via Cation Exchange Cartridges: Versatile Options

Fig. 1

Successive steps of post-processing of ⁶⁸Ge/⁶⁸Ga radionuclide generator eluates via cation exchangers (Zhernosekov et al. 2007; Asti et al. 2008). a ⁶⁸Ga is adsorbed online by passing the ⁶⁸Ge/⁶⁸Ga radionuclide generator eluate through a 53 mg cation exchange (CEX) AG 50 Wx8 cartridge. Chemical impurities such as Fe^III, Zn^II, Ti^IV, but also a significant part of the breakthrough ⁶⁸Ge are eluted almost completely from the cation exchange column into waste. b In an additional washing step using 1 mL of 0.15 N HCl/acetone mixture (solution N1), remaining Fe^III, Zn^II, Ti^IV, and ⁶⁸Ge are removed from the cation exchange cartridge, while ⁶⁸Ga efficiently stays in the resin. c Transfer of purified ⁶⁸Ga from the CEX resin into a (labeling) vial by applying 400 μL of 0.05 N HCl/98% acetone (solution N2). Overall, 97 ± 2% of the ⁶⁸Ga initially obtained from the generator is isolated even by 3 min after the elution procedure

In an additional washing step using 1 mL of HCl/acetone mixture (solution N1), remaining impurities are removed from the cation exchange cartridge, while ⁶⁸Ga efficiently stays in the resin (Fig. 1b).

Finally, the transfer of purified ⁶⁸Ga from the resin into a (labeling) vial is almost quantitative. Applying 400 μL of 0.05 N HCl/98% acetone (solution N2), overall, 97 ± 2% of the ⁶⁸Ga initially obtained from the generator is isolated by even 3 min after the elution procedure (Fig. 1c).

This ⁶⁸Ga is chemically pure. The ⁶⁸Ge content/breakthrough is decreased from >10⁻³ initially to <10⁻⁷% finally. The final volume of the purified ⁶⁸Ga fraction is low, as is the pH (400 μL 0.05 N HCl/acetone). As the purified ⁶⁸Ga is eluted directly into a labeling vial containing amounts of precursor, the removal of metallic impurities results in high labeling yields and ⁶⁸Ga radiopharmaceuticals of high specific activities. For, e.g., DOTATOC, labeling is achieved in pure water (adding 5 mL ultrapure water to the precursor creates a final pH of 2.3 after adding the ⁶⁸Ga fraction of 400 μL 0.05 N HCl/acetone), thus avoiding any addition of buffers. About >95% labeling at 10 min of >450 MBq/nmol DOTATOC is obtained. Overall, ca. 65% product yields are achieved (not corrected for decay) with respect to the initially eluted ⁶⁸Ga.

3 Combined Cation and Anion Exchange-Based Post-Processing

The radionuclide ⁶⁸Ga is desorbed from the resin quantitatively with 0.4 mL of 0.05 N HCl/98% acetone solution (N2). Contents of the acetone in the reaction mixture are low and nontoxic (Zhernosekov et al. 2007; Roesch 2010). They are easily reduced to nondetectable levels within labeling procedures at elevated temperature. They might be, however, avoided for direct in vivo applications or for radiolabeling reactions performed under high temperature or for chemical reactions requiring pure aqueous media exclusively.

The aim of present work is to develop an improved column-based chemical strategy combining anion exchange (AEX) processing. Direct preconcentration of ⁶⁸Ga from the original eluate and its purification are supposed to be performed on the cation exchanger according to Zhernosekov et al. (2007). This ⁶⁸Ga can be eluted with hydrochloric acid solutions of >2 N concentration. For effective transfer of the purified ⁶⁸Ga into the aqueous phase of low acidity and small volume a secondary microcolumn, now AEX based, is introduced into the process, which allows direct readsorption of gallium eluted form the cation exchanger. From the AEX, ⁶⁸Ga can be finally striped with a small volume of pure water. For this purpose a typical anion exchanger and a novel extraction chromatographic resin based on N,N,N’,N’-tetra-n-octyldiglycolamide (TODGA) is applied (Loktionova et al. 2011).

