions.

Characteristics of SnO2-based 68Ge/68Ga generator and aspects of radiolabelling DOTA-peptides.

OBJECTIVES: PET scintigraphy with (68)Ga-labelled analogs is of increasing interest in Nuclear Medicine and performed all over the world. Here we report the characteristics of the eluate of SnO(2)-based (68)Ge/(68)Ga generators prepared by iThemba LABS (Somerset West, South Africa). Three purification and concentration techniques of the eluate for labelling DOTA-TATE and concordant SPE purifications were investigated. METHODS: Characteristics of 4 SnO(2)-based generators (range 0.4-1 GBq (68)Ga in the eluate) and several concentration techniques of the eluate (HCl) were evaluated. The elution profiles of SnO(2)-based (68)Ge/(68)Ga generators were monitored, while [HCl] of the eluens was varied from 0.3-1.0 M. Metal ions and sterility of the eluate were determined by ICP. Fractionated elution and concentration of the (68)Ga eluate were performed using anion and cation exchange. Concentrated (68)Ga eluate, using all three concentration techniques, was used for labelling of DOTA-TATE. (68)Ga-DOTA-TATE-containing solution was purified and RNP increased by SPE, therefore also 11 commercially available SPE columns were investigated. RESULTS: The amount of elutable (68)Ga activity varies when the concentration of the eluens, HCl, was varied, while (68)Ge activity remains virtually constant. SnO(2)-based (68)Ge/(68)Ga generator elutes at 0.6 M HCl >100% of the (68)Ga activity at calibration time and ±75% after 300 days. Eluate at discharge was sterile and Endotoxins were <0.5 EU/mL, RNP was always <0.01%. Metal ions in the eluate were <10 ppm (in total). Highest desorption for anion purification was obtained with the 30 mg Oasis WAX column (>80%). Highest desorption for cation purification was obtained using a solution containing 90% acetone at increasing molarity of HCl, resulted in a (68)Ga desorption of 68±8%. With all (68)Ge/(68)Ga generators and for all 3 purification methods a SA up to 50 MBq/nmol with >95% incorporation (ITLC) and RCP (radiochemical purity) by HPLC ±90% could be achieved. Purification and concentration of the eluate with anion exchange has the benefit of more elutable (68)Ga with 1 M HCl as eluens. The additional washing step of the anion column with NaCl and ethanol, resulted in a lower and less variable [H(+)] in the eluate, and, as a result the pH in the reaction vial is better controlled, more constant, and less addition of buffer is required and concordant smaller reaction volumes. Desorption of (68)Ga-DOTA-TATE of SPE columns varied, highest desorption was obtained with Baker C(18) 100 mg (84%). Purification of (68)Ga-DOTA-TATE by SPE resulted in an RNP of <10(-4)%. CONCLUSIONS: Eluate of SnO(2)-based (68)Ge/(68)Ga generator, either by fractionated elution as by ion exchange can be used for labelling DOTA-peptides with (68)Ga at a SA of 50 MBq/nmol at >95% incorporation and a RCP of ±90%. SPE columns are very effective to increase RNP.

Effective separation method of (64)Cu from (67)Ga waste product with a solvent extraction and chromatography.

A simple chemical process with a solvent extraction was investigated as an effective separation method for (64)Cu radionuclide from waste production, which is collected as solution after extracting (67)Ga and recovering (68)Zn target materials. For the production of radionuclide (67)Ga, the enriched (68)Zn material electroplated on Cu backing plate is usually exposed to energetic protons. The protons produce (67)Ga including other radionuclides, such as (57)Ni, (57,55)Co, (64,67)Cu by several nuclear reactions. After extracting (67)Ga and recovering (68)Zn through several steps of chemical processes, the residual solution is usually discarded even though it contains other species of radioisotopes. In this study, a simple chemical process having a high separation efficiency of (64)Cu from the waste solution was investigated. With this method, a promising radiotracer as a diagnostic in PET and a therapeutic in radio-immunotherapy, (64)Cu was estimated to be produced as high as 1,200mCi at EOB within 3h chemical processing after extraction of (67)Ga and (68)Zn.

