The Impact of the Ge-68/Ga-68 on Molecular Imaging

For more than 50 years, speculation has swirled about the tremendous potential of Ga-68 PET imaging to transform molecular imaging. The rapidly increasing number of publications reporting the results of Ga-68 PET imaging studies are evidence that many are working in this direction. (Fig 1.) There is little question that high-quality and clinically useful PET images can be obtained using Ga-68, while also imparting a lower radiation absorbed dose to patients. The ability to free PET imaging from the previously inextricable and sometimes onerous capital equipment costs, need for expert staff, and complex organic chemistry associated with the cyclotron production of PET radionuclides is indeed very attractive. The barriers to more widespread use of Ga-68 PET appear to lie in the lack of FDA/EMA-approved Ge-68/Ga-68 generators and kits for the preparation of ­Ga drugs.

[[{"fid":"18378","view_mode":"media_original","type":"media","attributes":{"style":"line-height: 1.538em; width: 300px; height: 129px; float: right;","alt":" - Fig.1","class":"media-element file-media-original"}}]]There are similarities between the current 99mTc SPECT paradigm and the possible future of Ga-68 PET. More than 40 years of experience with 99mTc kits in nuclear medicine has resulted in FDA-approved kit formulations capable of yielding highly reproducible 99mTc radiopharmaceuticals. These 99mTc imaging drugs are typically compounded in centralized nuclear pharmacies in the U.S. for distribution as patient-specific unit-doses to their points of use in clinics and hospitals, to enable more than 30,000 nuclear medicine procedures per day in the U.S. A similar distribution model could be employed to support Ga-68 PET radopharmaceuticals, although the range of distribution may be smaller than that of 99mTc or F-18 based drugs, owing to the shorter half-life of Ga-68 (68 minutes).

There are currently several obstacles to the commercialization of Ga-68 PET. The commercial production of the parent radionuclide Ge-68 is currently limited to iThemba and national laboratories in the U.S. and Russia. However, the declining demand for Tl-201 and Ga-67 from the medical community has idled existing commercial 30 MeV cyclotrons capable of producing Ge-68. There are now at least four commercially available Ge-68/Ga-68 generators in Europe and the U.S. (Table 1), however none are terminally sterilized. In contrast to the elegant simplicity of Mo-99/99mTc generators that are eluted using 0.9 percent sodium chloride, all of the currently available Ge-68/Ga-68 generators employ elution schemes that use hydrochloric acid (HCL) and organic solvents that are not suitable for direct injection, necessitating more complex pharmaceutical formulation and end product testing, including gas chromatography (GC). The presence of HCL in the eluate, together with the lack of terminal sterilization pose challenges for FDA/EMA approval of the currently available Ge-68/Ga-68 generators. The potential presence of residual solvents and need for GC end-product testing is a complexity that requires instrumentation not commonly available in commercial SPECT nuclear pharmacies, and takes time that is scarce when preparing short-lived Ga-68 radiotracers.

Concerns abound regarding potential breakthrough of the long-lived (t1/2 271 days) Ge-68 parent radionuclide. These concerns remain highly speculative and are easily assuaged using simple half-life observations of the Ga-68 eluate prior to patient use. A recent publication shows that Ge-68 is rapidly excreted in the urine, greatly diminishing the potential radiation absorbed dose, and calling into question the current threshold for Ge-68 breakthrough of 0.001 percent now found in the EU monograph.

Some have questioned the scalability of Ga-68 due to half-life and radiation safety concerns, as well as the current installation base of PET cameras. It is true that the 511keV photons from Ga-68 are 10 times more penetrating than 99mTc and may require automation and remote handling to produce the number of patient doses per day needed. However, the more than 30 years of experience with commercial production of F-18 FDG would seem to dispel these concerns. Each morning, commercial radiopharmacies may prepare 100 or more patient doses of 99mTc drugs for use throughout the day. The 68-minute half-life of Ga-68 may limit the number of doses prepared at one time. However, the rapid in-growth of Ga-68 on the generator will allow for multiple elutions, approximately every two hours.

History shows that nuclear medicine will embrace new technology and products that demonstrate utility, so long as they are not cost prohibitive. Nuclear medicine is ready to embrace Ga-68-PET, but further commercial development of Ge-68/Ga-68 generators and simple kit formulations for the preparation of Ga-68 drugs are needed to overcome the current barriers. Ultimately, any FDA/EMA-approved products for Ga-68 PET also must be appropriately reimbursed and demonstrate higher utility and/or cost-savings over the existing SPECT and PET drugs.

Adapt or fail. Evolve or go extinct …

Dr. Norenberg is executive director of the National Association of Nuclear Pharmacies. He is professor and director, Radiopharmaceutical Sciences associate director, New Mexico Center for Isotopes in Medicine College of Pharmacy, professor, Anesthesiology & Critical Care Medicine and director, Keck-UNM Small-Animal Imaging Resource University of New Mexico Health Sciences Center in Albuquerque.