A conceptual flow sheet of the system, including the combination of cation exchange and anion exchange, e.g., AG 1 × 8 or TODGA, columns is presented in Fig. 2. The columns are connected consecutively via three-way valves. In the first step, 7 mL 0.1 N HCl passes through the generator and the cation exchange resin into the waste. Step 2 involves eluting the cation exchanger with 1 mL of hydrochloric acid/acetone solution N1 into the waste. The third step is the nearly quantitative transfer of ⁶⁸Ga from the cation exchange column onto the anion exchanger resins with 3 mL of 5 or 4 M HCl. [This represents a significant improvement compared with other anion exchange-based procedures, as high concentrations of HCl and large volumes are avoided (Schumacher and Maier-Borst 1981; Meyer et al. 2004)]. While ⁶⁸Ga is quantitatively adsorbed on both resins, the 3 mL of HCl continues to the waste vial, thereby removing the acetone introduced at the CEX step via solution N1. (Use of acetone may even be completely avoided by removing the high-performance purification of ⁶⁸Ga from metallic impurities via solution N1. However, in view of the idea of almost completely removing ⁶⁸Zn, as much Fe as possible, and in particular ⁶⁸Ge, this special feature of the process should be retained.)

Fig. 2

Essentials of the combined cation (CEX) and anion exchanger (AEX)-based post-processing (Loktionova et al. 2011). The purified, solid-phase-adsorbed ⁶⁸Ga is effectively transfered to subsequent anion exchange-based processing and eluted from it using, e.g., water

From the supplementary anion exchange, e.g., AG or TODGA columns, ⁶⁸Ga is eluted using 0.3 or 1.0 mL water, respectively, into the product vial. With 98% effectivity for the cation exchange part, 92 and 98% yields were obtained for desorbing ⁶⁸Ga from the anion exchange and chromatographic TODGA columns, respectively. The overall yield in the final 0.3–1.0 mL water fraction is 87 ± 5% (for AG 400 1-X8) and 96% (for TODGA resin) with respect to the initial generator eluate.

4 Post-Processing Towards Nonaqueous Systems for Labeling Lipophilic Compounds

While almost all currently used ⁶⁸Ga radiopharmaceuticals, particularly labeling precursors, are compounds that are easily soluble in aqueous solutions, some promising ⁶⁸Ga tracers requiring nonaqueous synthesis conditions may be developed (Roesch and Riss 2010; Riss et al. 2010). The other direction for continuing development of the cation exchange post-processing thus proposes a convenient method for ⁶⁸Ga-labeling under anhydrous conditions using solid-phase-derived gallium acetylacetonate, [⁶⁸Ga]Ga(acac)₃. Again, the initial aqueous generator eluate is first transferred online to a cation exchange resin (SCX in the present case) and ⁶⁸Ga is absorbed quantitatively. From this resin, ⁶⁸Ga is eluted with different acetone-based, nonaqueous solvent systems (Zoller et al. 2010). The resin is washed with solution N1 (0.15 N, 20% in acetone, 1 mL). The resin is dried in a stream of argon for 2 min, followed by elution of the trapped radioactivity as a [⁶⁸Ga]Ga(acac)₃ complex using 2% acetylacetone in acetone in volumes ranging from 200 to 1,600 μL. For comparison, the cation exchange resin was also eluted with 97.6% acetone/0.05 M HCl or 100% acetone in the same manner (Fig. 3). More than 95% of the generator-eluted ⁶⁸Ga was obtained from the cation exchange resin with 600 μL of 98% acetone/2% acetylacetone mixture, providing n.c.a. [⁶⁸Ga]Ga(acac)₃ as labeling agent. The identity and purity of the labeling agent were verified via radio-thin-layer chromatography (TLC) using 1 μL sample aliquots on reverse-phase TLC sheets. Radio-TLC was developed in ethyl acetate:ethanol 1:1 (v/v) with [⁶⁸Ga]Ga(acac)₃ R _f = 0.85 and ⁶⁸Ga³⁺ R _f = 0.0.