The medicinal use of 68Ga was first described over 4 decades ago albeit with a very small clinical footprint for much of that time (1–4). Over the past 15 years, there has been a surge in 68Ga radiopharmaceutical development, exceeding that of other radiotracers, with a 100-fold increase in the number of 68Ga publications. Over the last decade, there has also been a marked increase in the clinical use of 68Ga that has been attributed to the ease of acquiring 68Ga from 68Ge/68Ga generators and the development and approval of new theranostic tracers (5). The diagnostic applications of 68Ga vary across jurisdictions/countries and include imaging of neuroendocrine tumors(1), infection/inflammation (4), prostate cancer (2, 3, 6), and most recently, fibroblast activation protein inhibitors (FAPI)(7) that was the Society of Nuclear Medicine and Molecular Imaging (SNMMI) 2019 image of the year. 68Ga is usually produced from a 68Ge/68Ga generator, and thus can be readily implemented in PET facilities that do not have a cyclotron. There are also many additional attributes of 68Ga that make it a desirable PET radionuclide. As the first widely available PET radiometal for routine use globally, 68Ga is a positron emitting (89% β+) radionuclide with a relatively short half-life (t1/2=68 min). The 68Ga3+ cation is small with an ionic radius of 0.62 Å, which behaves as a relatively hard Lewis acid with an affinity for binding ligands containing oxygen and nitrogen donors, and is suitable for conjugation to various biomolecular vectors using bifunctional chelators and various macromolecules including small molecules with rapid pharmacokinetic profiles, such as peptides and peptidomimetics (8–10). This synthetic diversity provides the ability for 68Ga kit development.
A main contributor to the expansion of 68Ga-based PET has been imaging of the prostate specific membrane antigen (PSMA) with [68Ga]Ga-PSMA-11. Prostate cancer is the second most common cancer found in men in the United States and the second most prevalent cause of cancer death in men (11). Survival rates depend on the type of prostate cancer and the stage at diagnosis. Men with localized disease have a 5-year survival rate of nearly 100%. However, 20–40% of these patients develop biochemical recurrence (BCR) and the recurrent disease can be loco-regional or more widespread. Patients with metastatic disease have a markedly decreased 5-year survival rate of 30% (11). The early and accurate identification of tumor recurrence and metastatic disease is essential for optimal patient management, but this remains a major challenge for traditional imaging methods with anatomical imaging and bone scintigraphy.
The imaging of PSMA expression with [68Ga]Ga-PSMA-11 and PET/CT has proven to be a highly effective and sensitive tool for patient management (8). While the primary use of [68Ga]Ga-PSMA-11 has been for detecting recurrent disease, it has also been successful at staging primary prostate cancer, and useful for guiding biopsies to improve sample accuracy, guiding surgery, and monitoring treatment response (2). Additionally, [68Ga]Ga-PSMA-11 has been used theranostically in conjunction with complementary 177Lu (i.e. β-) or 225Ac (i.e. α) therapeutic PSMA targeting agents. Such PSMA targeted therapies are currently undergoing evaluation in clinical trials in patients with castrate-resistant metastatic prostate cancer (12, 13). [68Ga]Ga-PSMA-11 is rapidly becoming the most commonly used radiotracer for prostate cancer management and has higher accuracy and sensitivity in detecting metastatic disease than [18F]fluorocholine, [11C]choline, and CT (8, 14–16).
There has been a positive clinical impact of [68Ga]Ga-PSMA-11 at the University of Michigan with a change in patient care management in 70% of the scanned patient population. A similar high impact has been reported in a large Australian study that cited a 51% change in care management (62% for BCR patients and 21% for primary staging) (17). In 2016 a study from Belgium reported that in patients who underwent a [68Ga]Ga-PSMA-11 scan there was a 76% impact in patient care management (18). A 2017 study from the University of California San Francisco reported a 53% change in patient management (19).
