Processing of generator-produced 68Ga for medical application

The Ge-68/Ga-68 generator provides an excellent source of positron-emitting Ga-68. However, newly available "ionic" Ge-68/Ga-68 radionuclide generators are not necessarily optimized for the synthesis of Ga-68-labeled radiopharmaceuticals. The eluates have rather large volumes, a high concentration of H+ (pH of 1), a breakthrough of Ge-68, increasing with time or frequency of use, and impurities such as stable Zn(II) generated by the decay of Ga-68, Ti(IV) as a constituent of the column material, and Fe(III) as a general impurity. Methods: We have developed an efficient route for the processing of generator-derived 68Ga eluates, including the labeling and purification of biomolecules. Preconcentration and purification of the initial generator eluate are performed using a miniaturized column with organic cation-exchanger resin and hydrochloric acid/acetone eluent. The purified fraction was used for the labeling of nanomolar amounts of octreotide derivatives either in pure aqueous solution or in buffers. Results: Using the generator post-eluate processing system, > 97% of the initially eluated Ga-68 activity was obtained within 4 min as a 0.4-mL volume of a hydrochloric acid/acetone fraction. The initial amount of 68Ge(IV) was decreased by a factor of 104, whereas initial amounts of Zn(II), Ti(IV), and Fe(III) were reduced by factors of 105, 102, and 10, respectively. The processed 68Ga fraction was directly transferred to solutions containing labeling precursors-for example, DOTA-DPhe(1)-Tyr(3)-octreotide (DOTATOC) (DOTA = 1,4,7,10-tetraazacyclododecane-N,N',N"N'"-tetraacetic acid). Labeling yields of > 95% were achieved within 10 min. Overall yields reached 70% at 20 min after generator elution relative to the eluted Ga-68 activity, not corrected for decay. Specific activities of Ga-68-DOTATOC were 50 MBq/nmol using a standard protocol, reaching 450 MBq/nmol under optimized conditions. Conclusion: Processing on a cation-exchanger in hydrochloric acid/acetone media represents an efficient strategy for the concentration and purification of generator-derived 68Ga(III) eluates. The developed scheme guarantees high yields and safe preparation of injectable 68Ga-labeled radiopharmaceuticals for routine application and is easy to automate. Thus, it is being successfully used in clinical environments and might contribute to a new direction for clinical PET, which could benefit significantly from the easy and safe availability of the radionuclide generatorderived metallic positron-emitter Ga-68.