Cyclotron-based production of 68Ga, [68Ga]GaCl3, and [68Ga]Ga-PSMA-11 from a liquid target

Abstract

Purpose: To optimize the direct production of 68Ga on a cyclotron, via the 68Zn(p,n)68Ga reaction using a liquid cyclotron target. We Investigated the yield of cyclotron-produced 68Ga, extraction of [68Ga]GaCl3 and subsequent [68Ga]Ga-PSMA-11 labeling using an automated synthesis module.Methods: Irradiations of a 1.0 M solution of [68Zn]Zn(NO3)2 in dilute (0.2-0.3 M) HNO3 were conducted using GE PETtrace cyclotrons and GE 68Ga liquid targets. The proton beam energy was degraded to a nominal 14.3 MeV to minimize the co-production of 67Ga through the 68Zn(p,2n)67Ga reaction without unduly compromising 68Ga yields. We also evaluated the effects of varying beam times (50-75 min) and beam currents (27-40 μA). Crude 68Ga production was measured. The extraction of [68Ga]GaCl3 was performed using a 2 column solid phase method on the GE FASTlab Developer platform. Extracted [68Ga]GaCl3 was used to label [68Ga]Ga-PSMA-11 that was intended for clinical use.Results: The decay corrected yield of 68Ga at EOB was typically >3.7 GBq (100 mCi) for a 60 min beam, with irradiations of [68Zn]Zn(NO3)2 at 0.3 M HNO3. Target/chemistry performance was more consistent when compared with 0.2 M HNO3. Radionuclidic purity of 68Ga was typically >99.8% at EOB and met the requirements specified in the European Pharmacopoeia (<2% combined 66/67Ga) for a practical clinical product shelf-life. The activity yield of [68Ga]GaCl3 was typically >50% (~1.85 GBq, 50 mCi); yields improved as processes were optimized. Labeling yields for [68Ga]Ga-PSMA-11 were near quantitative (~1.67 GBq, 45mCi) at EOS. Cyclotron produced [68Ga]Ga-PSMA-11 underwent full quality control, stability and sterility testing , and was implemented for human use at the University of Michigan as an Investigational New Drug through the US FDA and also at the Royal Prince Alfred Hospital (RPA).Conclusion: Direct cyclotron irradiation of a liquid target provides clinically relevant quantities of [68Ga]Ga-PSMA-11 and is a viable alternative to traditional 68Ge/68Ga generators.

Multi-curie production of gallium-68 on a biomedical cyclotron and automated radiolabelling of PSMA-11 and DOTATATE

“…a few patient doses), a generator is much less technically demanding, very reliable and does not require trained personnel to perform separation and radiolabelling on synthesis modules or major capital investment in a cyclotron facility. Liquid cyclotron targets where acidic solutions containing zinc-68 salts are bombarded with protons, provide an alternative solution to get a small number of patient doses but the reported production yields of < 10 GBq at EOB or approximately 5 GBq at EOP are inferior to the solid target route (Pandey et al 2019;Alves et al 2018;Pedersen et al 2019;do Carmo et al 2020;Melissa et al 2020). This method also carries the inherent risk of acids damaging targets and potentially cyclotron systems and require continuous target maintenance.…”

Recent Advances in the Clinical Translation of Silicon Fluoride Acceptor (SiFA) 18F-Radiopharmaceuticals

“…Currently, 68 Ga is primarily obtained from costly on-site 68 Ge/ 68 Ga-generators due to its relatively short t 1/2 . Furthermore, applicable patient numbers are constricted due to limited production amounts, although recent progress has made cyclotron production possible [ 64 , 65 , 66 , 67 , 68 , 69 ]. Additionally, the PET image resolution is hindered due to the high mean β + energy (E mean = 0.83 MeV) and concordant high mean β + range (R mean = 3.5 mm) of 68 Ga [ 63 ].…”

Comparison of three different methods in [68Ga]Ga‐PSMA11 radiolabeling

“…Therefore, this radiopharmaceutical (improvable synthesis algorithms, radiochemical yields, chemical impurities, bacteriological impurities, etc.) has started to be studied extensively by scientists 4–6 …”