The effect of macrocyclic chelators on the targeting properties of the 68Ga-labeled gastrin releasing peptide receptor antagonist PEG2-RM26

Zohreh Varasteh, Bogdan Mitran, Ulrika Rosenström, Irina Velikyan, Maria Rosestedt, Gunnar Lindeberg, Jens Sörensen, Mats Larhed, Vladimir Tolmachev, Anna Orlova

Research output: Contribution to journalArticlepeer-review

32 Citations (Scopus)


Introduction: Overexpression of gastrin-releasing peptide receptors (GRPR) has been reported in several cancers. Bombesin (BN) analogs are short peptides with a high affinity for GRPR. Different BN analogs were evaluated for radionuclide imaging and therapy of GRPR-expressing tumors. We have previously investigated an antagonistic analog of BN (D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2, RM26) conjugated to NOTA via a PEG2 spacer (NOTA-PEG2-RM26) labeled with 68Ga, 111In and Al18F. 68Ga-labeled NOTA-PEG2-RM26 showed high tumor-to-organ ratios. Methods: The influence of different macrocyclic chelators (NOTA, NODAGA, DOTA and DOTAGA) on the targeting properties of 68Ga-labeled PEG2-RM26 was studied in vitro and in vivo. Results: All conjugates were labeled with generator-produced 68Ga with high yields and demonstrated high stability and specific binding to GRPR. The IC50 values of natGa-X-PEG2-RM26 (X=NOTA, DOTA, NODAGA, DOTAGA) were 2.3±0.2, 3.0±0.3, 2.9±0.3 and 10.0±0.6nM, respectively. The internalization of the conjugates by PC-3 cells was low. However, the DOTA-conjugated analog demonstrated a higher internalization rate compared to other analogs. GRPR-specific uptake was found in receptor-positive normal tissues and PC-3 xenografts for all conjugates. The biodistribution of the conjugates was influenced by the choice of the chelator moiety. Although all radiotracers cleared rapidly from the blood, [68Ga]Ga-NOTA-PEG2-RM26 showed significantly lower uptake in lung, muscle and bone compared to the other analogs. The uptake in tumors (5.40±1.04 %ID/g at 2h p.i.) and the tumor-to-organ ratios (25±3, 157±23 and 39±4 for blood, muscle and bone, respectively) were significantly higher for the NOTA-conjugate than the other analogs. Conclusions: Chelators had a clear influence on the biodistribution and targeting properties of 68Ga-labeled antagonistic BN analogs. Positively charged [68Ga]Ga-NOTA-PEG2-RM26 provided a low kidney radioactivity uptake, high affinity, high tumor uptake and high image contrast.

Original languageEnglish
Pages (from-to)446-454
Number of pages9
JournalNuclear Medicine and Biology
Issue number5
Publication statusPublished - 1 May 2015
Externally publishedYes


  • Bombesin antagonistic analog
  • DOTA
  • Molecular imaging
  • NOTA

ASJC Scopus subject areas

  • Molecular Medicine
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

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