Measurements of the rubidium isotopic activities and the elution parameters of 81mKr generators using a standardized 114mIn source

A method is described for measuring a number of parameters associated with an inorganic ion-exchange krypton generator. These are the activities of rubidium isotopes in inorganic ion-exchange krypton generators, the 81mKr extraction rate, the 81mKr activity delivered to patients during ventilation studies, the elution efficiency, and the radionuclide purity of the eluted gas. The method is based on the calibration of detectors, Ge(Li) and NaI(Tl), with a standardized 114mIn source at matching photon energies. The average activities present in our generators at the end of bombardment (EOB) were 14.6 +/- 3.8 mCi (81Rb), 6.2 +/- 1.6 mCi (82mRb) and 53 +/- 9.4 microCi (83Rb). The 81mKr extraction rate 2 h post-EOB was 10.2 +/- 2.3 mCi/min at an air flowrate of 1 l/min. The 81mKr activity delivered to patients during a ventilation study was 91 +/- 16 mCi. The elution efficiency of the generators averaged 50% +/- 7% at an air flowrate of 1 l/min. The eluted gas contained Rb radioisotopic impurities in trace quantities of approximately 0.06 microCi/l.     

Excitation functions for the formation of some radioisotopes of rubidium in proton induced nuclear reactions on natKr, 82Kr and 83Kr with special reference to the production of 81Rb(81mKr) generator radionuclide

Excitation functions were measured using the “stacked gas cell” technique for the formation of ⁸¹Rb, ^82mRb, ⁸³Rb and ⁸⁴Rb in proton induced nuclear reactions on natural krypton and isotopically enriched ⁸²Kr and ⁸³Kr over the proton energy range of 5–30 MeV. From the experimental data for various enrichments of ⁸²Kr, ⁸³Kr, ⁸⁴Kr and ⁸⁶Kr in target gases, absolute cross-sections were deduced for the reactions ⁸²Kr(p,2n)⁸¹Rb, ⁸³Kr(p,3n)⁸¹Rb, ⁸²Kr(p,n)^82mRb, ⁸³Kr(p,2n)^82mRb, ⁸⁴Kr(p,3n)^82mRb, ⁸³Kr(p,n)⁸³Rb, ⁸⁴Kr(p,2n)⁸³Rb, ⁸⁴Kr(p,n)⁸⁴Rb and ⁸⁶Kr(p,3n)⁸⁴Rb. From those data the differential and integral thick target yields of ⁸¹Rb were calculated. The method of choice for the production of ⁸¹Rb(^81mKr) generator radionuclide is the ⁸²Kr(p,2n)-process on highly enriched ⁸²Kr. Our results show that the optimum energy range for production is E_p = 27 → 19 MeV: the thick target yield of ⁸¹Rb amounts to 48 mCi (1776 MBq)/μAh and the level of 6.47 h ^82mRb impurity to ∼7%. Due to the high yield of the process sufficient quantities of ⁸¹Rb can be produced even at cyclotrons with E_p ≈ 20 MeV.     

Production of 6.5 h 82mRb via the 82Kr(p,n)-process at a low-energy cyclotron—A potential substitute for 82Rb

The production of 6.5 h ^82mRb, a potential substitute for generator-produced 1.2 min ⁸²Rb in myocardial blood flow studies, is discussed. Using a ⁸²Kr gas target and a low-energy cyclotron it is possible to obtain >100 mCi (>3.7 GBq) of high purity ^82mRb. Results of radiation dose calculations for ⁸¹Rb/^81mKr, ⁸²Rb and ^82mRb are reported.     

A 81Rb/81mKr generator made by ion implantation

Isotopically pure ⁸¹Rb was implanted in plastic foils, and the daughter-^81mKr was eluted quantitatively by air or by a 0.9% NaCl solution. The elution yield, the purity of the ^81mKr, and the washing-out losses of ⁸¹Rb were studied as functions of the implantation density. It was seen that the densities below 5 × 10¹² Rb atoms/cm² provide a high yield for elution both by liquid and air. The first 100 MBq implantation-type generator was tested by making a lung-ventilation study in man.     

Kr-81m for determination of right ventricular ejection fraction (RVEF)

A 10–12 mCi ⁸¹Rb^81mKr generator was connected to a specially designed short-period infusion set, to produce an equilibrium activity distribution in the right heart. This procedure was tested in 25 individuals to calculate the right ventricular ejection fraction (RVEF). On average 30 heart cycles were analyzed per study. No background activity from the left heart was visualized because of the radionuclide exhalation. The background from the lungs could be neglected, which is partially due to the ultrashort half-life of the nuclide (t _1/2=13s). Thus, an easy automatic procedure can be applied to delineate the ventricle and to calculate the RVEF. The data showed excellent reproducibility, when investigations were repeated. The method would benefit from use of higher activity generators.     

