Reactor production of anhydrous18F ion

The direct production of anhydrous¹³F ion has been achieved through the incorporation of a new approach to hot atom reactions for reactor generated radiopharmaceuticals. Capitalizing on the traditional Li₂CO₃ method for hydrated¹⁸F production, a unique target design and geometry utilizing neutron generated energetic tritions emerging from the surface of a thin LiF embedded stainless steel matrix react with gaseous O₂ to produce¹⁸F as a free recoiling anhydrous species. Approximately 10–15 MBq of reactive anhydrous¹⁸F ion absorbed onto a metallic foil has been produced by this method. Verification of the production of¹⁸F was substantiated through decay measurements using Ge(Li) spectroscopic analysis, and by the synthesis of¹⁸F-fluoromethane gas. Cyclotron gas target chemistry which has been instrumental in the preparation of¹⁸F-2FDG and other metabolic tracers may be reproduced using this technique by the addition of 1% F₂ scavenger gas to a recirculating reactor gas handling system.     

Aerosol and gaseous radioidine concentration in the air of Prague after the Chernobyl accident

Data on¹³¹I concentration in the atmosphere of Prague observed during the first days after the Chernobyl accident are presented. The sampling device enabling the differentiation between aerosol-fixed and gaseous form of¹³¹I is briefly described. The highest total¹³¹I concentration, 63 Bq.m^–3, was observed between 30 April and 1 May. Until 9 May the level of¹³¹I activity ranged between 14 and 1 Bq.m^–3 and then dropped below 1 Bq.m^–3. The content of gaseous¹³¹I was found to be a significant and represented on average 60–80% of its total activity.     

Autoradiolysis of the 2-deoxy-2-[<Superscript>18</Superscript>F]fluoro-D-glucose radiopharmaceutical

Summary To control virtually the toxic compounds and to improve quality control of the solution of 2-deoxy-2-[¹⁸F]fluoro-d-glucose (2-[¹⁸F]FDG), the products of its autoradiolysis were analyzed by high-performance liquid chromatography with electrospray mass spectrometric and radiometric detectors (HPLC/MS/RAD), thin layer chromatography on TLC silica plate and HPTLC on amino modified silica plate. Except Kryptofix^™ 2.2.2, glucose and fluoride anion, no by-products and impurities were observed by LC/MS analysis of fresh 2-[¹⁸F]FDG samples. The analysis performed in the time interval of 6 to 48 hours after the end of 2-[¹⁸F]FDG synthesis indicated that the activity of the autoradiolysis products separated by HPLC did not exceed 1.3%. As the main autoradiolysis products of 3.3 ^. 10^-5 to 4.4 ^. 10^-5M 2-[¹⁸F]FDG solution of original specific activity 0.5-1.5 GBq ^. cm^-3 were established: arabinose - 2.8 μM (G= 0.07/100 eV), gluconic and glucuronic acids 1.8-0.5 μM (G =0.01-0.05/100 eV), arabinose and araburonic acids occurred under 0.5 μM concentration at residual glucose contents about 0.14 mM. Radiation chemical yields of active products were calculated from molar activity of 2-[¹⁸F]FDG and the percentage of their activity: 0.5% radiochemical yield of 2-[¹⁸F]fluoroglucuronic acid corresponds to the G = 0.004/100 eV and 0.3% yield of 2-[¹⁸F]fluorogluconic acid issues G = 0.003/100 eV.     

Production of18F using a natural water target at the CV-28 cyclotron at IPEN-CNEN/SP

The development of an automated water target for the production of¹⁸F is described. The system was fully fested and shown to be reliable and secure. The chemical separation of¹⁸F was carried out using an anionexchange resin and K₂CO₃ as eluent. The¹⁸F production yields were, on average, (4.81±0.42) MBq/Ah and the specific activity was higher than 6.623×10⁵ MBq/mmol. Heat transfer measurements and calculations were made.     

