Procedures for the GMP-Compliant Production and Quality Control of [18F]PSMA-1007: A Next Generation Radiofluorinated Tracer for the Detection of Prostate Cancer

Jens Cardinale, René Martin, Yvonne Remde, Martin Schäfer, Antje Hienzsch, Sandra Hübner, Anna-Maria Zerges, Heike Marx, Ronny Hesse, Klaus Weber, Rene Smits, Alexander Hoepping, Marco Müller, Oliver C Neels, Klaus Kopka, Jens Cardinale, René Martin, Yvonne Remde, Martin Schäfer, Antje Hienzsch, Sandra Hübner, Anna-Maria Zerges, Heike Marx, Ronny Hesse, Klaus Weber, Rene Smits, Alexander Hoepping, Marco Müller, Oliver C Neels, Klaus Kopka

Abstract

Radiolabeled tracers targeting the prostate-specific membrane antigen (PSMA) have become important radiopharmaceuticals for the PET-imaging of prostate cancer. In this connection, we recently developed the fluorine-18-labelled PSMA-ligand [18F]PSMA-1007 as the next generation radiofluorinated Glu-ureido PSMA inhibitor after [18F]DCFPyL and [18F]DCFBC. Since radiosynthesis so far has been suffering from rather poor yields, novel procedures for the automated radiosyntheses of [18F]PSMA-1007 have been developed. We herein report on both the two-step and the novel one-step procedures, which have been performed on different commonly-used radiosynthesisers. Using the novel one-step procedure, the [18F]PSMA-1007 was produced in good radiochemical yields ranging from 25 to 80% and synthesis times of less than 55 min. Furthermore, upscaling to product activities up to 50 GBq per batch was successfully conducted. All batches passed quality control according to European Pharmacopoeia standards. Therefore, we were able to disclose a new, simple and, at the same time, high yielding production pathway for the next generation PSMA radioligand [18F]PSMA-1007. Actually, it turned out that the radiosynthesis is as easily realised as the well-known [18F]FDG synthesis and, thus, transferable to all currently-available radiosynthesisers. Using the new procedures, the clinical daily routine can be sustainably supported in-house even in larger hospitals by a single production batch.

Keywords: PET; PSMA; [18F]PSMA-1007; automation; fluorine-18; prostate cancer.

Conflict of interest statement

René Martin, Alexander Hoepping, Sandra Hübner, Anna-Maria Zerges, Rene Smits, Ronny Hesse, A. Hoepping and M. Müller are employees of ABX advanced biochemical compounds GmbH. [F]PSMA-1007 is the subject of a patent application by DKFZ Heidelberg with contributing inventors Jens Cardinale and Klaus Kopka et al. The one-step synthesis method using Precursor 3 is the subject of a patent application by ABX advanced biochemical compounds with contributing inventors René Martin, Ronny Hesse, Rene Smits, Marco Müller and Alexander Hoepping.

Figures

Scheme 1
Scheme 1
Routes for the radiosynthesis of [18F]PSMA-1007 (TBAHCO3: tetrabutylammonium hydrogen carbonate; TBAF: tetrabutylammonium fluoride; tBuOH: tert-butanol; MeCN: acetonitrile; F-Py-TFP: 6-fluoropyridine-3-carboxylic acid 2,3,5,6-tetrafluorophenyl ester; DIPEA: diisopropylethylamine; DMSO: dimethylsulfoxide).
Figure 1
Figure 1
Relevant chromatograms for the release of [18F]PSMA-1007 from the two-step production on the AllInOne radiosynthesiser: Full chromatogram of the [18F]PSMA-1007 formulation showing co-elution of cold PSMA-1007 and radioactive product (A) and zoomed around the radioactive product peak (B).
Figure 2
Figure 2
Typical chromatographic radio- and ultraviolet (UV)-traces of [18F]PSMA-1007 injection solution (ABX advanced chemical compounds) using the one-step method (Prec. = Precursor).
Figure 2
Figure 2
Typical chromatographic radio- and ultraviolet (UV)-traces of [18F]PSMA-1007 injection solution (ABX advanced chemical compounds) using the one-step method (Prec. = Precursor).
Figure 3
Figure 3
Iodine-stained TLC from the tetrabutylammonium (TBA) test showing the reference solution 0.1 mg/mL in the middle and respective final solutions from TRACERlab MX (left) and mosaic-RS (right).
Figure 4
Figure 4
Activity trails during a typical production of [18F]PSMA-1007 by the two-step procedure on Trasis AllInOne radiosynthesiser.
Figure 5
Figure 5
Radio-chromatogram of the [18F]PSMA-1007 separation on integrated HPLC of the Trasis AllInOne radiosynthesiser.
Figure 6
Figure 6
General setup of the synthesis cassette for two-step production of [18F]PSMA-1007 with HPLC purification on AllInOne (Exh: Exhaust to vacuum pump).
Figure 7
Figure 7
General setup of the radiosynthesiser for the one-step production of [18F]PSMA-1007 with SPE cartridge purification on the Nuclear Interface Tracerlab FX FN system.
Figure 8
Figure 8
General setup of the radiosynthesiser for one-step production of [18F]PSMA-1007 with SPE cartridge purification on GE TRACERlab MX and the NEPTIS mosaic-RS system.
Figure 9
Figure 9
General setup of the radiosynthesiser for the one-step production of [18F]PSMA-1007 with SPE cartridge purification on the IBA SYNTHERA+ system.