Bromine-82 contamination in fission product 99mTc-generator eluate

Following receipt of fission product ^99mTc-generators, results of radionuclide purity analysis, performed within 30 min after the first elution, demonstrated detectable levels of a contaminate radionuclide not previously reported. Gamma spectroscopy and half-life determinations confirmed the presence of ⁸²Br. Bromine-82 activity, in eluates from the first elution of 30 generators, received weekly during a 7-month period, ranged from 0.22 Ci (8.235 kBq) to 0.67 Ci (24.68 kBq) per eluate. The ratio of ⁹⁹Mo to ^99mTc ranged from 0.13 nCi to 0.39 nCi per mCi ^99mTc. The presence of ⁸²Br in ^99mTc-generator eluate resulted in falsely elevated ⁹⁹Mo assay determinations using whole vial ⁹⁹Mo assay procedures. For every 0.1 Ci ⁸²Br present in ^99mTc eluate the ⁹⁹Mo assay results were elevated by 1 Ci. Gamma spectroscopy of eluates from additional elutions of these generators failed to detect the presence of ⁸²Br demonstrating the displacement of monovalent bromine anions from the alumina column during the first elution.     

Clearance of thallium-201 from the peripheral blood: Comparison of immediate and standard thallium-201 reinjection

As several reinjection procedures have shown encouraging results in terms of imaging, we investigated whether the kinetics of thallium-201 would differ between the standard stress-redistribution-reinjection approach and the stress-immediate reinjection approach. In 53 consecutive patients with undiagnosed chest pain, 75 MBq (2 mCi)²⁰¹Tl was injected at maximal exercise. In 26 of these patients (group I), 37 MBq (1 mCi)²⁰¹Tl was reinjected immediately after completing the exercise images (the immediate reinjection procedure) and in 27 patients (group II), 37 MBq (1 mCi)²⁰¹Tl was reinjected after completing 3-h redistribution images (the standard reinjection procedure). Mean peak²⁰¹Tl blood activity after exercise was 17.7±12.5 kBq/ml (4.8±3.4 mCi/ml) for group I versus 16.4±9.2 kBq/ml (4.4±2.5 mCi/ml) for group II (NS). The relative increase in²⁰¹Tl blood activity after reinjection of half the initial dose [37 MBq (1 mCi)] exceeded 50% of the initial peak in both groups. The relative amount of²⁰¹Tl delivered to the myocardium was assessed by the area under the curve after both exercise and reinjection, and was 117%±72% for group I and 112%±73% for group II (NS). Blood clearance of²⁰¹Tl was at least biexponential. Mean early decay constants (₁) after exercise and reinjection were 0.30±0.18 min^–1 and 0.22±0.046 min^–1 respectively for group I (T _1/2 2.3 min and 3.2 min respectively, NS), and 0.30±0.12 min^–1 and 0.24±0.07 min^–1 respectively for group II (T _1/2 2.3 min and 2.9 min respectively, NS). For both procedures no significant differences were found between ₁ after exercise and ₁ after injection. The mean late clearance (₂) from the blood was 0.032±0.056 min^–1 and 0.012±0.012 min^–1 respectively for group I (T _1/2 21.6 min and 57.7 min respectively, NS), and 0.036±0.030 min^–1 and 0.014±0.014 min^–1 respectively for group II (T _1/2 19.3 min and 49.5 min respectively, NS). Also, no significant differences were found between ₂ after exercise for both groups and between ₂ after reinjection for both groups. We conclude that reinjection of 37 MBq (1 mCi)²⁰¹Tl (half the initial dose) results in a relative increase in the initial peak and a relative increase in the amount of²⁰¹Tl delivered to the myocardium of more than 50% for both the standard and the immediate reinjection procedure. The clearance of²⁰¹Tl from the blood was not influenced by exercise or by the time of reinjection. Based on²⁰¹Tl kinetics as measured in the peripheral blood, there is no reason to postpone reinjection until 3–4 h following exercise.     

Integral excitation functions for natKr + p up to 116 MeV and optimization of the production of 81Rb for 81mKr generators

Effective cross-sections for the production of ^{79,81,81m,82m,83,84,84m,86}Rb, ^77,79,85mKr and ^77,82Br in the bombardment of ^natKr with protons were measured from threshold up to 116 MeV. Thick-target production-rate curves based on the measured integral excitation functions were also derived for ^{81,82m,83,84,86}Rb, and the optimum incident energy for the production of ⁸¹Rb/^81mKr, as a function of the target thickness in MeV, was determined. Geometry-dependent hybrid-model calculations performed by means of the computer code ALICE/85/300 were found to be in good agreement with the experimental results as well as the derived thick-target production-rate curves.     

