68Ga activity calibrations for nuclear medicine applications in Cuba.

The realization and dissemination of the 68Ga activity measurement unit in Cuba is presented. Firstly, the implementation of the Triple to Double Coincidence Ratio (TDCR) method is described for the calibration of the activity concentration of a 68Ga solution using a Hidex™ commercial liquid scintillation counter and a FORTRAN code developed for the calculation of the 68Ga counting efficiencies in the given measurement system. The relative expanded uncertainty (k = 2) associated with the 68Ga activity concentration obtained with the TDCR method is equal to 2%. With the aim to validate this measurement uncertainty estimate, the method is also applied to an Amersham standard solution of 22Na - a positron emitter with a similar decay mode to the 68Ga disintegration scheme from the point of view of type of emitted particles detected in the measurement system. The observed difference between the measured 22Na activity concentration by the TDCR method and the corresponding reference value traceable to NIST is equal to 0.16%. Outcomes of transferring the 68Ga activity standard, realized with the TDCR method, to the secondary standard radionuclide calibrator Capintec CRC™ 15R and to three radionuclide calibrators used for 68Ga PET applications in a hospital are also shown.

Diagnostic sensitivity of Tc-99m HYNIC PSMA SPECT/CT in prostate carcinoma: A comparative analysis with Ga-68 PSMA PET/CT.

BACKGROUND: Emerging data from published studies are demonstrating the superiority of Ga-68 PSMA PET/CT imaging in prostate cancer. However, the low yield of the Ge-68/Ga-68 from which Gallium-68 is obtained and fewer installed PET/CT systems compared to the SPECT imaging systems may limit its availability. We, therefore, evaluated in a head-to-head comparison, the diagnostic sensitivity of Ga-68 PSMA PET/CT and Tc-99m PSMA SPECT/CT in patients with prostate cancer. METHODS: A total of 14 patients with histologically confirmed prostate cancer were prospectively recruited to undergo Ga-68 PSMA PET/CT and Tc-99m HYNIC PSMA SPECT/CT. The mean age of patients was 67.21 ± 8.15 years and the median PSA level was 45.18 ng/mL (range = 1.51-687 ng/mL). SUVmax of all lesions and the size of lymph nodes with PSMA avidity on Ga-68 PSMA PET/CT were determined. Proportions of these lesions detected on Tc-99m HYNIC PSMA SPECT/CT read independent of PET/CT findings were determined. RESULTS: A total of 46 lesions were seen on Ga-68 PSMA PET/CT localized to the prostate (n = 10), lymph nodes (n = 24), and bones (n = 12). Of these, Tc-99m HYNIC PSMA SPECT/CT detected 36 lesions: Prostate = 10/10 (100%), lymph nodes = 15/24 (62.5%), and bones = 11/12 (91.7%) with an overall sensitivity of 78.3%. Lesions detected on Tc-99m HYNIC PSMA SPECT/CT were bigger in size (P < 0.001) and had higher SUVmax (P < 0.001) as measured on Ga-68 PSMA PET/CT compared to those lesions that were not detected. All lymph nodes greater than 10 mm in size were detected while only 28% of nodes less than 10 mm were detected by Tc-99m HYNIC PSMA SPECT/CT. In a univariate analysis, Lymph node size (P = 0.033) and the SUVmax of all lesions (P = 0.007) were significant predictors of lesion detection on Tc-99m HYNIC PSMA SPECT/CT. CONCLUSION: Tc-99m HYNIC PSMA may be a useful in imaging of prostate cancer although with a lower sensitivity for lesion detection compared to Ga-68 PSMA PET/CT. Its use is recommended when Ga-68 PSMA is not readily available, in planning radio-guided surgery or the patient is being considered for radio-ligand therapy with Lu-177 PSMA. It performs poorly in detecting small-sized lesions hence its use is not recommended in patients with small volume disease.

Optimization of Labeling PSMAHBED with Ethanol-Postprocessed 68Ga and Its Quality Control Systems.

