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.

Rapid and automated production of [68Ga]gallium chloride and [68Ga]Ga-DOTA-TATE on a medical cyclotron.

INTRODUCTION: The demand for Gallium-68 (68Ga) for labelling PET radiopharmaceuticals has increased over the past few years. 68Ga is obtained through the decayed parent radionuclide 68Ge using commercial 68Ge/68Ga generators. The principal limitation of commercial 68Ge/68Ga generators is that only a limited and finite quantity of 68Ga (<1.85 GBq at start of synthesis) may be accessed. The focus of this study was to investigate the use of a low energy medical cyclotron for the production of greater quantities of 68Ga and to develop an automated and rapid procedure for processing the product. METHODS: Enriched ZnCl2 was electrodeposited on a platinum backing using a NH4Cl (pH 2-4) buffer. The Zn target was irradiated with GE PETtrace 880 at 35 µA and 14.5 and 12.0 MeV beam energy. The irradiated Zn target was purified using octanol resin on an automated system. RESULTS: Following the described procedure, 68Ga was obtained in 6.30 ±â€¯0.42 GBq after 8.5 min bombardment and with low radionuclidic impurities (66Ga (<0.005%) and 67Ga (<0.09%)). Purification on a single octanol resin gave 82% recovery with resulting [68Ga]GaCl3 obtained in 3.5 mL of 0.2 M HCl. [68Ga]GaCl3 production from irradiation to final product was <45 min. To highlight the utility of the automated procedure, [68Ga]Ga-DOTA-TATE labelling was incorporated to give 1.56 GBq at EOS of the labelled peptide with RCY of >70%. CONCLUSIONS: A straightforward procedure for producing 68Ga on a low energy medical cyclotron was described. Current efforts are focus on high activity production and radiolabelling using solid target produced 68Ga.

Cyclotron production of 68Ga in a liquid target: Effects of solution composition and irradiation parameters.

OBJECTIVES: To optimize 68Ga production using a liquid cyclotron target, investigations were performed to compare production yields using different concentrations of [68Zn]Zn(NO3)2, nitric acid, and irradiation parameters. METHODS: Different concentrations of [68Zn]Zn(NO3)2 (0.6 M, 1.2 M and 1.42 M) in varying normality of nitric acid (0.8-1.5 N) were prepared and irradiated with protons (incident energy ~14 MeV) using a BMLT-2 liquid target at different beam currents (30-50 µA) and irradiation times (30-60 min). The 68Ga production and saturation yields were calculated and compared. [68Ga]GaCl3 was isolated using in-house developed hydroxamate resin and optimized for routine application. Recycling of [68Zn]Zn(NO3)2 from the recovered target solution was also investigated. RESULTS: On increasing concentration of [68Zn]Zn(NO3)2 from 0.6 M to 1.2 M in 0.8 N nitric acid, decay corrected yield of 68Ga at EOB was found to be 1.64 GBq (44.4 mCi) and 3.37 GBq (91.0 mCi), respectively at 30 µA beam current, indicating production yield was proportional to zinc nitrate concentration for a 30 min irradiation. However, when beam current was increased to 40 µA while maintaining nitric acid concentration at 0.8 N, the proportional relationship of 68Zn-concentration with 68Ga production yield was lost [0.6 M, 2.29 GBq (61.9 mCi); 1.2 M, 3.6 GBq (97.3 mCi)] for a 30 min irradiation. In fact, the effect was more profound for 60 min irradiations [0.6 M, 2.96 GBq (80.0 mCi); 1.2 M, 4.25 GBq (115 mCi)]. Increasing nitric acid concentration to 1.25-1.5 N improved 68Ga production yield for 40 µA, 60-min irradiations (1.2 M; 5.17 GBq (140 mCi)). MP-AES analysis showed metal impurities as <0.20 µg Ga (n = 3), <0.93 µg Zn (n = 3) and < 2.7 µg Fe (n = 3). Based on above finding, 1.42 M [68Zn]Zn(NO3)2 in 1.2 N-HNO3 solutions were also studied to achieve highest production yields of 9.85 ±â€¯2.09 GBq (266 ±â€¯57 mCi) for 60 min irradiation at 40 µA beam current. After recycling,> 99% pure recycled [68Zn]zinc nitrate was obtained in 82.6 ±â€¯13.6% yield. CONCLUSIONS: 68Ga production yields were dependent on all four variables: concentrations of [68Zn]Zn(NO3)2 and nitric acid, beam current and duration of irradiation. Of note, increasing beam current and irradiation time may require increased concentrations of nitric acid to achieve expected increments in 68Ga production yield.

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.

Production of curie quantities of 68Ga with a medical cyclotron via the 68Zn(p,n)68Ga reaction.

PET imaging with 68Ga-labeled tracers has seen a dramatic increase over the past five years primarily due to the increased accessibility of 68Ge/68Ga generators, the availability of tracers with superb targeting properties for labeling, straightforward labeling procedures and the approval of these tracers by regulatory entities. Available 68Ge/68Ga generators nominally deliver up to 1.85 GBq (50mCi) when fresh limiting production and distribution of 68Ga-labeled tracers to a few daily doses per generator. The focus of this study was to provide a simple and efficient method for 68Ga production in clinically relevant quantities using a low energy medical cyclotron with a solid target.