Since its FDA approval in 2012, [11C]choline has been one of the most widely used radiotracers for the imaging of prostate cancer patients with suspected recurrence (20). The busiest cancer centers in the US reportedly perform 10–15 [11C]choline scans daily for prostate cancer management (21). It has been possible to service this volume of patients given the high yielding [11C]choline synthesis (> 200 mCi/dose) (22, 23), coupled with the ability to run multiple times per day, depending on the specific capabilities of the PET facility, and thus provides the proper framework to provide for 10–15 [11C]choline scans daily. Many PET imaging sites in the US and Australia are moving to exclusively using [68Ga]Ga-PSMA-11 rather than [11C]choline, given the superior clinical performance (2, 14, 16). However, transferring that patient population to receive [68Ga]Ga-PSMA-11 instead of [11C]choline scans is not feasible using 68Ge/68Ga generators exclusively. While 68Ge/68Ga generators offer workflow simplicity for tracer production but there are a number of limitations: a) current GMP generators have a maximum activity of 50 mCi and are restricted to elutions every 3-4-hour increments, which in practice typically means 2 production runs per day with 2–4 doses per day; b) two or more generators increase the number of patients does to 6 or more, but still less than the requirements of busy cancer centers; c) commercial supply has not kept pace with the clinical demand and lead times for generator delivery can be up to 18 months in some markets (24); d) the eluted activity constantly declines over time and so to ensure a regular clinical supply of [68Ga]Ga-PSMA-11, multiple sequential and overlapping generators must be purchased throughout the year and; e) there is the potential for long lived parent 68Ge contamination and/or breakthrough. To this end, an additional source of 68Ga needs to be explored and implemented into the clinical setting to meet the current and future patient demand (24).
An attractive alternative to diversifying the supply of 68Ga is the direct production of 68Ga on a cyclotron, via the 68Zn(p,n)68Ga reaction. This alternative approach has garnered significant interest by the community, including the drafting of a European Pharmacopeia monograph for the direct accelerator-based production of [68Ga]GaCl3 which was published late 2018 (25) and a technical document published by the IAEA in support of direct production of 68Ga via liquid and solid targets (26). There are two strategies for producing 68Ga via the 68Z(p,n)68Ga reaction on a cyclotron - namely, liquid (25–33) and solid targets (34–41). Liquid targets offer implementation simplicity for sites familiar with [18F]FDG production as they present a similar workflow to production of [18F]F− and are compatible with laboratory set-ups in existing PET radiopharmaceutical production centers. Solid targets, however, typically impose increased requirements on infrastructure and/or local site expertise but offer more than order of magnitude higher 68Ga yields (e.g. several Ci (37, 38). Regardless of opting for liquid or solid targets an efficient means for purifying the 68Ga from the irradiated 68Zn is required. The limitations of cyclotron produced 68Ga are obviously: a) a cyclotron with suitable targets, b) the co-production of 67Ga and 66Ga and, c) the potential for residual levels of 68Zn and other metal impurities affecting labeling efficiencies. These factors place stringent demands on the proton energy, the target material and reagent quality, and finally 68Zn/68Ga separation methods.
We present results of the liquid target-based production of 68Ga on GE PETtrace cyclotrons, with focus on yield of 68Ga and extraction of [68Ga]GaCl3 using the GE FASTlab Developer platform. Furthermore, to demonstrate the clinical relevance of this direct production method, a single FASTlab cassette was used to perform the 68Zn/68Ga purification and subsequent labeling of [68Ga]Ga-PSMA-11. The cyclotron produced [68Ga]Ga-PSMA-11 underwent full quality control, stability and sterility testing, and has been used in humans at the UM (University of Michigan, Michigan, USA) via an IND (FDA) and at RPA (Royal Prince Alfred Hospital, Sydney, Australia) under exemption of the Therapeutic Goods Act in a TGA GMP-licensed facility. The results from UM, GEMS (GE Healthcare Uppsala, Sweden) and RPA are presented.