Radiolabeling of the prostate-specific membrane antigen (PSMA) inhibitor Glu-NH-CO-NH-Lys(Ahx) using the 68Ga chelator HBED-CC (PSMAHBED) allows imaging of prostate cancer lesions because of high expression of PSMA in prostate carcinoma cells and in bone metastases and lymph nodes related to the disease. The aim of this work was to optimize labeling of 68Ga-PSMAHBED using the efficient cation-exchange postprocessing of 68Ga as well as the development of a thin-layer chromatography (TLC)-based quality control system. Methods: Labeling was optimized for online ethanol-postprocessed 68Ga eluate investigating various parameters, such as buffer molarity (0.1-1 M), temperature (25°C-90°C), tracer amount (0.11-0.74 nmol), and labeling time. In addition, purification of the crude product was tested. For radio-TLC quality control, various mobile phases were analyzed using silica gel 60 plates and the results were validated using high-performance liquid chromatography. The most superior mobile phases were also applied on instant thin-layer chromatography (ITLC) silica gel plates. Results: Using optimized conditions, labeling yields of more than 95% were obtained within 10 min when ethanol-based postprocessing was applied using PSMAHBED amounts as low as 0.1 nmol. A higher precursor concentration (0.7 nmol) further increased labeling and quantitative yields to more than 98% within 5 min. In clinical routine, patient batches (>200 applications) with radiochemical purity greater than 98% and specific activities of 326 ± 20 MBq/nmol are obtained reproducibly. When TLC quality control was performed on silica gel 60 plates, 4 mobile phases with suitable separation properties and complementary Rf values were identified. Two systems showed equivalent separation on ITLC silica gel plates, with ITLC analysis finished within 5 min, in contrast to 20 min for the TLC system. Labeling of PSMAHBED was optimized for cation-exchange postprocessing methods, ensuring almost quantitative labeling and high nuclide purity of final 68Ga-PSMAHBED, making subsequent purification steps unnecessary. Conclusion: The new radio-TLC method allows quality control in a short time using a fast, reliable, low-cost method with little equipment complexity. Using this approach, the synthesis is easily adopted by automated synthesis modules.

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.

Current status and future needs for standards of radionuclides used in positron emission tomography.

Positron Emission Tomography (PET) is being increasingly used as a quantitative technique for detecting disease and monitoring patient progress during treatment. To ensure the validity of the quantitative information derived from the imaging data, it is imperative that all radioactivity measurements that are part of the imaging procedure be traceable to national or international standards. This paper reviews the current status of standards for positron emitting radionuclides (e.g., (18)F, (68)Ge/(68)Ga, and (124)I) and suggests needs for future work.

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.

Standardization of Ga-68 by coincidence measurements, liquid scintillation counting and 4πγ counting.

The radionuclide (68)Ga is one of the few positron emitters that can be prepared in-house without the use of a cyclotron. It disintegrates to the ground state of (68)Zn partially by positron emission (89.1%) with a maximum energy of 1899.1 keV, and partially by electron capture (10.9%). This nuclide has been standardized in the frame of a cooperation project between the Radionuclide Metrology laboratories from CIEMAT (Spain) and CNEA (Argentina). Measurements involved several techniques: 4πß-γ coincidences, integral gamma counting and Liquid Scintillation Counting using the triple to double coincidence ratio and the CIEMAT/NIST methods. Given the short half-life of the radionuclide assayed, a direct comparison between results from both laboratories was excluded and a comparison of experimental efficiencies of similar NaI detectors was used instead.

Standardization of 64Cu and 68Ga by the 4π(PC)ß-γ coincidence method and calibration of the ionization chamber.

The paper treats the application of the 4π(PC)ß-γ coincidence method for the standardization of the radionuclides (64)Cu and (68)Ga. The general coincidence equations are written. Two types of extrapolation were described and used in measurement: the positron-annihilation coincidence, and the counting of all emitted radiations; both methods are compared with respect to results, advantages and drawbacks. The impurities' content correction was applied. The standardized solutions were used to calibrate the ionization chamber CENTRONIC IG12/20A and to determine the gamma-rays emission intensities.