81mKr gas generator for lung ventilation study

A generator of ^81mKr was designed and tested. The parent nuclide ⁸¹Rb was produced by the 70 MeV proton induced reactions on a Rb₂SO₄ target. ^81mKr was bubbled out with oxygen gas from the ⁸¹Rb solution, and collected in a reservoir for lung ventilation studies. The generator was continuously operated at the high flow rate up to 101/min. The generator efficiency was 86%. The collection rates in the reservoir were examined under several flow rates. The pure ^81mKr isomer was observed with a NaI (T1) detector at the reservoir.     

Excitation functions of 3He- and α-particle induced nuclear reactions on natural krypton: Production of 82Sr at a compact cyclotron

Excitation functions have been measured for ^natKr(³He, xn)^{82,83,85m,85g,87m}Sr and ^natKr(³He, pxn)^{81,82m,83,84m,84g,86}Rb reactions over the energy range of 10–33 MeV and for ^natKr(α, xn)^{82,83,85m,85g,87m}Sr and ^natKr(α, pxn)^{81,82m,83,84,86}Rb processes from 10 to 25 MeV. Cross section data and calculated thick target yields show that for the production of ⁸²Sr in this energy region the ³He-particle induced process is more suitable than the alpha-induced process. A high current gas target was constructed to test the ⁸²Sr-production yield under actual production conditions using 36 MeV ³He-particles. A thick target yield of 1.49 μCi (55 kBq)/μAh was achieved using natural krypton. The ⁸²Kr(³He, 3n)⁸²Sr process is technically feasible for production and, if long parasitic irradiations could be carried out, the method would be of considerable interest for use at a medium-sized cyclotron.     

A simple radioaerosol generator and delivery system for pulmonary ventilation studies

Details of a simple radioaerosol generator and delivery system are presented. Aerosol streams of ^99mTc-DTPA solution of different distributions were produced. The most useful distribution had an activity median aerodynamic diameter (AMAD) of 0.9 m with a geometric standard deviation of 1.5. This distribution also had more than 96% of aerosol particles with aerodynamic diameter <2 m. The system has been used for patient lung ventilation studies. The aerosol breathing-in period to achieve a satisfactory count rate was 1.8±0.38 min. The radioaerosol images were excellent and comparable to those obtained with ^81mKr gas.     

An extension set for 81Rb-81mKr solution generators for lung ventilation studies

For ⁸¹Rb-^81mKr solution generators, an extension set has been developed, which strips the ^81mKr from the liquid eluate with a stream of air for use in lung ventilation studies. Via a three-way valve the ⁸¹Rb-^81mKr solution generator can be operated alternately in the perfusion mode or in the ventilation mode. Measurements and calculations have been performed to get more insight into the parameters of interest for an optimum design of the extension set and its operation conditions.     

Krypton-81 m and 5-μm radioaerosol images in asymptomatic asthma: a blind marking assessment

Gamma camera images recorded during tidal breathing of krypton-81m (^81mKr) and after slow inhalation of ^99mTc-labelled monodisperse 5-m polystyrene particles were assessed by three independent observers. Results from 20 symptom-free asthmatic subjects, all with a forced expiratory volume in 1 s (FEV₁) at least equal to 75% of the predicted value, were compared with those from 16 healthy non-smoking volunteers. Blind marking scores for the ^81mKr images of the asthmatic subjects related significantly to small airways function. Radioaerosol abnormalities in the asthmatic subjects included excessive deposition of the radioaerosol in the central airways and related significantly to small airways function. Radioaerosol imaging performed better than ^81mKr imaging at differentiating asthmatic from normal subjects. Radioaerosol abnormalities in patients with poor small airways function probably reflect (1) uneven distribution of ventilation to different regions of the lung periphery and (2) changed patterns of airflow in the bronchial tree. Image abnormalities detected in routine clinical ventilation imaging-with ^81mKr or radioaerosol-may sometimes be caused by small airways fysfunction even when the patient's FEV₁ is normal.     

