RT Journal Article
SR Electronic
T1 Bombesin Antagonist–Based Radioligands for Translational Nuclear Imaging of Gastrin-Releasing Peptide Receptor–Positive Tumors
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 1970
OP 1978
DO 10.2967/jnumed.111.094375
VO 52
IS 12
A1 Abiraj, Keelara
A1 Mansi, Rosalba
A1 Tamma, Maria-Luisa
A1 Fani, Melpomeni
A1 Forrer, Flavio
A1 Nicolas, Guillaume
A1 Cescato, Renzo
A1 Reubi, Jean Claude
A1 Maecke, Helmut R.
YR 2011
UL http://jnm.snmjournals.org/content/52/12/1970.abstract
AB Bombesin receptors are overexpressed on a variety of human tumors. In particular, the gastrin-releasing peptide receptor (GRPr) has been identified on prostate and breast cancers and on gastrointestinal stromal tumors. The current study aims at developing clinically translatable bombesin antagonist–based radioligands for SPECT and PET of GRPr-positive tumors. Methods: A potent bombesin antagonist (PEG4-d-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 [AR]) was synthesized; conjugated to the chelators DOTA, 6-carboxy-1,4,7,11-tetraazaundecane (N4), 1,4,7-triazacyclononane, 1-glutaric acid-4,7 acetic acid (NODAGA), and 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (CB-TE2A); and radiolabeled with 111In, 99mTc, 68Ga, and 64Cu, respectively. The radioconjugates were evaluated in vitro and in vivo in PC-3 tumor–bearing nude mice. Antagonist potency was determined by Ca2+-flux measurements and immunofluorescence. Results: All the conjugates showed high binding affinity to GRPr (inhibitory concentration of 50% [IC50], 2.5–25 nmol/L). The immunofluorescence and Ca2+-flux assays confirmed the antagonist properties of the conjugates. Biodistribution revealed high and specific uptake in PC-3 tumor and in GRPr-positive tissues. Tumor uptake of 64Cu-CB-TE2A-AR (31.02 ± 3.35 percentage injected activity per gram [%IA/g]) was higher than 99mTc-N4-AR (24.98 ± 5.22 %IA/g), 111In-DOTA-AR (10.56 ± 0.70 %IA/g), and 68Ga-NODAGA-AR (7.11 ± 3.26 %IA/g) at 1 h after injection. Biodistribution at later time points showed high tumor-to-background ratios because of the fast washout of the radioligand from normal organs, compared with tumor. High tumor-to-background ratios were further illustrated by PET and SPECT images of PC-3 tumor–bearing nude mice acquired at 12 h after injection showing high tumor uptake, clear background, and negligible or no radioactivity in the abdomen. Conclusion: The chelators do influence the affinity, antagonistic potency, and pharmacokinetics of the conjugates. The promising preclinical results warrant clinical translation of these probes for SPECT and PET.