Synthesis of <Emphasis Type="Italic">O</Emphasis>-(2-[<Superscript>18</Superscript>F]fluoroethyl)-<Emphasis Type="Italic">L</Emphasis>-tyrosine and its biological evaluation in B16 melanoma-bearing mice as PET tracer for tumor imaging

O-(2-[¹⁸F]fluoroethyl)-L-tyrosine ([¹⁸F]FET), a fluorine-18 labeled analogue of tyrosine, has been synthesized and biologically evaluated in tumor-bearing mice. The whole synthesis procedure is completed within 50 min. The radiochemical yield is about 40% (no decay corrected) and radiochemical purity more than 97% after simplified solid phase extraction. [¹⁸F]FET shows rapid, high uptake and long retention in the tumor as well as low uptake in the brain. The ratios of tumor-to-muscle (T/M) and tumor-to-blood (T/B) of [¹⁸F]FET are similar to those of [¹⁸F]FDG, but the ratios of tumor-to-brain (T/Br) are 2–3 times higher than that of [¹⁸F]FDG. Autoradiography of [¹⁸F]FET demonstrates a remarkable accumulation in melanoma with high contrast. It appears to be a probable competitive candidate for melanoma imaging with PET. Supported by the Knowledge Innovation Project of Chinese Academy of Sciences (No. KJCX1-SW-08) and the National Natural Science Foundation of China (Grant No. 30371634)     

Determination of atmospheric lead-210 by alpha-scintillation counting of air filters

Alpha-counting of filters used to sample large volumes of air provides a convenient way of determining atmospheric concentrations of²¹⁰Pb. Following decay of short-lived²²²Rn and²²⁰Rn progeny, alpha activity of the filters increases as²¹⁰Pb decays to²¹⁰Po. After transient equilibrium is reached at about 3 y, alpha activity diminishes with the 22.3 y halflife of²¹⁰Pb. The degree of equilibrium between²¹⁰Pb and²¹⁰Po can be calculated subsequent to sampling, and the average concentration of²¹⁰Pb in the air during the sampling period can be computed. Contributions to the total²¹⁰Pb from ambient short-lived radon progeny are small, typically 2–4%. Using high volume air samplers with collection rates of 1.1–1.7 m³/min for 24 h periods, and using counting times of 2 h for 20 cm² filter sections, we measured alpha counts ranging from 0.0100±0.0050 to 0.200±0.0200 dps. Periodic measurements on 100 of these filters over a 4 y period yielded mean²¹⁰Pb levels with standard deviations less than ±15%. The method requires minimal sample preparation and can be used to determine past atmospheric²¹⁰Pb concentrations on filters stored for up to 20 y and more.     

Automated synthesis of hypoxia imaging agent [18F]FMISO based upon a modified Explora FDG4 module

A new automated synthesis procedure of 1-H-1-(3-[¹⁸F]fluoro-2-hydroxypropyl)-2-nitroimidazole ([¹⁸F]FMISO), a specific hypoxia imaging agent with great significances for the noninvasive, dynamic hypoxia evaluation of cancer, was developed by modifying Explora FDG₄ module, a commercial [¹⁸F]FDG production system, in this study. Its radiochemical synthesis was carried out via two sequent reaction steps, i.e. the nucleophilic displacement of labeling precursor 1-(2′-nitro-1′-imidazolyl)-2-O-tetrahydropyranyl-3-O-tosyl-propanediol (NITTP) with activated ¹⁸F- ion at 100 °C for 8 minutes, and the following hydrolysis with 1M HCl at 100 °C for 5 minutes and neutralization with 1M NaOH. Two-pot reaction with two independent separations was adopted to assure the good separation of final product via solid phase extraction (SPE) based upon combined Sep-pak cartridges instead of high performance liquid chromatography (HPLC). This fast, reliable preparation route of ¹⁸F-FMISO could complete within 50 minutes with about 55% of high radiochemical yield (with decay correction) and more than 98% of good radiochemical purity. The modified module could perform multiple runs of production of [¹⁸F]FMISO.     

