PT  - JOURNAL ARTICLE
AU  - de Jong, Marion
AU  - Marsouvanidis, Pantelis
AU  - van der Graaf, Linda
AU  - Melis, Marleen
AU  - Krenning, Eric
AU  - Martinez, Jean
AU  - Brunel, Luc
AU  - Fehrentz, Jean-Alain
AU  - Nock, Berthold
AU  - Maina, Theodosia
TI  - Radiopeptide antagonists for imaging and therapy of GRPR<sup>+</sup> tumors
DP  - 2011 May 01
TA  - Journal of Nuclear Medicine
PG  - 189--189
VI  - 52
IP  - supplement 1
4099  - http://jnm.snmjournals.org/content/52/supplement_1/189.short
4100  - http://jnm.snmjournals.org/content/52/supplement_1/189.full
SO  - J Nucl Med2011 May 01; 52
AB  - 189 Objectives GRP receptor (GRPR) targeted imaging and therapy of tumors, e.g. breast and prostate cancer, by radiolabeled bombesin analogs is a challenging goal. Recent studies have revealed the superior profile of GRPR-antagonists as compared to agonists. Better targeting of PC-3 xenografts in mice plus fast clearance from the GRPR-rich pancreas and background tissues was observed. Combined with their biosafety and tumor growth inhibition GRPR antagonists are attractive alternatives to agonists. We evaluated 2 new linear bombesin antagonists coupled with the chelator DOTA. The latter allows tagging of radionuclides for both diagnostic and therapeutic applications. Methods H-(β-Ala)2-JMV594 and H-(β-Ala)3-JMV594 were assembled on solid support and coupled to DOTA. The peptides were labelled with 111In. In vitro assays using GRPR+ PC-3 cells were performed to determine affinity and internalization in comparison to the agonist 111In-AMBA. Biodistribution studies with PC-3-xenografted female SCID mice were performed at 4 and 24 h post injection (p.i.) of radiopeptides (10 pmol). Results Of the 2 compounds, DOTA-(β-Ala)2-JMV594 appeared to be the most promising. Receptor affinity was high (IC50 1.3 nM), whereas the internalization rate was low, characteristic for antagonists. Biodistribution results revealed very high uptake of radioactivity in the GRPR+ PC-3 tumor (17.0±2.8%ID/g - block 1.3±0.3%ID/g) versus the pancreas (3.1 ±1.3%ID/g - block 0.8±0.2%ID/g) at 4 h p.i. and 5.2±0.5%ID/g vs. 1.0±0.2%ID/g in PC-3 and pancreas at 24 h p.i., resulting in a tumor/pancreas ratio > 5. Retention of radioactivity in the kidneys was low, 3.5±0.5%ID/g and 1.9±0.3%ID/g at 4 and 24 h p.i., respectively. 111In-DOTA-(β-Ala)3-JMV594 revealed less promising in vivo data. Conclusions Based on favourable in vitro and in vivo characteristics, we conclude that DOTA-(β-Ala)2-JMV594 is a most promising GRPR antagonist for future use in clinical studies