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.

Evaluation of excitation functions of the (68,67,66)Zn(p,xn)(68,67,66)Ga and 67Zn(p,α)64Cu reactions: validation of evaluated data through comparison with experimental excitation functions of the (nat)Zn(p,x)(66,67)Ga and (nat)Zn(p,x)64Cu processes.

Experimentally available cross section data for formation of the radionuclides (68)Ga, (67)Ga, (66)Ga and (64)Cu in proton induced reactions on enriched (68)Zn, (67)Zn and (66)Zn were evaluated by comparison with the excitation functions calculated by the nuclear model codes, EMPIRE and TALYS, followed by statistical fitting of the selected data. The recommended cross sections were used to obtain the integral yields. The validation of the recommended excitation functions was also attempted by normalization to (nat)Zn and comparison with the experimental data for the (nat)Zn(p,x)(67)Ga, (nat)Zn(p,x)(66)Ga and (nat)Zn(p,x)(64)Cu processes.

Thermal diffusion of 67Ga from irradiated Zn targets.

Gallium-67 is a cyclotron produced radionuclide and 67Ga-citrate complex scans are performed in a variety of applications in Nuclear Medicine. The aim of this study was to evaluate a new method for the chemical separation of 67Ga from Zn targets. The method has 2 steps, first the thermal diffusion of 67Ga with concentrated acetic acid and then purification by cation exchange in ammonium medium. The final 67Ga solution was obtained in 0.1 mol L⁻¹ HCl with the desirable high purity.

Quantitative online isolation of 68Ge from 68Ge/68Ga generator eluates for purification and immediate quality control of breakthrough.

The breakthrough of 68Ge from a 68Ge/68Ga-generator is one of the most sensitive parameters in the context of the clinical application of 68Ga-radiopharmaceuticals. The difficulty in its determination lies in the "spectroscopic invisibility" of 68Ge within an excess of 68Ga. The introduced method for determining the 68Ge content of the 68Ge/68Ga-generator eluate involves the quantitative separation of 68Ga from 68Ge, using a cation-exchanger. The eluate contains 68Ga free of 68Ge, which can be determined immediately, i.e. prior to the application of the 68Ga-radiopharmaceutical.

(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.

Maturation of a key resource - the germanium-68/gallium-68 generator: development and new insights.

(68)Ge/(68)Ga radionuclide generators have been investigated for almost fifty years, since the cyclotron-independent availability of positron emitting (68)Ga via the (68)Ge/(68)Ga system had always attracted researches working in basic nuclear chemistry as well as radiopharmaceutical chemistry. However, it took decades and generations of research (and researchers) to finally reach a level of (68)Ge/(68)Ga radionuclide generator designs adequate to the modern requirements of radiometal labelling chemistry. Nevertheless, most of the existing commercial generator systems address aspects of (68)Ge breakthrough and safe synthesis of (68)Ga radiopharmaceuticals by adopting eluate post-processing technologies. Among the strategies to purify (68)Ga eluates, the cation exchange based version is relevant in terms of purification efficiency. In addition, it offers more options towards further developments of (68)Ga radiopharmaceuticals. Today, one may expect that the (68)Ge/(68)Ga radionuclide generator systems could contribute to the clinical impact of nuclear medicine diagnoses for PET similar to the established (99)Mo/(99m)Tc generator system for SPECT. The exciting perspective for the (68)Ge/(68)Ga radionuclide generator system, in turn, asks for systematic chemical, radiochemical, technological and radiopharmaceutical efforts, to guarantee reliable, highly-efficient and medically approved (68)Ge/(68)Ga generator systems.

Gallium-68 -- a new opportunity for PET available from a long shelf-life generator - automation and applications.

(68)Ge/(68)Ga generators have received tremendous attention in the last years based on the success of (68)Ga-labelled Somatostatin analogues for Positron-Emission Tomography (PET), which are today used routinely worldwide. Various commercially available generator types are based on different column matrices including TiO(2), SnO(2) or organic (68)Gechelate coated silica, providing (68)Ga as Ga(3+) in HCl for radiolabeling procedures. These systems can serve as a stable source of (68)Ga for PET applications over periods of more than one year with high yields. A number of methods for post processing of the eluate including fractionation, anion or cation exchange purification have been developed. These methods are particularly important for high specific activity labeling of biomolecules such as peptides ensuring small volumes, low metallic contamination and low (68)Ge breakthrough. These systems have been implemented into fully automated modules allowing generator elution, post processing radiolabeling and formulation, complying with high regulatory demands. Quality aspects regarding the clinical use of (68)Ga for patient applications including limit of (68)Ge content, metal contamination, microbiological safety and radiochemical purity have been addressed. Overall, the establishment of (68)Ge/(68)Ga generator technology together with the development of novel (68)Ga-radiopharmaceuticals make (68)Ga a most promising radionuclide for PET in the years to come.