[(68)Ga-labeled peptides for clinical trials - production according to the German Drug Act: the Göttingen experience]. / (68)Ga-markierte Peptide für klinische Studien. Herstellung gemäß Arzneimittelgesetz: Göttinger Erfahrungen.

The AMG implies far-reaching implications for the synthesis of new radiopharmaceuticals for clinical trials. AIM, METHODS: As a part of the DFG-funded Clinical Research Group (KFO 179) a project designated "Immuno-PET for assessment of early response to radiochemotherapy of advanced rectal cancer" was initiated. This trial is focused on a trivalent bispecific humanized monoclonal antibody, and a 68Ga-labeled peptide. Following the new regulatory framework we established a GMP-compliant cleanroom laboratory and applied for a manufacturing permission. RESULTS: During the project constructural, personnel and organizational conditions for a successful application were established, including a quality management system. A GMP-conform cleanroom laboratory class C was constructed, equipped with a two-chamber lock. The actual manufacturing is performed in a closed system with subsequent sterile filtration. The manufacturing processes have been automatised and validated as well as the necessary quality controls. The manufacturing permission was granted after an official inspection. CONCLUSIONS: The new German Drug Act is considered as a break in the production practice of nuclear medicine. The early involvement and communication with the authorities avoids time-consuming and costly planning errors. It is much to be hoped that the new legal situation in Germany will not cause serious impairments in the realization of clinical trials in German nuclear medicine.

Quantifying and reducing the effect of calibration error on variability of PET/CT standardized uptake value measurements.

UNLABELLED: The purpose of this study was to measure the errors introduced by regular calibration of PET/CT scanners and to minimize the effect of calibration error on standardized uptake value measurements. METHODS: Global calibration factors from 2 PET/CT scanners were recorded for 3.5 and 1.8 y, comparing manufacturer-recommended protocols with modified protocols to evaluate error contributions due to operator-influenced procedures. Dose calibrator measurements were evaluated using National Institute of Standards and Technology-traceable sources. RESULTS: Dose calibrator variability was less than 1%, although there was a consistent bias. Global scaling variability was reduced from 6% to 4% for scanner 1 and from 11% to 4% for scanner 2 when quality assurance and quality control procedures were applied to the calibration protocol. When calibrations were done using a (68)Ge/(68)Ga phantom, the variability for both scanners was reduced to approximately 3%. CONCLUSION: Applying quality assurance and quality control procedures to scanner calibration reduces variability, but there is a still a residual longitudinal scanner variability of 3%-4%. The procedures proposed here reduce the impact of operator error on scanner calibration and thereby minimize longitudinal variability in standardized uptake value measurements.

Primary standardization of (67)Ga radiopharmaceuticals.

The two-dimensional extrapolation technique and dead time extrapolation technique of 4pibeta-gamma-coincidence counting were used to standardize the activity of (67)Ga. The counting results of the two absolute counting techniques showed good agreement while the two-dimensional extrapolation technique could save about 50% of the total counting time in this study. The accuracy of the Capintec CRC-15R radionuclide calibrator used by the radiopharmacy of INER was studied in this research. A new calibration setting number, 99, was recommended to the radiopharmacy of INER in the Bayer 10mL sterile empty vial geometry.

Processing of generator-produced 68Ga for medical application.