References

    1. Afshar-Oromieh A., Haberkorn U., Eder M., Eisenhut M., Zechmann C.M. [68Ga]Gallium-labelled PSMA ligand as superior PET tracer for the diagnosis of prostate cancer: Comparison with 18F-FECH. Eur. J. Nucl. Med. Mol. Imaging. 2012;39:1085–1086. doi: 10.1007/s00259-012-2069-0.
    1. Schwenck J., Rempp H., Reischl G., Kruck S., Stenzl A., Nikolaou K., Pfannenberg C., la Fougère C. Comparison of 68Ga-labelled PSMA-11 and 11C-choline in the detection of prostate cancer metastases by PET/CT. Eur. J. Nucl. Med. Mol. Imaging. 2017;44:92–101. doi: 10.1007/s00259-016-3490-6.
    1. Afshar-Oromieh A., Zechmann C.M., Malcher A., Eder M., Eisenhut M., Linhart H.G., Holland-Letz T., Hadaschik B.A., Giesel F.L., Debus J., et al. Comparison of PET imaging with a 68Ga-labelled PSMA ligand and 18F-choline-based PET/CT for the diagnosis of recurrent prostate cancer. Eur. J. Nucl. Med. Mol. Imaging. 2014;41:11–20. doi: 10.1007/s00259-013-2525-5.
    1. Evangelista L., Briganti A., Fanti S., Joniau S., Reske S., Schiavina R., Stief C., Thalmann G.N., Picchio M. New Clinical Indications for 18F/11C-choline, New Tracers for Positron Emission Tomography and a Promising Hybrid Device for Prostate Cancer Staging: A Systematic Review of the Literature. Eur. Urol. 2016;70:161–175. doi: 10.1016/j.eururo.2016.01.029.
    1. Oliveira J.M., Gomes C., Faria D.B., Vieira T.S., Silva F.A., Vale J., Pimentel F.L. 68Ga-prostate-specific Membrane Antigen Positron Emission Tomography/Computed Tomography for Prostate Cancer Imaging: A Narrative Literature Review. World J. Nucl. Med. 2017;16:3–7. doi: 10.4103/1450-1147.198237.
    1. Pfister D., Porres D., Heidenreich A., Heidegger I., Knuechel R., Steib F., Behrendt F.F., Verburg F.A. Detection of recurrent prostate cancer lesions before salvage lymphadenectomy is more accurate with 68Ga-PSMA-HBED-CC than with 18F-Fluoroethylcholine PET/CT. Eur. J. Nucl. Med. Mol. Imaging. 2016;43:1410–1417. doi: 10.1007/s00259-016-3366-9.
    1. Eder M., Neels O., Müller M., Bauder-Wüst U., Remde Y., Schäfer M., Hennrich U., Eisenhut M., Afshar-Oromieh A., Haberkorn U., et al. Novel Preclinical and Radiopharmaceutical Aspects of [68Ga]Ga-PSMA-HBED-CC: A New PET Tracer for Imaging of Prostate Cancer. Pharmaceuticals. 2014;7:779–796. doi: 10.3390/ph7070779.
    1. Afshar-Oromieh A., Hetzheim H., Kratochwil C., Benesova M., Eder M., Neels O.C., Eisenhut M., Kübler W., Holland-Letz T., Giesel F.L., et al. The Theranostic PSMA Ligand PSMA-617 in the Diagnosis of Prostate Cancer by PET/CT: Biodistribution in Humans, Radiation Dosimetry, and First Evaluation of Tumor Lesions. J. Nucl. Med. 2015;56:1697–1705. doi: 10.2967/jnumed.115.161299.
    1. Weineisen M., Schottelius M., Simecek J., Baum R.P., Yildiz A., Beykan S., Kulkarni H.R., Lassmann M., Klette I., Eiber M., et al. 68Ga- and 177Lu-Labeled PSMA I & T: Optimization of a PSMA-Targeted Theranostic Concept and First Proof-of-Concept Human Studies. J. Nucl. Med. 2015;56:1169–1176. doi: 10.2967/jnumed.115.158550.