Fully automated and simplified radiosynthesis of [<Superscript>18</Superscript>F]-3′-deoxy-3′-fluorothymidine using anhydro precursor and single neutral alumina column purification

[¹⁸F]-3′-deoxy-3′-fluorothymidine ([¹⁸F]FLT) is an established positron emission tomograph (PET)—radiopharmaceutical to study cell-proliferation rate in tumors. Very low practical yield, uncertain and time-consuming high performance liquid chromatography (HPLC) purification, are the main obstacles for the routine use of [¹⁸F]FLT in clinical PET. To obviate these difficulties, we have developed a fully automated radiosynthesis procedure for [¹⁸F]FLT using 5′-O-(4,4′-dimethoxytriphenylmethyl)-2,3′-anhydro-thymidine (DMTThy) and simplified single neutral alumina column purification. The [¹⁸F]FLT yield was 8.48 ± 0.93% (n = 5) (without radioactive decay correction) in a synthesis time of 68 ± 3 min. The radiochemical purity was greater than 95% as confirmed by analytical HPLC using reference standard FLT and also free of non-radioactive impurity. Soluble aluminum in the final product was much below the permissible limits. Di-methyl sulfoxide (DMSO), the reaction medium, could be detected in the final product in trace amounts, well below the permissible levels. The synthesized [¹⁸F]FLT was sterile and bacterial endotoxin free by appropriate tests. PET imaging study in normal rabbits showed distinct localization of [¹⁸F]FLT in organs having rapid cell division rate like bone marrow, guts and snout and the excretion was through the renal route. There were no significant uptakes in bone and brain. The former finding confirms the in vivo stability of the [¹⁸F]FLT. This simplified radiosynthesis procedure can easily be adapted in any commercial or indigenous [¹⁸F]FDG synthesis module for routine [¹⁸F]FLT synthesis without the need of additional automation for HPLC purification.     

Clinical Relevance of [18F]Florbetaben and [18F]FDG PET/CT Imaging on the Management of Patients with Dementia

PET of β-Amyloid plaques (Aβ) using [¹⁸F]florbetaben ([¹⁸F]FBB) and [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG) increasingly aid clinicians in early diagnosis of dementia, including Alzheimer’s disease (AD), frontotemporal disease, dementia with Lewy bodies, and vascular dementia. The aim of this retrospective analysis was to evaluate clinical relevance of [¹⁸F]FBB, [¹⁸F]FDG PET and complimentary CSF measurements in patients with suspected dementia. In this study, 40 patients with clinically suspected or history of dementia underwent (1) measurement of Aβ peptides, total tau, and p-tau protein levels in the cerebrospinal fluid (CSF) compared with healthy controls (HC); (2) clinical and neuropsychological assessment, which included Consortium to Establish a Registry for Alzheimer’s Disease neuropsychological assessment battery (CERAD-NAB); (3) [¹⁸F]FBB and [¹⁸F]FDG PET imaging within an average of 3 weeks. The subjects were within 15 days stratified using PET, CSF measurements as HC, mild cognitive impaired (MCI) and dementia including Alzheimer´s disease. The predictive dementia-related cognitive decline values were supporting the measurements. PET images were evaluated visually and quantitatively using standard uptake value ratios (SUVR). Twenty-one (52.5%) subjects were amyloid-positive (Aβ+), with a median neocortical SUVR of 1.80 for AD versus 1.20 relative to the respective 19 (47.5 %) amyloid-negative (Aβ-) subjects. Moreover, the [¹⁸F]FDG and [¹⁸F]FBB confirmed within a sub-group of 10 patients a good complimentary role by correlation between amyloid pathology and brain glucose metabolism in 8 out of 10 subjects. The results suggest the clinical relevance for [¹⁸F]FBB combined with [¹⁸F]FDG PET retention and CFS measurements serving the management of our patients with dementia. Therefore, [¹⁸F]FBB combined with [¹⁸F]FDG PET is a helpful tool for differential diagnosis, and supports the patients’ management as well as treatment.     

