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

Varasteh Z, Mitran B, Rosenström U, Velikyan I, Rosestedt M, Lindeberg G, Sörensen J, Larhed M, Tolmachev V, Orlova A

Nucl. Med. Biol. 42 (5) 446-454 [2015-05-00; online 2014-12-20]

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-NH(2), RM26) conjugated to NOTA via a PEG(2) spacer (NOTA-PEG(2)-RM26) labeled with (68)Ga, (111)In and Al(18)F. (68)Ga-labeled NOTA-PEG(2)-RM26 showed high tumor-to-organ ratios. The influence of different macrocyclic chelators (NOTA, NODAGA, DOTA and DOTAGA) on the targeting properties of (68)Ga-labeled PEG(2)-RM26 was studied in vitro and in vivo. All conjugates were labeled with generator-produced (68)Ga with high yields and demonstrated high stability and specific binding to GRPR. The IC(50) values of (nat)Ga-X-PEG(2)-RM26 (X = NOTA, DOTA, NODAGA, DOTAGA) were 2.3 ± 0.2, 3.0 ± 0.3, 2.9 ± 0.3 and 10.0 ± 0.6 nM, 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, [(68)Ga]Ga-NOTA-PEG(2)-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 2 h 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. Chelators had a clear influence on the biodistribution and targeting properties of (68)Ga-labeled antagonistic BN analogs. Positively charged [(68)Ga]Ga-NOTA-PEG(2)-RM26 provided a low kidney radioactivity uptake, high affinity, high tumor uptake and high image contrast.

Affiliated researcher

PubMed 25684649

DOI 10.1016/j.nucmedbio.2014.12.009

Crossref 10.1016/j.nucmedbio.2014.12.009

pii: S0969-8051(14)00574-5


Publications 7.2.9