Abstract
Gallium-68 (68Ga) is a generator-produced radionuclide with a short half-life (t½ = 68 min) that is particularly well suited for molecular imaging by positron emission tomography (PET). Methods have been developed to synthesize 68Ga-labeled imaging agents possessing certain drawbacks, such as longer synthesis time because of a required final purification step, the use of organic solvents or concentrated hydrochloric acid (HCl). In our manuscript, we provide a detailed protocol for the use of an advantageous sodium chloride (NaCl)-based method for radiolabeling of chelator-modified peptides for molecular imaging. By working in a lead-shielded hot-cell system, 68Ga3+ of the generator eluate is trapped on a cation exchanger cartridge (100 mg, ∼8 mm long and 5 mm diameter) and then eluted with acidified 5 M NaCl solution directly into a sodium acetate-buffered solution containing a DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) or DOTA-like chelator-modified peptide. The main advantages of this procedure are the high efficiency and the absence of organic solvents. It can be applied to a variety of peptides, which are stable in 1 M NaCl solution at a pH value of 3–4 during reaction. After labeling, neutralization, sterile filtration and quality control (instant thin-layer chromatography (iTLC), HPLC and pH), the radiopharmaceutical can be directly administered to patients, without determination of organic solvents, which reduces the overall synthesis-to-release time. This procedure has been adapted easily to automated synthesis modules, which leads to a rapid preparation of 68Ga radiopharmaceuticals (12–16 min).
Highlights
68Ga-labeled compounds for molecular positron emission tomography (PET) imaging are of increasing interest in nuclear medicine
68Ga-labeled compounds for molecular PET imaging are of increasing interest in nuclear medicine
The predominant advantage of 68Ga radiopharmaceuticals is that the synthesis is based on generator-produced 68Ga and that it can be performed on site, without the need for a medical cyclotron
Summary
The requirement for two cartridges has limited the routine use of this method in practice All these methods are limited in their use for the routine production of radiopharmaceuticals, either because of the use of organic solvents or because of the use of semiconcentrated, corrosive-acting HCl. In contrast, the procedure described in this protocol focuses on a 68Ga radiolabeling procedure (method 6 in Table 1), which requires the use of only one single cation exchanger cartridge, and purification of 68Ga for radiolabeling reactions is achieved just by manipulating cationic/anionic speciation of 68Ga. The method, pioneered by Mueller et al, uses the behavior of 68Ga to form anionic species present in concentrated NaCl solution[13]. Rinsing the column with acidified 5 M NaCl solution transforms the cationic 68Ga3+instantly and in situ, which results in desorption and elution of 68Ga as anionic [68GaCl4]− This eluate is directed to a buffered solution that contains a chelator-modified DOTA-like peptide for labeling (see Fig. 1). ▲ CRITICAL The generator eluate must be diluted with five times the volume with water before transferring the eluate through the SCX cartridge
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