    1. Fendler W.P., Eiber M., Beheshti M., Bomanji J., Ceci F., Cho S., Giesel F., Haberkorn U., Hope T.A., Kopka K., et al. 68Ga-PSMA PET/CT: Joint EANM and SNMMI procedure guideline for prostate cancer imaging: Version 1.0. Eur. J. Nucl. Med. Mol. Imaging. 2017;44:1014–1024. doi: 10.1007/s00259-017-3670-z.
    1. Afshar-Oromieh A., Holland-Letz T., Giesel F.L., Kratochwil C., Mier W., Haufe S., Debus N., Eder M., Eisenhut M., Schäfer M., et al. Diagnostic performance of 68Ga-PSMA-11 (HBED-CC) PET/CT in patients with recurrent prostate cancer: Evaluation in 1007 patients. Eur. J. Nucl. Med. Mol. Imaging. 2017;44:1258–1268. doi: 10.1007/s00259-017-3711-7.
    1. Afshar-Oromieh A., Avtzi E., Giesel F.L., Holland-Letz T., Linhart H.G., Eder M., Eisenhut M., Boxler S., Hadaschik B.A., Kratochwil C., et al. The diagnostic value of PET/CT imaging with the 68Ga-labelled PSMA ligand HBED-CC in the diagnosis of recurrent prostate cancer. Eur. J. Nucl. Med. Mol. Imaging. 2015;42:197–209. doi: 10.1007/s00259-014-2949-6.
    1. Eiber M., Maurer T., Souvatzoglou M., Beer A.J., Ruffani A., Haller B., Graner F.P., Kübler H., Haberhorn U., Eisenhut M., et al. Evaluation of Hybrid 68Ga-PSMA Ligand PET/CT in 248 Patients with Biochemical Recurrence After Radical Prostatectomy. J. Nucl. Med. 2015;56:668–674. doi: 10.2967/jnumed.115.154153.
    1. Perera M., Papa N., Christidis D., Wetherell D., Hofman M.S., Murphy D.G., Bolton D., Lawrentschuk N. Sensitivity, Specificity, and Predictors of Positive 68Ga-Prostate-specific Membrane Antigen Positron Emission Tomography in Advanced Prostate Cancer: A Systematic Review and Meta-analysis. Eur. Urol. 2016;70:926–937. doi: 10.1016/j.eururo.2016.06.021.
    1. Cardinale J., Schäfer M., Benešová M., Bauder-Wüst U., Leotta K., Eder M., Neels O.C., Haberkorn U., Kopka K. Preclinical Evaluation of 18F-PSMA-1007, a New Prostate-Specific Membrane Antigen Ligand for Prostate Cancer Imaging. J. Nucl. Med. 2017;58:425–431. doi: 10.2967/jnumed.116.181768.
    1. Mease R.C., Dusich C.L., Foss C.A., Ravert H.T., Dannals R.F., Seidel J., Prideaux A., Fox J.J., Sgouror G., Kozikowski A.P., et al. N-[N-[(S)-1,3-Dicarboxypropyl]Carbamoyl]-4-[18F]Fluorobenzyl-L-cysteine, [18F]DCFBC: A New Pmaging Probe for Prostate Cancer. Clin. Cancer Res. 2008;14:3036–3043. doi: 10.1158/1078-0432.CCR-07-1517.
    1. Chen Y., Pullambhatla M., Foss C.A., Byun Y., Nimmagadda S., Senthamizhchelvan S., Sgouros G., Mease R.C., Pomper M.G. 2-(3-{1-Carboxy-5-[(6-[18F]Fluoro-Pyridine-3-Carbonyl)-Amino]-Pentyl}-Ureido)-Pentanedioic Acid, [18F]DCFPyL, a PSMA-Based PET Imaging Agent for Prostate Cancer. Clin. Cancer Res. 2011;17:7645–7653. doi: 10.1158/1078-0432.CCR-11-1357.
    1. Malik N., Zlatopolskiy B., Machulla H.J., Reske S.N., Solbach C. One pot radiofluorination of a new potential PSMA ligand [Al18F]NOTA-DUPA-Pep. J. Label. Compd. Radiopharm. 2012;55:320–325. doi: 10.1002/jlcr.2944.