One-step conjugation of glycylglycine with [<Superscript>18</Superscript>F]FDG and a pilot PET imaging study

This study describes a single step conjugation of Glycylglycine (GlyGly) which is a small peptide, with [¹⁸F]FDG via oxime formation. Amiooxy-functionalization of GlyGly (AO-GlyGly) was accomplished through the reaction of Boc-aminooxy succinimide ester. Conjugation reaction was performed at 100 °C for 30 min in a vial containing AO-GlyGly and [¹⁸F]FDG solution. The radiolabeled product ([¹⁸F]FDG-GlyGly) was obtained with 98.65?±?0.35% yield without any purification step which makes this method more attractive for ¹⁸F radiolabeling. The present study is concluded with an in vivo pilot animal PET study to assess biodistribution and kinetics of chemoselectively [¹⁸F]FDG tagged GlyGly in vivo.     

Determination of Total Radiochemical Purity of [18F]FDG and [18F]FET by High-Performance Liquid Chromatography Avoiding TLC Method

The goal of this work was to present two high-performance liquid chromatography (HPLC) method that could be applied for the determination of the total radioactive purity of 2-deoxy-2-[¹⁸F]fluoro-D-glucose ([¹⁸F]FDG) and O-(2-[¹⁸F]fluoroethyl)-L-tyrosine ([¹⁸F]FET). The separation of [¹⁸F]fluoride ions, [¹⁸F]FET and [¹⁸F]FET intermediate was accomplished on LiChrosper RP-18, 250?×?4 mm, 5 µm (Merck) analytical column. For mobile phase 10 mM potassium dihydrogen phosphate buffer at pH7 (A) and acetonitrile (B) was used: 0–2 min: 15% B; 2–12 min: 85% B; 12–15 min: 15% B, respectively. Analysis of [¹⁸F]FDG was performed using LiChrosper 100 NH₂, 250?×?4.5 mm, 5 µm (Merck) analytical column. The initial mobile phase composition was 10 mM KH₂PO₄ buffer (pH7) and acetonitrile (15:85, v/v) and the acetonitrile ratio was decreased to 15% at 2 min after the sample injection and held for 5 min. Complete elution of [¹⁸F]fluoride ions from stationary phases could be achieved by adding 10 mg/mL K[¹⁹F]F to radioactive samples in a ratio 1:1 during the sample preparation. Recovery of [¹⁸F]fluoride ions ranged from 99.5 to 100.6%. The validation of the developed methods showed good results for linearity (r²?=?0.9981–0.9996), specificity (R_S?=?3.7–10.2), repeatability (%Area RSD_%?=?1.2–4.3%) and limit of quantitation (LOQ?=?1.6–4.5 kBq). During the cross-validation similar radiochemical purity values were obtained by the novel HPLC methods and thin layer chromatography performed according to the recommendations of the Ph. Eur. monographs.

     

Determination of organic,inorganic and particulate iodine in the coastal atmosphere of Japan

A reliable method for the sampling and analysis of atmospheric iodine species was developed. The air filtering system consisted of a 0.4 m Nuclepore^® filter, 47 mm in diameter, for particulate collection followed by two, 47 mm in diameter, cellulose filters for inorganic iodine collection. The latter filters had been impregnated with 1N LiOH in a 10% glycerol-water mixture. The organic iodine was collected by two beds holding 0.2 g of fibriform activated charcoal produced from phenol resin. Supplementation of the charcoal with triethylendiamine (TEDA) enhanced the sorption ability for gaseous iodine. The filters were analyzed by neutron activation analysis. The background radioactivity could be reduced by using the fibriform activated charcoal due to the low content of impurities in the phenol resin. The background count for¹²⁸I (443 keV) obtained from the fibriform activated charcoal was about one order of magnitude lower than that of the conventional granular one (plant origin). Approximate detection limits for particulate, inorganic and organic iodine were 1, 0.5 and 0.5 ng/m³, respectively, when 50 m³ of air was sampled by this system. The air was sampled at two locations along the coast of Ibaraki, Japan. The concentration ranges of particulate, inorganic and organic iodine were 0.3–3.4, 1.2–3.3 and 7.8–20.4 ng/m³, respectively. Almost 90% of the atmospheric iodine was in a gaseous form in which organic iodine was dominant.     

