Optimization and Scale Up of Production of the PSMA Imaging Agent [F]AlF-P16-093 on a Custom Automated Radiosynthesis Platform

Overview

Journal EJNMMI Radiopharm Chem

Date 2024 Feb 23

PMID 38393404

Authors

David Alexoff

Seok Rye Choi

Karl Ploessl

Dohyun Kim

Ruiyue Zhao

Lin Zhu

Hank Kung

Affiliations

Soon will be listed here.

Abstract

Background: Recent advancements in positron emission tomograph (PET) using prostate specific membrane antigen (PSMA)-targeted radiopharmaceuticals have changed the standard of care for prostate cancer patients by providing more accurate information during staging of primary and recurrent disease. [Ga]Ga-P16-093 is a new PSMA-PET radiopharmaceutical that demonstrated superior imaging performance in recent head-to-head studies with [Ga]Ga-PSMA-11. To improve the availability of this new PSMA PET imaging agent, [F]AlF-P16-093 was developed. The F-analog [F]AlF-P16-093 has been synthesized manually at low activity levels using [F]AlF and validated in pre-clinical models. This work reports the optimization of the production of > 15 GBq of [F]AlF-P16-093 using a custom automated synthesis platform.

Results: The sensitivity of the radiochemical yield of [F]AlF-P16-093 to reaction parameters of time, temperature and reagent amounts was investigated using a custom automated system. The automated system is a low-cost, cassette-based system designed for 1-pot syntheses with flow-controlled solid phase extraction (SPE) workup and is based on the Raspberry Pi Zero 2 microcomputer/Python3 ecosystem. The optimized none-decay-corrected yield was 52 ± 4% (N = 3; 17.5 ± 2.2 GBq) with a molar activity of 109 ± 14 GBq/µmole and a radiochemical purity of 98.6 ± 0.6%. Run time was 30 min. A two-step sequence was used: SPE-purified [F]F was reacted with 80 nmoles of freeze-dried AlCl·6HO at 65 °C for 5 min followed by reaction with 160 nmoles of P16-093 ligand at 40 °C for 4 min in a 1:1 mixture of ethanol:0.5 M pH 4.5 NaOAc buffer. The mixture was purified by SPE (> 97% recovery). The final product formulation (5 mM pH 7 phosphate buffer with saline) exhibited a rate of decline in radiochemical purity of ~ 1.4%/h which was slowed to ~ 0.4%/h when stored at 4 °C.

Conclusion: The optimized method using a custom automated system enabled the efficient (> 50% none-decay-corrected yield) production of [F]AlF-P16-093 with high radiochemical purity (> 95%). The method and automation system are simple and robust, facilitating further clinical studies with [F]AlF-P16-093.

References

Jani A, Ravizzini G, Gartrell B, Siegel B, Twardowski P, Saltzstein D . Diagnostic Performance and Safety of F-rhPSMA-7.3 Positron Emission Tomography in Men With Suspected Prostate Cancer Recurrence: Results From a Phase 3, Prospective, Multicenter Study (SPOTLIGHT). J Urol. 2023; 210(2):299-311. DOI: 10.1097/JU.0000000000003493. View

Zhao R, Zha Z, Yao X, Ploessl K, Choi S, Liu F . VMAT2 imaging agent, D6-[F]FP-(+)-DTBZ: Improved radiosynthesis, purification by solid-phase extraction and characterization. Nucl Med Biol. 2019; 72-73:26-35. DOI: 10.1016/j.nucmedbio.2019.07.002. View

Malik N, Baur B, Winter G, Reske S, Beer A, Solbach C . Radiofluorination of PSMA-HBED via Al(18)F(2+) Chelation and Biological Evaluations In Vitro. Mol Imaging Biol. 2015; 17(6):777-85. DOI: 10.1007/s11307-015-0844-6. View

McBride W, Sharkey R, Karacay H, DSouza C, Rossi E, Laverman P . A novel method of 18F radiolabeling for PET. J Nucl Med. 2009; 50(6):991-8. DOI: 10.2967/jnumed.108.060418. View

Heilinger J, Weindler J, Roth K, Krapf P, Schomacker K, Dietlein M . Threshold for defining PSMA-positivity prior to Lu-PSMA therapy: a comparison of [Ga]Ga-PSMA-11 and [F]F-DCFPyL in metastatic prostate cancer. EJNMMI Res. 2023; 13(1):83. PMC: 10511392. DOI: 10.1186/s13550-023-01033-x. View

Kersemans K, De Man K, Courtyn J, Van Royen T, Piron S, Moerman L . Automated radiosynthesis of Al[F]PSMA-11 for large scale routine use. Appl Radiat Isot. 2018; 135:19-27. DOI: 10.1016/j.apradiso.2018.01.006. View

