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Preclinical and first clinical experience with the gastrin-releasing peptide receptor-antagonist [68Ga]SB3 and PET/CT

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

A Protocol for this article was published on 12 May 2016

Abstract

Purpose

Gastrin-releasing peptide receptors (GRPR) represent attractive targets for tumor diagnosis and therapy because of their overexpression in major human cancers. Internalizing GRPR agonists were initially proposed for prolonged lesion retention, but a shift of paradigm to GRPR antagonists has recently been made. Surprisingly, radioantagonists, such as [99mTc]DB1 (99mTc-N4′-DPhe6,Leu-NHEt13]BBN(6–13)), displayed better pharmacokinetics than radioagonists, in addition to their higher inherent biosafety. We introduce here [68Ga]SB3, a [99mTc]DB1 mimic-carrying, instead of the 99mTc-binding tetraamine, the chelator DOTA for labeling with the PET radiometal 68Ga.

Methods

Competition binding assays of SB3 and [natGa]SB3 were conducted against [125I-Tyr4]BBN in PC-3 cell membranes. Blood samples collected 5 min postinjection (pi) of the [67Ga]SB3 surrogate in mice were analyzed using high-performance liquid chromatography (HPLC) for degradation products. Likewise, biodistribution was performed after injection of [67Ga]SB3 (37 kBq, 100 μL, 10 pmol peptide) in severe combined immunodeficiency (SCID) mice bearing PC-3 xenografts. Eventually, [68Ga]SB3 (283 ± 91 MBq, 23 ± 7 nmol) was injected into 17 patients with breast (8) and prostate (9) cancer. All patients had disseminated disease and had received previous therapies. PET/CT fusion images were acquired 60–115 min pi.

Results

SB3 and [natGa]SB3 bound to the human GRPR with high affinity (IC50: 4.6 ± 0.5 nM and 1.5 ± 0.3 nM, respectively). [67Ga]SB3 displayed good in vivo stability (>85 % intact at 5 min pi). [67Ga]SB3 showed high, GRPR-specific and prolonged retention in PC-3 xenografts (33.1 ± 3.9%ID/g at 1 h pi – 27.0 ± 0.9%ID/g at 24 h pi), but much faster clearance from the GRPR-rich pancreas (≈160%ID/g at 1 h pi to <17%ID/g at 24 h pi) in mice. In patients, [68Ga]SB3 elicited no adverse effects and clearly visualized cancer lesions. Thus, 4 out of 8 (50 %) breast cancer and 5 out of 9 (55 %) prostate cancer patients showed pathological uptake on PET/CT with [68Ga]SB3.

Conclusion

[67Ga]SB3 showed excellent pharmacokinetics in PC-3 tumor-bearing mice, while [68Ga]SB3 PET/CT visualized lesions in about 50 % of patients with advanced and metastasized prostate and breast cancer. We expect imaging with [68Ga]SB3 to be superior in patients with primary breast or prostate cancer.

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    Authors and Affiliations

    1. Molecular Radiopharmacy, INRASTES, NCSR “Demokritos”, Ag. Paraskevi Attikis, 15310, Athens, Greece

      Theodosia Maina, David Charalambidis & Berthold A. Nock

    2. Department of Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands

      Hendrik Bergsma, Eric P. Krenning & Marion de Jong

    3. Department of Radiology, Erasmus MC, Rotterdam, The Netherlands

      Marion de Jong

    4. Molecular Radiotherapy and Molecular Imaging, Zentralklinik, Bad Berka, Germany

      Harshad R. Kulkarni, Dirk Mueller & Richard P. Baum

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    1. Theodosia Maina
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    Correspondence to Theodosia Maina.

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    All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

    All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

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    Theodosia Maina and Hendrik Bergsma contributed equally to this work

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    Glossary

    [99mTc]DB1

    99mTc-(N′4)-DPhe-Gln-Trp-Ala-Val-Gly-His-Leu-NHEt)

    [99mTc]DB4

    99mTc-N4-Pro-Gln-Arg-Tyr-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Nle-NH2

    DOTA

    1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid

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    Maina, T., Bergsma, H., Kulkarni, H.R. et al. Preclinical and first clinical experience with the gastrin-releasing peptide receptor-antagonist [68Ga]SB3 and PET/CT. Eur J Nucl Med Mol Imaging 43, 964–973 (2016). https://doi.org/10.1007/s00259-015-3232-1

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