Depth distribution of239,240Pu and137Cs in soils of South Korea

Depth distribution of^239,240Pu and¹³⁷Cs in the soils of South Korea have been studied. The average accumulated depositions were estimated roughly to be 54.8±32.1 Bq·m^–2 for^239,240Pu, 1.6±1.0 Bq· ·m^–2 for²³⁸Pu and 1982.8±929.1 Bq·m^–2 for¹³⁷Cs. The activity ratios of^239,240Pu/¹³⁷Cs in soils were found to be in the narrow range of 0.0153 to 0.0364 with a mean value of 0.0230±0.006. The concentrations of^239,240Pu and¹³⁷Cs in soils decrease exponentially with increasing the soil depth. A significant correlation was found between the concentration of^239,240Pu and that of¹³⁷Cs. The activity ratios of^239,240Pu/¹³⁷Cs tend to increase slightly with increasing soil depth.     

Radiosynthesis and preliminary biological evaluation of the 2-[<Superscript>18</Superscript>F]fluoropropionic acid enantiomers for tumor PET imaging

The aim of this study was to synthesize the optically pure [¹⁸F]FPA, and to investigate the diagnostic value of different isomers. Semi-automated radiosynthesis of R-[¹⁸F]FPA or S-[¹⁸F]FPA was respectively from the chiral precursor (S)- or (R)-ethyl 2-(((trifluoromethyl)sulfonyl)oxy)propanoate via a two-step reaction and performed on the commercial FDG synthesizer. The improved radiochemical yields of R-[¹⁸F]FPA and S-[¹⁸F]FPA were 30–40% (decay-uncorrected, n = 10) in 35 min. There was no significant difference on the biodistribution of two enantiomers in normal mice (P > 0.05), but positron emission tomography imaging demonstrated that R-[¹⁸F]FPA was more suitable for PC3 tumor imaging than S-[¹⁸F]FPA and [¹⁸F]FDG.     

The analysis of radiolysis impurities in <Superscript>18</Superscript>F-FDG and methods of repurification

To investigate the radio impurity in the radiolysis of ¹⁸F-FDG at high radiodose and radioconcentrated solutions and develop methods of repurification. The radiolysis of ¹⁸F-FDG was analyzed by TLC. The radio-impurity was confirmed by biodistribution and small animal PET/CT studies. ¹⁸F-FDG was unstable at high radioconcentrition over 37 GBq/mL or under basic condition. TLC, biodistribution and PET/CT all indicated that the main autoradiolysis byproduct was free fluoride ion. The radiolyzed ¹⁸F-FDG was repurified by solid-phase extraction (SPE) column. The repurified ¹⁸F-FDG had a radiochemical purity (RCP) of over 99% and significantly lower bone uptake than that was before repurification (P = 0.0003). There was a positive correlation between the recovery yield and the purity of ¹⁸F-FDG (R ² = 0.66).     

Synthesis of18F-2-deoxy-2-fluoro-d-glucose and18F-3-deoxy-3-fluoro-d-glucose with no-carrier-added18F-fluoride

Using a distillation method for the separation of¹⁸F-fluoride from aqueous¹⁸F-solutions obtained after cyclotron irradiation of a water target by means of the¹⁶O(³He, p)¹⁸F reaction, the radiohalogen could be generated as a highly reactive species for nucleophilic substitution reactions. Thus, with the starting compounds 1,3,4,6-tetra-O-acetyl-2-O-trifluoromethanesulfonyl--D-mannopyranose and 1,2:5,6-di-O-isopropylidene-3-O-trifluoromethanesulfonyl--D-allofuranose¹⁸F-2-deoxy-2-fluoro-D-glucose (2-¹⁸FDG) and¹⁸F-3-deoxy-3-fluoro-D-glucose (3-¹⁸FDG) could be synthesized with radiochemical yields of 71.6% and 85.9%, respectively. Including purification by HPLC, the total preparation time was 70 min, yielding the glucose derivatives in a no-carrier-added state. Specific activities coold be calculated to be greater than 10³ Ci/mmol.     

