Influence of transport line material on the molar activity of cyclotron produced [18F]fluoride
Introduction
Production of fluorine-18-labeled radiopharmaceuticals is problematic because it not only produces the desired radiolabeled product but also is always associated with the production of various levels of the same compound without the radioactive label. In practice, this effect can be seen as variability in the molar activity (Am), defined as the radioactivity of a radionuclide divided by its molar amount (Bq/mol). Am is an important quality parameter that should be taken into account when manufacturing radiopharmaceuticals to be used as tracers, and a low Am is considered undesirable. Indeed, the Working Group on Nomenclature in Radiopharmaceutical Chemistry initiated by the European Association of Nuclear Medicine has recently suggested the use of Am instead of specific activity if the molar amount of radioactive compound is expressed. The significance of Am has been extensively discussed in a recent article by Lapi and Welch [1].
As noted, Am is defined (Eq. 1) as the radioactivity (Ai) of a radionuclide divided by the molar amount of the radionuclide (ni). Usually, the mass of the stable form of a nuclide is much greater than that of its radioactive form, especially for positron emitters commonly used for positron emission tomography (PET).
The theoretical maximum Am for fluorine-18 is 63 TBq/μmol (1710 Ci/μmol), implying no presence of stable fluoride. The highest value reported in the literature for fluorine-18 at end of bombardment (EOB) in irradiated oxygen-18 water is 43 TBq/μmol (1160 Ci/μmol) [2]. This value is remarkable because other reported values are significantly lower, varying from 22 to 9900 GBq/μmol (0.6 to 270 Ci/μmol) [[3], [4], [5], [6], [7], [8], [9]].
A high Am of the starting material fluorine-18 can lead to a high Am of the labeled radiopharmaceutical. High Am is considered especially advantageous, for example when imaging various receptor systems, because the low mass of the radioligand (tracer) does not saturate the binding sites, and tracer molecules can have pharmacological or toxic effects [2, 10, 11]. However, high Am is in many cases not straightforward to achieve, and to improve the value, the stable form of the nuclide must be excluded as much as possible during the production of fluorine-18 and labeling synthesis. If the mass of the stable form of the nuclide is constant, the Am can be elevated by increasing the amount of the radioactive form of the nuclide. Thus, to minimize the amount of stable fluoride, sources of it need to be identified. Potential sources that have been widely discussed include oxygen-18 water, length of irradiation, synthesis reagents, transfer lines, and radiolytic degradation of fluorinated materials [2, 4, 9, 10, [12], [13], [14], [15], [16], [17], [18], [19], [20]].
Here we have studied the role of the transport tubing materials as sources of stable fluoride in production of fluorine-18. Four different tubing materials were chosen to transport cyclotron-irradiated oxygen-18 water from the target chamber to the hot cell. Polyether ether ketone (PEEK) and polypropylene (PP) tubing represented non-fluorinated polymers while polytetrafluoroethylene (PTFE) and ethylene tetrafluoroethylene (ETFE) were fluorinated polymers. Batches of oxygen-18 water, irradiated or non-irradiated, were transported via tubing or without tubing (no-tubing) and divided into two fractions (A and B). Fluoride concentrations in fractions A were measured using ion liquid chromatography (ILC) equipped with conductometric detection, and a few A fractions were also analyzed in two outside laboratories. Ams were calculated by combining the concentration results of fluoride with radioactivity measurements. To verify these Am results, 18 syntheses of [18F]fluciclatide, an integrin-targeted PET radiopharmaceutical, were made using the other fraction (fraction B) of the oxygen-18 water. The concentration of fluciclatide and the Am of [18F]fluciclatide in the end product were determined using high-performance liquid chromatography (HPLC) for mass determination. Flow charts of the study are presented in Fig. 1 and in more detail in the supplementary material (Fig. S1). Our results suggest that removing fluorinated tubing as a source of carrier fluoride might increase Am.
Section snippets
Targetry and transport lines
No-carrier-added aqueous [18F]fluoride was produced by irradiating enriched oxygen-18 water (GMP grade, 98%, Rotem Industries Ltd., Medical Imaging, Dimona, Israel) with 17 MeV protons from a CC-18/9 cyclotron (Efremov Institute of Electrophysical Apparatuses, St. Petersburg, Russia). The beam current was 20–40 μA, and irradiation time was 40–85 min. The average activity ± SD of the collected total water bolus (see 2.1.2) was 41 ± 17 GBq corrected to EOB. An in-house-made target chamber of
ILC
The method to analyze fluoride ion in samples from non-irradiated and irradiated oxygen-18 water was validated under isocratic conditions in terms of specificity, linearity, limit of detection (LOD), limit of quantitation (LOQ), repeatability, and accuracy. Results are summarized in the supplemental material (Table S1).
The linear regression parameters also are shown in the supplemental material (Table S1). At low fluoride concentration (<25 ng/mL), the calibration curve was not in the linear
Conclusions
Our results show that the use of fluorinated polymers as material for the transport line of fluorine-18 containing oxygen-18 water negatively affects radiopharmaceutical quality, i.e., Am. By replacing PTFE or ETFE tubes with non-fluorinated tubing (PEEK or PP), the amount of fluoride can be decreased and Am increased.
We now have several years of experience in using PP tubing for transport lines. The PP lines are, in our opinion superior to e.g. PEEK lines, as the transport is more effortless,
Acknowledgements
Metrohm Nordic Oy and Thermo Fisher Scientific AB are acknowledged for their help in ILC analysis.
References (27)
- et al.
A historical perspective on the specific activity of radiopharmaceuticals: what have we learned in the 35 years of the ISRC?
Nucl Med Biol
(2013) - et al.
Automated synthesis and purification of [18F]bromofluoromethane at high specific radioactivity
Appl Radiat Isot
(2001) - et al.
A simple 18O water target for 18F production
Int J Appl Radiat Isot
(1984) - et al.
An improved [18O]water target for [18F]fluoride production
Int J Appl Radiat Isot
(1985) - et al.
Production of F-18 from water targets — specific radioactivity and anionic contaminants
Appl Radiat Isot
(1988) - et al.
Increased [18F]2-fluoro-2-deoxy-d-glucose ([18F]FDG) yield with recycled target [18O]water: factors affecting the [18F]FDG yield
Appl Radiat Isot
(2002) - et al.
Impurities in the [18O]water target and their effect on the yield of an aromatic displacement reaction with [18F]fluoride
Appl Radiat Isot
(1993) - et al.
Synthesis of fluorine-18-labelled TSPO ligands for imaging neuroinflammation with positron emission tomography
J Fluor Chem
(2012) - et al.
Carboxylic acids measurements with ionic chromatography
Atmos Environ
(1998) - et al.
Factors affecting the specific activity of [18F]fluoride from a [18O]water target
Nuklearmedizin
(2008)