UNLABELLED: The (68)Ge/(68)Ga generator provides an excellent source of positron-emitting (68)Ga. However, newly available "ionic" (68)Ge/(68)Ga radionuclide generators are not necessarily optimized for the synthesis of (68)Ga-labeled radiopharmaceuticals. The eluates have rather large volumes, a high concentration of H(+) (pH of 1), a breakthrough of (68)Ge, increasing with time or frequency of use, and impurities such as stable Zn(II) generated by the decay of (68)Ga, Ti(IV) as a constituent of the column material, and Fe(III) as a general impurity. METHODS: We have developed an efficient route for the processing of generator-derived (68)Ga eluates, including the labeling and purification of biomolecules. Preconcentration and purification of the initial generator eluate are performed using a miniaturized column with organic cation-exchanger resin and hydrochloric acid/acetone eluent. The purified fraction was used for the labeling of nanomolar amounts of octreotide derivatives either in pure aqueous solution or in buffers. RESULTS: Using the generator post-eluate processing system, >97% of the initially eluated (68)Ga activity was obtained within 4 min as a 0.4-mL volume of a hydrochloric acid/acetone fraction. The initial amount of (68)Ge(IV) was decreased by a factor of 10(4), whereas initial amounts of Zn(II), Ti(IV), and Fe(III) were reduced by factors of 10(5), 10(2), and 10, respectively. The processed (68)Ga fraction was directly transferred to solutions containing labeling precursors-for example, DOTA-dPhe(1)-Tyr(3)-octreotide (DOTATOC) (DOTA = 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid). Labeling yields of >95% were achieved within 10 min. Overall yields reached 70% at 20 min after generator elution relative to the eluted (68)Ga activity, not corrected for decay. Specific activities of (68)Ga-DOTATOC were 50 MBq/nmol using a standard protocol, reaching 450 MBq/nmol under optimized conditions. CONCLUSION: Processing on a cation-exchanger in hydrochloric acid/acetone media represents an efficient strategy for the concentration and purification of generator-derived (68)Ga(III) eluates. The developed scheme guarantees high yields and safe preparation of injectable (68)Ga-labeled radiopharmaceuticals for routine application and is easy to automate. Thus, it is being successfully used in clinical environments and might contribute to a new direction for clinical PET, which could benefit significantly from the easy and safe availability of the radionuclide generator-derived metallic positron-emitter (68)Ga.

Standardization of (67)Ga using a 4pi(LS)beta-gamma anti-coincidence system.

(67)Ga is an interesting radionuclide as it is widely used in nuclear medicine. The meta-stable level related to the 93.3keV gamma-transition represents the main difficulty when using the coincidence method to standardize this radionuclide. The 4pi(LS)beta-gamma anti-coincidence system implemented at LNHB is based on the use of electronic modules specifically designed for radioactivity metrology. On the contrary to classical coincidence systems, activity measurements of (67)Ga are carried out as for prompt beta-gamma emitters; indeed, when using a live-timed anti-coincidence system with extendable dead times, the problem due to the excess of counting generated by the meta-stable level is avoided. Considering that the standardization of (67)Ga does not depend on the decay scheme parameters (except for the half-life), the measurement of the gamma-emission intensities has been performed. The standardization of this radionuclide was also a good opportunity for a new participation of our laboratory in the SIR of (67)Ga (International Reference System); the result obtained with the 4pi(LS)beta-gamma anti-coincidence system is compared with those submitted by other National Metrology Institutes (NMIs). The non-extendable dead times used in most of the participations could be one of the causes responsible for the abnormal dispersion of the results. The optimization of the standard solution of (67)Ga for the radioactive source preparation is also discussed.

Primary standardization of 72Ga.

The activity of 72Ga sources produced by irradiation at the IEA-R1 reactor have been performed in a 4pibeta-gamma coincidence system by using the extrapolation technique. The measurements were undertaken selecting two windows in the gamma-channel, in order to check the consistency of the results. A Monte Carlo calculation was performed in order to predict the behavior of the observed activity as a function of the 4pibeta detector efficiency and the results were compared to experimental values.

Standardization of 68(Ge+Ga).

The radionuclide 68Ga is mainly a positron emitter (89.2%), with a half-life of 67.7 min. It is used in nuclear medicine, being chemically extracted from the mixture 68(Ge+Ga); its precursor, 68Ge, disintegrates 100% by electron capture, with a half-life of 270.8d (Table of radionuclides, comments and Evaluation). A 4pibeta-gamma coincidence method was used for standardization, with a 4pi proportional beta-detector and a NaI(Tl) gamma detector. Registration of the capture radiations was avoided using foil absorption and a high beta threshold. Using supplementary foils for positron absorption, extrapolation graphs were obtained, with a mean slope of -4.4%. Care was taken to compensate for the loss of 68Ge during the preparation of solid sources for measurement. A combined uncertainty of 1.1% was estimated.