Positron Emission Tomography Imaging of Prostate Cancer with Ga-68-Labeled Gastrin-Releasing Peptide Receptor Agonist BBN7-14 and Antagonist RM26

Bioconjug Chem. 2018 Feb 21;29(2):410-419. doi: 10.1021/acs.bioconjchem.7b00726. Epub 2018 Jan 9.

Abstract

Radiolabeled bombesin (BBN) analogs have long been used for developing gastrin-releasing peptide receptor (GRPR) targeted imaging probes, and tracers with excellent in vivo performance including high tumor uptake, high contrast, and favorable pharmacokinetics are highly desired. In this study, we compared the 68Ga-labeled GRPR agonist (Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2, BBN7-14) and antagonist (d-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2, RM26) for the positron emission tomography (PET) imaging of prostate cancer. The in vitro stabilities, receptor binding, cell uptake, internalization, and efflux properties of the probes 68Ga-1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA)-Aca-BBN7-14 and 68Ga-NOTA-poly(ethylene glycol)3 (PEG3)-RM26 were studied in PC-3 cells, and the in vivo GRPR targeting abilities and kinetics were investigated using PC-3 tumor xenografted mice. BBN7-14, PEG3-RM26, NOTA-Aca-BBN7-14, and NOTA-PEG3-RM26 showed similar binding affinity to GRPR. In PC-3 tumor-bearing mice, the tumor uptake of 68Ga-NOTA-PEG3-RM26 remained at around 3.00 percentage of injected dose per gram of tissue within 1 h after injection, in contrast with 68Ga-NOTA-Aca-BBN7-14, which demonstrated rapid elimination and high background signal. Additionally, the majority of the 68Ga-NOTA-PEG3-RM26 remained intact in mouse serum at 5 min after injection, while almost all of the 68Ga-NOTA-Aca-BBN7-14 was degraded under the same conditions, demonstrating more-favorable in vivo pharmacokinetic properties and metabolic stabilities of the antagonist probe relative to its agonist counterpart. Overall, the antagonistic GRPR targeted probe 68Ga-NOTA-PEG3-RM26 is a more-promising candidate than the agonist 68Ga-NOTA-Aca-BBN7-14 for the PET imaging of prostate cancer patients.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cell Line, Tumor
  • Female
  • Gallium Radioisotopes / chemistry*
  • Gallium Radioisotopes / pharmacokinetics
  • Heterocyclic Compounds / chemistry
  • Heterocyclic Compounds / pharmacokinetics
  • Heterocyclic Compounds, 1-Ring
  • Humans
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Peptides / chemistry*
  • Peptides / pharmacokinetics
  • Positron-Emission Tomography / methods*
  • Prostate / diagnostic imaging*
  • Prostatic Neoplasms / diagnostic imaging*
  • Receptors, Bombesin / agonists*
  • Receptors, Bombesin / antagonists & inhibitors*

Substances

  • Gallium Radioisotopes
  • Heterocyclic Compounds
  • Heterocyclic Compounds, 1-Ring
  • Peptides
  • Receptors, Bombesin
  • 1,4,7-triazacyclononane-N,N',N''-triacetic acid
  • Gallium-68