Automated synthesis of [18F]Ga-rhPSMA-7/ -7.3: results, quality control and experience from more than 200 routine productions

Abstract

Introduction The radiohybrid (rh) prostate-specific membrane antigen (PSMA)-targeted ligand [18F]Ga-rhPSMA-7 has previously been clinically assessed and demonstrated promising results for PET-imaging of prostate cancer. The ligand is present as a mixture of four stereoisomers ([18F]Ga-rhPSMA-7.1, − 7.2, − 7.3 and − 7.4) and after a preclinical isomer selection process, [18F]Ga-rhPSMA-7.3 has entered formal clinical trials. Here we report on the establishment of a fully automated production process for large-scale production of [18F]Ga-rhPSMA-7/ -7.3 under GMP conditions (EudraLex). Methods [18F]Fluoride in highly enriched [18O]H2O was retained on a strong anion exchange cartridge, rinsed with anhydrous acetonitrile and subsequently eluted with a solution of [K+ ⊂ 2.2.2]OH− in anhydrous acetonitrile into a reactor containing Ga-rhPSMA ligand and oxalic acid in DMSO. 18F-for-19F isotopic exchange at the Silicon-Fluoride Acceptor (SiFA) was performed at room temperature, followed by dilution with buffer and cartridge-based purification. Optimum process parameters were determined on the laboratory scale and thereafter implemented into an automated synthesis. Data for radiochemical yield (RCY), purity and quality control were analyzed for 243 clinical productions (160 for [18F]Ga-rhPSMA-7; 83 for [18F]Ga-rhPSMA-7.3). Results The automated production of [18F]Ga-rhPSMA-7 and the single isomer [18F]Ga-rhPSMA-7.3 is completed in approx. 16 min with an average RCY of 49.2 ± 8.6% and an excellent reliability of 98.8%. Based on the different starting activities (range: 31–130 GBq, 89 ± 14 GBq) an average molar activity of 291 ± 62 GBq/μmol (range: 50–450 GBq/μmol) was reached for labeling of 150 nmol (231 μg) precursor. Radiochemical purity, as measured by radio-high performance liquid chromatography and radio-thin layer chromatography, was 99.9 ± 0.2% and 97.8 ± 1.0%, respectively. Conclusion This investigation demonstrates that 18F-for-19F isotopic exchange is well suited for the fast, efficient and reliable automated routine production of 18F-labeled PSMA-targeted ligands. Due to its simplicity, speed and robustness the development of further SiFA-based radiopharmaceuticals is highly promising and can be of far-reaching importance for future theranostic concepts.

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

“…In 2019, Wester et al published their important work regarding the production of radiohybrid prostate-specific membrane antigen (rhPSMA) inhibitors, constituting a great contribution to the field of medical imaging, as well as therapeutics [ 32 ]. These radiotracers incorporate both a SiFA BB and a metal chelator.…”

“…These results further validate its potential as an imaging agent, although further studies are required to determine its efficacy as a theranostic agent in combination with the radiometal 177 Lu. Importantly, due to its favorable outcome, 18 F-synthesis has been fully automated using the Munich Method, which is perfectly suited for SiFA IE [ 32 ]. This allows for the synthesis to occur with extremely high reliability (98.8%), meaning the production procedure was successful for 240/243 runs resulting in an average RCY and RCP of 50% and 99.9%, respectively [ 32 ].…”

“…Importantly, due to its favorable outcome, 18 F-synthesis has been fully automated using the Munich Method, which is perfectly suited for SiFA IE [ 32 ]. This allows for the synthesis to occur with extremely high reliability (98.8%), meaning the production procedure was successful for 240/243 runs resulting in an average RCY and RCP of 50% and 99.9%, respectively [ 32 ]. This is a huge achievement and substantial step forward in the process of introducing this radiotracer into routine clinical applications.…”

“…As such, the use of SiFAs in peptide-, protein- and small-molecule-containing 18 F-radiopharmaceuticals and their respective clinical translations will be further described. This includes the recently developed radiohybrid ligands, which link 18 F PET imaging with radioligand therapy for the first time [ 30 , 31 , 32 , 33 ]. The emphasis of this review is on the development of [ 18 F]SiTATE (TATE = Tyr 3 -octreotate), a novel SiFA 18 F-labeled radiopharmaceutical that provides exemplary PET images of neuroendocrine tumors (NETs) in patients [ 29 , 34 , 35 , 36 , 37 , 38 , 39 , 40 ].…”

Feasibility and Outcome of PSMA-PET-Based Dose-Escalated Salvage Radiotherapy Versus Conventional Salvage Radiotherapy for Patients With Recurrent Prostate Cancer

“…Before DE-SRT, each patient received PET imaging with [68Ga] PSMA-11 (8) or a [18F]-labeled PSMA-ligand ([18F]PSMA-1007 ( 9), [18F]rhPSMA-7 (10), or [18F]rhPSMA-7.3 (11)). PET acquisition was performed according to the joint EANM and SNMMI guidelines (12).…”