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

  • Theodosia MainaEmail author
  • Hendrik Bergsma
  • Harshad R. Kulkarni
  • Dirk Mueller
  • David Charalambidis
  • Eric P. Krenning
  • Berthold A. Nock
  • Marion de Jong
  • Richard P. Baum
Original Article



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.


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.


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.


[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.


PET/CT tumor imaging 68Ga radiotracer Gastrin-releasing peptide receptor antagonist Prostate cancer Breast cancer 


Compliance with ethical standards

Conflicts of interest


Ethical approval

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.

Informed consent

Informed consent was obtained from all individual participants included in the study.







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

Supplementary material

259_2015_3232_MOESM1_ESM.pdf (483 kb)
ESM 1 (PDF 482 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Theodosia Maina
    • 1
    Email author
  • Hendrik Bergsma
    • 2
  • Harshad R. Kulkarni
    • 4
  • Dirk Mueller
    • 4
  • David Charalambidis
    • 1
  • Eric P. Krenning
    • 2
  • Berthold A. Nock
    • 1
  • Marion de Jong
    • 2
    • 3
  • Richard P. Baum
    • 4
  1. 1.Molecular RadiopharmacyINRASTES, NCSR “Demokritos”AthensGreece
  2. 2.Department of Nuclear MedicineErasmus MCRotterdamThe Netherlands
  3. 3.Department of RadiologyErasmus MCRotterdamThe Netherlands
  4. 4.Molecular Radiotherapy and Molecular ImagingZentralklinikBad BerkaGermany

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