[18F]FDG synthesis by Anatech RB-86 robotic system: Improvements and general considerations

A series of changes and updatings to the [¹⁸F]FDG setup of the Anatech RB-86 robotic system are described. They include improved [¹⁸O]H₂O recovery, “one-pot” reaction, elimination of the SPE step and base-assisted hydrolysis. Considerations on this last point are also reported. Thus, a remarkable improvement in the radiochemical yield, which is now 81% (decay corrected to SOS) with a synthesis time of just 40 minutes, has been achieved. The influence of several different reaction vessel materials on the synthesis is also briefly examined.     

Statistical analysis of the results of99mTc-MDP quality control

The methods used for control of radiochemical purity of^99mTc-MDP are presented. TLC method on silica gel, developed with methanol and acetone (11 v/v), was convenient for determination of^99mTcO ₄ ^– with the content of 2.6±1.2%. The reliable results on detection of^99mTc hydrolyzate (2.2±1.3%) and for another^99mTc-MDP complex (13.2±2.8%) were obtained by application of ITLC (SA), developed with Sn-MDP. By Sephadex G-25 column chromatography (1.5 cm×5 cm) the separation of^99mTcO ₄ ^– was not achieved. The range of normal^99mTc-MDP biodistribution values in the organs of experimental animals have been determined. The mean value of bone distribution was 8.4±1.13%/g, in muscles 0.071±0.033%/g, while uptake in liver and kidneys was below 5%. Chi-square test and P show that the results on biodistribution of^99mTc-MDP in liver, bones and muscles are arranged around their mean values, which is statistically allowed.     

Radiolabeling of HER2-specific Affibody molecule with F-18

The presence of human epidermal growth factor type 2 (HER2) on 20-30% of human breast cancer is a prognostic indicator of more rapid disease progression and a therapeutic indicator for anti-HER2 monoclonal antibodies. Because the literature has demonstrated some discordance between primary and metastatic tumors in the same patient for expression of the HER2 marker, we set out to develop an imaging agent that could be used to assess the marker concentration in vivo in an individual patient. The pharmaceutical company Affibody^® AB has optimized the specificity of Affibody^® molecules for HER2. Two Affibody^® molecules, a 7 kDa and an 8 kDa protein, were designed with a single carboxy terminal cysteine in order to provide a specific location for the purposes of labeling for various types of imaging. We have prepared [¹⁸F]FBEM utilizing a coupling reaction between [¹⁸F]fluorobenzoic acid and aminoethylmaleimide. We then optimized the conjugation of this radiolabeled maleimide to the free sulfhydryl of cysteine by incubating at pH 7.4 in phosphate buffered saline containing 0.1% sodium ascorbate. An overall uncorrected yield of radiolabeled Affibody^® molecule of approximately 10% from [¹⁸F]fluoride was achieved in a 2 h synthesis. These conjugated Affibody^® molecules were obtained with a specific activity of 2.51 ± 0.92 MBq/μg. Characterization of the product by HPLC-MS supported the conjugation of [¹⁸F]FBEM with the Affibody^® molecule. The radiolabeled Affibody^® molecule retained its binding specificity as demonstrated by successful imaging of xenografts expressing HER2.     

Electrospray ionization mass spectra of pentoses,hexoses, and 2-deoxy-2-fluoro-<Emphasis Type="SmallCaps">d</Emphasis>-glucose

Electrospray ionization (ESI) mass spectra of hexoses, pentoses, and 2-deoxy-2-fluoro-d-glucose (FDG) were investigated and compared using liquid chromatography/mass spectroscopy (LC/MS). ¹⁸F-FDG is one of the most widely used radiopharmaceuticals. This work is aimed at the possible interpretations of ESI mass spectra and at the comparison of various pentoses (arabinose, ribose, xylose), and hexoses (glucose, fructose, galactose, mannose) which can be formed during the ¹⁸F-FDG’s synthesis or decomposition. As a result, nine major associates were found in the positive and four in the negative mass spectra of all examined saccharides of which intensities and mass can be used with their retention times to determine the saccharide. M · NH₄⁺ and M · COOH⁻ were identified as the most stable associates.