Wurzer A, Di Carlo D, Schmidt A, Beck R, Eiber M, Schwaiger M . Radiohybrid Ligands: A Novel Tracer Concept Exemplified by F- or Ga-Labeled rhPSMA Inhibitors. J Nucl Med. 2019; 61(5):735-742. PMC: 7198388. DOI: 10.2967/jnumed.119.234922. View

Zha Z, Ploessl K, Choi S, Wu Z, Zhu L, Kung H . Synthesis and evaluation of a novel urea-based Ga-complex for imaging PSMA binding in tumor. Nucl Med Biol. 2018; 59:36-47. DOI: 10.1016/j.nucmedbio.2017.12.007. View

Dietlein F, Kobe C, Neubauer S, Schmidt M, Stockter S, Fischer T . PSA-Stratified Performance of F- and Ga-PSMA PET in Patients with Biochemical Recurrence of Prostate Cancer. J Nucl Med. 2016; 58(6):947-952. DOI: 10.2967/jnumed.116.185538. View

10.

Yao X, Zha Z, Zhao R, Choi S, Ploessl K, Liu F . Optimization of solid-phase extraction (SPE) in the preparation of [F]D3FSP: A new PET imaging agent for mapping Aβ plaques. Nucl Med Biol. 2019; 71:54-64. DOI: 10.1016/j.nucmedbio.2019.05.002. View

11.

Carlucci G, Ippisch R, Slavik R, Mishoe A, Blecha J, Zhu S . Ga-PSMA-11 NDA Approval: A Novel and Successful Academic Partnership. J Nucl Med. 2021; 62(2):149-155. PMC: 8679592. DOI: 10.2967/jnumed.120.260455. View

12.

Bahler C, Green M, Tann M, Swensson J, Collins K, Alexoff D . Assessing extra-prostatic extension for surgical guidance in prostate cancer: Comparing two PSMA-PET tracers with the standard-of-care. Urol Oncol. 2022; 41(1):48.e1-48.e9. DOI: 10.1016/j.urolonc.2022.10.003. View

13.

Houshmand S, Lawhn-Heath C, Behr S . PSMA PET imaging in the diagnosis and management of prostate cancer. Abdom Radiol (NY). 2023; 48(12):3610-3623. PMC: 10682054. DOI: 10.1007/s00261-023-04002-z. View

14.

Giglio J, Zeni M, Savio E, Engler H . Synthesis of an AlF radiofluorinated GLU-UREA-LYS(AHX)-HBED-CC PSMA ligand in an automated synthesis platform. EJNMMI Radiopharm Chem. 2018; 3(1):4. PMC: 5829129. DOI: 10.1186/s41181-018-0039-y. View

15.

Eiber M, Kroenke M, Wurzer A, Ulbrich L, Jooss L, Maurer T . F-rhPSMA-7 PET for the Detection of Biochemical Recurrence of Prostate Cancer After Radical Prostatectomy. J Nucl Med. 2019; 61(5):696-701. PMC: 7198386. DOI: 10.2967/jnumed.119.234914. View

16.

Fallah J, Agrawal S, Gittleman H, Fiero M, Subramaniam S, John C . FDA Approval Summary: Lutetium Lu 177 Vipivotide Tetraxetan for Patients with Metastatic Castration-Resistant Prostate Cancer. Clin Cancer Res. 2022; 29(9):1651-1657. PMC: 10159870. DOI: 10.1158/1078-0432.CCR-22-2875. View

17.

Surasi D, Eiber M, Maurer T, Preston M, Helfand B, Josephson D . Diagnostic Performance and Safety of Positron Emission Tomography with F-rhPSMA-7.3 in Patients with Newly Diagnosed Unfavourable Intermediate- to Very-high-risk Prostate Cancer: Results from a Phase 3, Prospective, Multicentre Study (LIGHTHOUSE). Eur Urol. 2023; 84(4):361-370. DOI: 10.1016/j.eururo.2023.06.018. View

18.

Green M, Hutchins G, Bahler C, Tann M, Mathias C, Territo W . [Ga]Ga-P16-093 as a PSMA-Targeted PET Radiopharmaceutical for Detection of Cancer: Initial Evaluation and Comparison with [Ga]Ga-PSMA-11 in Prostate Cancer Patients Presenting with Biochemical Recurrence. Mol Imaging Biol. 2019; 22(3):752-763. PMC: 7028523. DOI: 10.1007/s11307-019-01421-7. View

19.

Thisgaard H, Kumlin J, Langkjaer N, Chua J, Hook B, Jensen M . Multi-curie production of gallium-68 on a biomedical cyclotron and automated radiolabelling of PSMA-11 and DOTATATE. EJNMMI Radiopharm Chem. 2021; 6(1):1. PMC: 7790954. DOI: 10.1186/s41181-020-00114-9. View

20.

Al-Momani E, Israel I, Samnick S . Validation of a [AlF]PSMA-11 preparation for clinical applications. Appl Radiat Isot. 2017; 130:102-108. DOI: 10.1016/j.apradiso.2017.09.003. View