Full automation of (68)Ga labelling of DOTA-peptides including cation exchange prepurification.

Here we describe a fully automated approach for the synthesis of (68)Ga-labelled DOTA-peptides based on pre-concentration and purification of the generator eluate by using a cation exchange-cartridge and its comparison with fully automated direct labelling applying fractionated elution. Pre-concentration of the eluate on a cation exchange cartridge both using a resin-based and a disposable cation-exchange cartridge efficiently removed (68)Ge as well as major metal contaminations with Fe and Zn. This resulted in a high labelling efficiency of DOTA-peptides at high specific activity (SA) with short synthesis times.

Biosorption of Ga-67 radionuclides from aqueous solutions onto waste pomace of an olive oil factory.

The aim of this research was to test the removal of Ga-67 radionuclides from aqueous solutions by biosorption onto waste pomace of an olive oil factory (WPOOF). Batch adsorption studies were performed in order to investigate the temperature, the initial pH of the solution, the stirring speed, the biosorbent dose, and the nominal particle size of the biosorbent in the experimental work. The most effective parameter was found to be the initial pH. A high biosorption yield of 98 was obtained. The equilibrium values were fitted to the isotherm models. The values of DeltaG and DeltaH were calculated to be negative. The adsorption kinetics calculations showed that the kinetics of the biosorption process fitted well to the pseudo-second order rate model.

68Ga-labelled DOTA-derivatised peptide ligands.

68Ge/68Ga generators provide cyclotron-independent access to positron emission tomography (PET) radiopharmaceuticals. We describe a system which allows the safe and efficient handling of 68Ge/68Ga generator eluates for labelling of DOTA-derivatised peptide ligands. The system comprises concentration and purification of the 68Ga eluate as well as labelling and purification steps for peptides, and can be used with different 68Ge/68Ga generator types. The suitability and efficiency were tested with two different DOTA-derivatised somatostatin derivatives and a DOTA-derivatised bombesin derivative. Amounts of 10-20 nmol of the peptides were sufficient and resulted in labelling yields of 50% for all peptides. The built-in safety precautions have proven to be appropriate in allowing use of the method for routine clinical applications. The system was set up and operated in a "hot lab" by personnel with no previous experience in the preparation of PET radiopharmaceuticals.

Production and purification of gallium-66 for preparation of tumor-targeting radiopharmaceuticals.

Gallium-66 (T(1/2) = 9.49 h) is an intermediate-lived radionuclide that has potential for positron emission tomography (PET) imaging of biological processes with intermediate to slow target tissue uptake. We have produced (66)Ga by the (66)Zn(p,n) (66)Ga nuclear reaction using a small biomedical cyclotron and have investigated methods for purifying (66)Ga that could be applied to the development of an automated processing system. Measured yields of (66)Ga were very high with a production yield of nearly 14 mCi/microA-h at 14.5 MeV bombardment energy, a value in excellent agreement with theoretical predictions based on literature cross sections for the (66)Zn(p,n) (66)Ga reaction. Gallium-66 has been purified from irradiated zinc targets two ways, by cation-exchange chromatography and diisopropyl ether extraction. The concentrations of stable contaminants in (66)Ga following the two processing methods were determined, and it was found that iron and zinc were present at levels up to an order of magnitude higher after cation-exchange chromatography. The bioconjugates DOTA-Tyr(3)-octreotide and DOTA-biotin were labeled with (66)Ga purified by both methods. Following purification of (66)Ga by solvent extraction, radiochemical yields in excess of 85% were obtained for both compounds, in contrast to much lower labeling yields (less than 20%) obtained after the cation-exchange separation. Higher concentrations of stable contaminants likely contributed to the poor radiochemical yields for labeling DOTA-Tyr(3)-octreotide and DOTA-biotin with cation-exchanged (66)Ga. The lower purity and radiolabeling yields obtained using cation-exchange do not warrant the development of an automated processing system based on this method. Therefore, work is in progress to automate the diisopropyl ether extraction method for routine processing of (66)Ga.