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

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