PET of somatostatin receptor-positive tumors using 64Cu- and 68Ga-somatostatin antagonists: the chelate makes the difference

J Nucl Med. 2011 Jul;52(7):1110-8. doi: 10.2967/jnumed.111.087999. Epub 2011 Jun 16.


Somatostatin-based radiolabeled peptides have been successfully introduced into the clinic for targeted imaging and radionuclide therapy of somatostatin receptor (sst)-positive tumors, especially of subtype 2 (sst2). The clinically used peptides are exclusively agonists. Recently, we showed that radiolabeled antagonists may be preferable to agonists because they showed better pharmacokinetics, including higher tumor uptake. Factors determining the performance of radioantagonists have only scarcely been studied. Here, we report on the development and evaluation of four (64)Cu or (68)Ga radioantagonists for PET of sst2-positive tumors.

Methods: The novel antagonist p-Cl-Phe-cyclo(D-Cys-Tyr-D-4-amino-Phe(carbamoyl)-Lys-Thr-Cys)D-Tyr-NH(2) (LM3) was coupled to 3 macrocyclic chelators, namely 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (CB-TE2A), 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA), and DOTA. (64/nat)Cu- and (68/nat)Ga-NODAGA-LM3 were prepared at room temperature, and (64/nat)Cu-CB-TE2A-LM3 and (68/nat)Ga-DOTA-LM3 were prepared at 95°C. Binding affinity and antagonistic properties were determined with receptor autoradiography and immunofluorescence microscopy using human embryonic kidney (HEK)-sst2 cells. In vitro internalization and dissociation was evaluated using the same cell line. Biodistribution and small-animal PET studies were performed with HEK-sst2 xenografts.

Results: All metallopeptides demonstrated antagonistic properties. The affinities depend on chelator and radiometal and vary about 10-fold; (68/nat)Ga-NODAGA-LM3 has the lowest half maximal inhibitory concentration (1.3 ± 0.3 nmol/L). The biodistribution studies show impressive tumor uptake at 1 h after injection, particularly of (64)Cu- and (68)Ga-NODAGA-LM3 (∼40 percentage injected dose per gram of tissue [%ID/g]), which were proven to be specific. Background clearance was fast and the tumor washout relatively slow for (64)Cu-NODAGA-LM3 (∼15 %ID/g, 24 h after injection) and almost negligible for (64)Cu-CB-TE2A-LM3 (26.9 ± 3.3 %ID/g and 21.6 ± 2.1 %ID/g, 4 and 24 h after injection, respectively). Tumor-to-normal-tissue ratios were significantly higher for (64)Cu-NODAGA-LM3 than for (64)Cu-CB-TE2A-LM3 (tumor-to-kidney, 12.8 ± 3.6 and 1.7 ± 0.3, respectively; tumor-to-muscle, 1,342 ± 115 and 75.2 ± 8.5, respectively, at 24 h, P < 0.001). Small-animal PET shows clear tumor localization and high image contrast, especially for (64)Cu- and (68)Ga-NODAGA-LM3.

Conclusion: This article demonstrates the strong dependence of the affinity and pharmacokinetics of the somatostatin-based radioantagonists on the chelator and radiometal. (64)Cu- and (68)Ga-NODAGA-LM3 and (64)Cu-CB-TE2A-LM3 are promising candidates for clinical translation because of their favorable pharmacokinetics and the high image contrast on PET scans.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Chelating Agents / chemistry*
  • Copper Radioisotopes*
  • Female
  • Gallium Radioisotopes
  • HEK293 Cells
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Mice
  • Neoplasms / diagnostic imaging*
  • Neoplasms / metabolism*
  • Positron-Emission Tomography / methods*
  • Protein Transport
  • Radiochemistry
  • Receptors, Somatostatin / antagonists & inhibitors*
  • Receptors, Somatostatin / metabolism
  • Somatostatin* / chemistry
  • Somatostatin* / metabolism
  • Somatostatin* / pharmacology


  • Chelating Agents
  • Copper Radioisotopes
  • Gallium Radioisotopes
  • Receptors, Somatostatin
  • Somatostatin