External radiation exposure of personnel working with 99mTechnetium

Radiation from ^99mTc was measured at typical locations in those areas of a nuclear medicine department where approximately 50 Ci ^99mTc is used per year. In addition, measurements of shielded and unshielded syringes containing ^99mTc-labelled radiopharmaceuticals were carried out. From these data radiation exposure of hands and of the whole body of personnel was calculated, taking into consideration the mean working times in the areas and the times of direct and indirect handling of ^99mTc. They were compared with the mean values obtained by personnel dosimetry through quartz fibre pocket dosimeters and TLD finger ring dosimeters. The whole body radiation calculated from local measurements for technicians (163±15 mR/year) (mean±SE) and for physicians (260±15 mR/year) was very low judged by the maximum permissible dose of 5,000 mrem/year and correlated well with those of personnel dosimetry (165±15 R and 265±15 R/year respectively). Although local radiation was rather high during generator elution and while preparing radiopharmaceuticals (13±1.2 mR/h) the radiation exposure to the hands of the radiochemists measured by the TLD finger ring dosimeter was low (2.6±0.2 R/year). This was attained by consistently using long distance tools in order to avoid direct contact with ^99mTc-containing vials and syringes. The most critical point of radiation exposure in our investigation were the finger tips during injection of ^99mTc, when syringe shielding was not used (80–130 mR/injection of 10 mCi). Under our conditions this amounts to 330–560 R/year when a total of 40 Ci is injected by the same physician. This by far exceeds the maximum permissible dose of 60 rem/year. The dose can be reduced extensively to only 2–3 R/year when tungsten shielding of the syringe is consistently used.     

Automated determination of the right ventricular ejection fraction by digital processing of 81mKr scintigrams

A method is presented for the automated determination of the right ventricular ejection fraction (RVEF) by digital image processing of scintigrams obtained by intravenous infusion of Krypton 81m (^81mKr) dissolved in a glucose solution. End-diastolic and end-systolic sum pictures were computed by the addition of approximately 30–40 frames selected from the time-activity curve of a preliminary, manually drawn, right ventricular region of interest. After processing these two images with an adaptive Wiener filter, the right ventricular contour was determined by a recently developed algorithm using morphological and functional criteria. The RVEF was calculated for a series of 51 patients from the counts in the detected right ventricular regions in the end-diastolic and end-systolic sum images. In 16 patients without evidence of cardiopulmonary disease, the mean RVEF was 50±6.1%. RVEF was significantly reduced in 18 patients with obstructive pulmonary disease (42±6.5%) and in 17 patients with congestive cardiomyopathy (36±7.1%). The correlation coefficient between two determinations of the RVEF was r=0.94. Through digital image processing, the determination of the RVEF by radioimage processing, the determination of the RVEF by radioventriculography with ^81mKr showed high reliability and reproducibility.     

Studies on commercially available 99Mo/99mTc radionuclide generators—II. Operating characteristics and behavior of 99Mo/99mTc generators

Two ⁹⁹Mo/^99mTc generators from each of the four U.S. manufacturers were tracked through their clinical lifetimes by monitoring elution efficiency and the amount of total technetium per mCi ^99mTc in the individual generator eluants. The resulting values of (moles Tc)/(mCi ^99mTc) were compared to theoretical values calculated using an existing nomograph. The nomograph consistently underestimates the mass of total technetium in generator eluants by 25–300%. Also, there are statistically significant (P < 0.05) differences in the amount of total technetium per mCi of ^99mTc in the eluants from generators of different manufacturers. These results are interpreted in terms of absorbed radiation dose causing a transient holdback of ^99mTc and in terms of excess technetium being loaded onto the generators at the time of manufacture. The relevance of these experimental results to the preparation of reduced ^99mTc radiopharmaceuticals is discussed.     

81mKr: Production,application, and use of computer for ventilation studies

Theoretical excitation functions have been used for the production of neutron-deficient rubidium isotopes by (, kn) reactions on ⁷⁹Br and ⁸¹Br. Krypton generators have been produced using the internal beam of the cyclotron of the Rudjer Bokovi Institute. New methods for target preparation and radiochemical separation have been developed.Preliminary clinical studies have been performed with the aim of investigating the possible use of krypton generators in conjunction with a gamma camera and a digital computer.The digital computer was used to normalize images of regional ventilation and to calculate and display isoventilation regions.Clinical examples of images of regional ventilation that permit resolution between nonventilated and well-ventilated regions are given.     

