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Synthesis and preclinical evaluation of an Al18F radiofluorinated GLU-UREA-LYS(AHX)-HBED-CC PSMA ligand

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Abstract

Purpose

The aim of this study was to synthesize and preclinically evaluate an 18F-PSMA positron emission tomography (PET) tracer. Prostate-specific membrane antigen (PSMA) specificity, biodistribution, and dosimetry in healthy and tumor-bearing mice were determined.

Methods

Several conditions for the labeling of 18F-PSMA-11 via 18F-AlF-complexation were screened to study the influence of reaction temperature, peptide amount, ethanol volume, and reaction time. After synthesis optimization, biodistribution and dosimetry studies were performed in C57BL6 mice. For proof of PSMA-specificity, mice were implanted with PSMA-negative (PC3) and PSMA-positive (LNCaP) tumors in contralateral flanks. Static and dynamic microPET/computed tomography (CT) imaging was performed.

Results

Quantitative labeling yields could be achieved with >97 % radiochemical purity. The 18F-PSMA-11 uptake was more than 24-fold higher in PSMA-high LNCaP than in PSMA-low PC3 tumors (18.4 ± 3.3 %ID/g and 0.795 ± 0.260 %ID/g, respectively; p < 4.2e-5). Results were confirmed by ex vivo gamma counter analysis of tissues after the last imaging time point. The highest absorbed dose was reported for the kidneys. The maximum effective dose for an administered activity of 200 MBq was 1.72 mSv.

Conclusion

18F-PSMA-11 using direct labeling of chelate-attached peptide with aluminum-fluoride detected PSMA-expressing tumors with high tumor-to-liver ratios. The kidneys were the dose-limiting organs. Even by applying the most stringent dosimetric calculations, injected activities of up to 0.56 GBq are feasible.

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Acknowledgment

We thank Larry Pang and Andreea Stuparu (members of the Ahmanson Translational Imaging Division) for their support and assistance.

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    Authors and Affiliations

    1. Department of Nuclear Medicine, S.Orsola-Malpighi University Hospital, Via Massarenti 9, 40138, Bologna, Italy

      Stefano Boschi, Filippo Lodi & Stefano Fanti

    2. Crump Institute for Molecular Imaging, David Geffen School of Medicine at UCLA, Los Angeles, USA

      Jason T. Lee

    3. Department of Nuclear Medicine, University Hospital Würzburg, Würzburg, Germany

      Seval Beykan, Uta Eberlein, Andreas K. Buck, Michael Lassmann & Ken Herrmann

    4. Ahmanson Translational Imaging Division, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave. CHS AR-255, Los Angeles, CA, 90095, USA

      Roger Slavik, Liu Wei, Claudio Spick, Johannes Czernin & Ken Herrmann

    5. Department of Medical Physics, S. Orsola-Malpighi University Hospital, Bologna, Italy

      Gianfranco Cicoria

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    1. Stefano Boschi
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    Correspondence to Ken Herrmann.

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    Funding

    This study was partly supported by an unrestricted grant from the Movember Foundation—MOVEMBER GAP2 FUNDING AWARD.

    Conflict of interest

    Johannes Czernin is founder of Sofie Biosciences, which manufactures the Genisys4 scanner used in this manuscript. No other potential conflicts of interest are reported.

    Ethical approval

    Animal studies were approved by the UCLA Animal Research Committee and were carried out according to the guidelines of the Division of Laboratory Animal Medicine at UCLA. All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. This article does not contain any studies with human participants.

    Author’s contributions

    Initials: Stefano Boschi (SB), Jason T. Lee (JTL), Seval Beykan (SeB), Roger Slavik (RS), Liu Wei (LW), Uta Eberlein (UE), Andreas K. Buck (AKB), Filippo Lodi (FL), Gianfranco Coria (GC), Johannes Czernin (JC), Michael Lassmann (ML), Ken Herrmann (KH), Stefano Fanti (SF)

    Conception and design: SB, AKB, JC, ML, KH, SF

    Development of methodology: SB, JTL, RS, GC, ML, KH, SF

    Acquisition of data: SB, JTL, RS, LW, FL, GC

    Analysis and interpretation of data: JTL, SeB, RS, ML, KH, SF

    Writing, review, and/or revision of the manuscript: all authors

    Administrative, technical, or material support: SB, AKB, JC, ML, KH, SF

    Supervision: SB, JC, ML, KH, SF

    Additional information

    Stefano Boschi and Jason T. Lee contributed equally to this work.

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    Boschi, S., Lee, J.T., Beykan, S. et al. Synthesis and preclinical evaluation of an Al18F radiofluorinated GLU-UREA-LYS(AHX)-HBED-CC PSMA ligand. Eur J Nucl Med Mol Imaging 43, 2122–2130 (2016). https://doi.org/10.1007/s00259-016-3437-y

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