    1. Graham K., Lesche R., Gromov A.V., Böhnke N., Schäfer M., Hassfeld J. Radiofluorinated Derivatives of 2-(Phosphonomethyl)pentanedioic Acid as Inhibitor of Prostate Specific Membrane Antigen (PSMA) for the Imaging of Prostate Cancer. J. Med. Chem. 2012;55:9510–9520. doi: 10.1021/jm300710j.
    1. Giesel F.L., Cardinale J., Schäfer M., Neels O., Benešová M., Mier W., Haberkorn U., Kopka K., Kratochwil C. 18F-Labelled PSMA-1007 shows similarity in structure, biodistribution and tumour uptake to the theragnostic compound PSMA-617. Eur. J. Nucl. Med. Mol. Imaging. 2016;43:1929–1930. doi: 10.1007/s00259-016-3447-9.
    1. Giesel F.L., Hadaschik B., Cardinale J., Radtke J., Vinsensia M., Lehnert W., Kesch C., Tolstov Y., Singer S., Grabe N., et al. F-18 labelled PSMA-1007: Biodistribution, radiation dosimetry and histopathological validation of tumor lesions in prostate cancer patients. Eur. J. Nucl. Med. Mol. Imaging. 2017;44:678–688. doi: 10.1007/s00259-016-3573-4.
    1. Giesel F.L., Kesch C., Yun M., Cardinale J., Haberkorn U., Kopka K., Kratochwil C., Hadaschik B.A. 18F-PSMA-1007 PET/CT Detects Micrometastases in a Patient With Biochemically Recurrent Prostate Cancer. Clin. Genitourin. Cancer. 2017;15:e497–e499. doi: 10.1016/j.clgc.2016.12.029.
    1. Freitag M., Kesch C., Cardinale J., Schlemmer H., Haberkorn U., Kopka K. Giesel Simultaneous whole-body 18F-PSMA-1007-PET/MRI with integrated multi-parametric MRI of the prostatic fossa for comprehensive oncological staging of patients with prostate cancer. J. Nucl. Med. 2017;58:538.
    1. Martin R., Hesse R., Smits R, Hübner S., Müller M., Hoepping A. Präkursoren für die Radiofluorierung. Application No. DE 10 2016 122 273.9. German Patent. 2016 submitted.
    1. The European Pharmacopoeia, 9.2. European Directorate for the Quality of the Medicines (EDQM); Strasbourg, France: 2017.
    1. Cardinale J., Schäfer M., Neels O.C., Remde Y., Haberkorn U., Giesel F.L., Kopka K. F-18-PSMA-1007—Von der Präklinik zur ersten Humananwendung. Nuklearmedizin. 2017;56:A29.
    1. Olberg D.E., Arukwe J.M., Grace D., Hjelstuen O.K., Solbakken M., Kindberg G.M., Cuthbertson A. One Step Radiosynthesis of 6-[18F]Fluoronicotinic Acid 2,3,5,6-Tetrafluorophenyl Ester ([18F]F-Py-TFP): A New Prosthetic Group for Efficient Labeling of Biomolecules with Fluorine-18. J. Med. Chem. 2010;53:1732–1740. doi: 10.1021/jm9015813.
    1. Block D., Klatte B., Knöchel A., Beckmann R., Holm U.N.C.A. [18F]-labelling of aliphatic compounds in high yields via aminopolyether—Supported nucleophilic substitution. J. Label. Compd. Radiopharm. 1986;23:467–477. doi: 10.1002/jlcr.2580230503.
    1. Kuntzsch M., Lamparter D., Brüggener N., Müller M., Kienzle G.J., Reischl G. Development and Successful Validation of Simple and Fast TLC Spot Tests for Determination of Kryptofix® 2.2.2 and Tetrabutylammonium in 18F-Labeled Radiopharmaceuticals. Pharmaceuticals. 2014;7:621–633. doi: 10.3390/ph7050621.

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