Abstract
PurposeTo 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.MethodsIrradiations 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.ResultsThe 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, 45 mCi) 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).ConclusionDirect 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.
Highlights
The medicinal use of 68Ga was first described over 4 decades ago albeit with a very small clinical footprint for much of that time (Eder et al 2014; Graham et al 2017; Lenzo et al 2018; Velikyan 2018)
68Ga yields Total 68Ga yields from the target were assessed by: (a) downloading the total irradiated target contents into a vial placed in a dose calibrator without chemical purification and ensuring suitable decay time (90–120 min) or curve fitting to avoid any 13N contribution, or (b) measurement of residual activity of cassette components and product post [68Ga]GaCl3 isolation or post [68Ga]Ga-prostate specific membrane antigen (PSMA)-11 labeling chemistry
A process for isolating high purity [68Ga]GaCl3 from cyclotron-produced 68Ga and subsequent labeling of PSMA-11 on the GE FASTlab synthesizer with both steps being performed on a single cassette has been developed
Summary
The medicinal use of 68Ga was first described over 4 decades ago albeit with a very small clinical footprint for much of that time (Eder et al 2014; Graham et al 2017; Lenzo et al 2018; Velikyan 2018). Subsequent development of theranostic agents for infection/inflammation (Velikyan 2018), prostate cancer (Eder et al 2014; Lenzo et al 2018; Ruangma et al 2018), C-X-C chemokine receptor type 4 (CXCR4) (Gourni et al 2011; Herrmann et al 2016) and, most recently, fibroblast activation protein inhibitors (FAPI) (Kratochwil et al 2019) is further driving demand and highlights the need for access to a reliable (and economical) supply of 68Ga8 that is the focus of this paper. Analogous development of a reliable pipeline of therapeutic radionuclides is an urgent need for the nuclear medicine community (Herrmann et al 2020), but beyond the scope of this article
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