Comparative biodistribution of indium- and yttrium-labeled B3 monoclonal antibody conjugated to either 2-(p-SCN-Bz)-6-methyl-DTPA (1 B4M-DTPA) or 2-(p-SCN-Bz)-1,4,7,10-tetraazacyclododecane tetraacetic acid (2B-DOTA)

The biodistribution of indium-111/yttrium-88-labeled B3 monoclonal antibody, a murine IgG1k, was evaluated in non-tumor-bearing mice. B3 was conjugated to either 2-(p-SCN-Bz)-6-methyl-DTPA (1B4M) or 2-(p-SCN-Bz)-1,4,7,10 tetraazacyclododecane tetra-acetic acid (2B-DOTA) and labeled with ¹¹¹In at 1.4–2.4 mCi/mg and ⁸⁸Y at 0.1–0.3 mCi/mg. Non-tumor-bearing nude mice were co-injected i.v. with 5–10 Ci/4–10 g of ¹¹¹In/⁸⁸Y-labeled B3 conjugates and sacrificed at 6 h and daily up to 168 h post-injection. Mice injected with ¹¹¹In/⁸⁸Y (IB4M)-B3 showed a similar biodistribution of the two radiolabels in all tissues except the bones, where significantly higher accretion of ⁸⁸Y than ¹¹¹In was observed, with 2.8% ± 0.2% vs 1.3% ± 0.16% ID/g in the femur at 168 h, respectively (P<0.0001). In contrast, mice receiving the ¹¹¹In/⁸⁸Y-(DOTA)-B3 conjugate showed significantly higher accumulation of ¹¹¹In than ⁸⁸Y in most tissues, including the bones, with 2.0% ± 0.1% vs 1.2% ± 0.09% ID/g in the femur at 168 h, respectively (P<0.0001). Whereas the ratios of the areas underneath the curve (%ID × h/g) in the blood, liver, kidney and bone were 0.96, 1.12, 1.13, and 0.74 for ¹¹¹In/⁸⁸Y-(IB4M)-B3 and 0.84, 1.23, 1.56, and 1.31 for ¹¹¹In/⁸⁸Y (DOTA)-B3, respectively, ratios 1 were observed between ¹¹¹In-(IB4M)-B3 and ⁸⁸Y-(DOTA)-B3. In summary, while neither IB4M nor DOTA was equally stable for ¹¹¹In and ⁸⁸Y, the fate of ⁸⁸Y- (DOTA)-B3 could be closely traced by that of ¹¹¹ In-(IB4M)-B3.     

Single-photon emission tomography studies of rubidium-81 in the detection of ischaemic heart disease,using a stress-reinjection protocol

The present study was designed to determine the feasibility of using single-photon emission tomography (SPET) imaging with rubidium-81 (T _1/2 = 4.54 h) to detect ischaernic heart disease, using a stress-reinjection protocol and a specially constructed 511-keV hexagonal hole collimator for a standard gamma camera. The diagnostic performance of ⁸¹Rb SPET in detecting coronary artery disease (CAD) was investigated in 52 patients with a high prevalence of CAD. Coronary arteriography was performed in 34 patients, 25 of whom were classified as having significant stenosis (50%). At peak exercise (Cornell protocol), 111–222 MBq ⁸¹Rb was injected i.v. for stress imaging, and after 3 h of rest, 74–111 MBq was reinjected for rest imaging. The displayed short- and long-axis slices and the polar map images were interpreted qualitatively. In comparison to coronary arteriography, which served as the gold standard, the performance of ⁸¹Rb SPET revealed a sensitivity of 95% for the detection of CAD. Images of diagnostic quality were obtained in all patients, these being comparable to thallium-201 SPET images. In conclusion, these results indicate that the described method can be routinely used for the positron emitter ⁸¹Rb with a conventional gamma camera and special shielding. ⁸¹Rb has the well-known advantages of a potassium analogue and ⁸¹Rb SPET permits better visualization, particularly of the posterior wall of the myocardium, due to the higher photon energy. Considering the typical dose of ²⁰¹Tl used for SPET (74–148 MBq), a ⁸¹Rb SPET scan imposes a significantly lower radiation burden on the patient.     

Regional distribution of ventilation and perfusion in patients with obstructive pulmonary disease and alpha1-antitrypsin deficiency

Regional distribution of pulmonary ventilation and perfusion has been determined of 13 patients with chronic obstructive pulmonary disease (COPD). Eight patients had alpha₁-antitrypsin deficiency (α₁ATD). Ventilation studies were carried out using xenon-133 (¹³³Xe) and krypton-81m (^81mKr) gases. Trapping indices were determined from the wash-out part of the xenon ventilation studies. Results obtained from patients were compared with those of normal controls. Ventilation studies with ^81mKr showed pulmonary changes more clearly than did ¹³³Xe studies and the trapping of radio-xenon was more extensive in lung bases than in apices whether or not the patients had α₁ATD. The distribution of perfusion followed a pattern similar to that of ventilation, but did not differ statistically from that of the normal controls.