PT  - JOURNAL ARTICLE
AU  - Melpomeni Fani
AU  - Friederike Braun
AU  - Beatrice Waser
AU  - Karin Beetschen
AU  - Renzo Cescato
AU  - Judit Erchegyi
AU  - Jean E. Rivier
AU  - Wolfgang A. Weber
AU  - Helmut R. Maecke
AU  - Jean Claude Reubi
TI  - Unexpected Sensitivity of sst<sub>2</sub> Antagonists to N-Terminal Radiometal Modifications
AID  - 10.2967/jnumed.112.102764
DP  - 2012 Sep 01
TA  - Journal of Nuclear Medicine
PG  - 1481--1489
VI  - 53
IP  - 9
4099  - http://jnm.snmjournals.org/content/53/9/1481.short
4100  - http://jnm.snmjournals.org/content/53/9/1481.full
SO  - J Nucl Med2012 Sep 01; 53
AB  - Chelated somatostatin agonists have been shown to be sensitive to N-terminal radiometal modifications, with Ga-DOTA agonists having significantly higher binding affinity than their Lu-, In-, and Y-DOTA correlates. Recently, somatostatin antagonists have been successfully developed as alternative tracers to agonists. The aim of this study was to evaluate whether chelated somatostatin antagonists are also sensitive to radiometal modifications and how. We have synthesized 3 different somatostatin antagonists, DOTA-p-NO2-Phe-c[d-Cys-Tyr-d-Aph(Cbm)-Lys-Thr-Cys]-d-Tyr-NH2, DOTA-Cpa-c[d-Cys-Aph(Hor)-d-Aph(Cbm)-Lys-Thr-Cys]-d-Tyr-NH2 (DOTA-JR11), and DOTA-p-Cl-Phe-c[d-Cys-Tyr-d-Aph(Cbm)-Lys-Thr-Cys]-d-Tyr-NH2, and added various radiometals including In(III), Y(III), Lu(III), Cu(II), and Ga(III). We also replaced DOTA with 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA) and added Ga(III). The binding affinity of somatostatin receptors 1 through 5 was evaluated in all cases. In all 3 resulting antagonists, the Ga-DOTA analogs were the lowest-affinity radioligands, with a somatostatin receptor 2 binding affinity up to 60 times lower than the respective Y-DOTA, Lu-DOTA, or In-DOTA compounds. Interestingly, however, substitution of DOTA by the NODAGA chelator was able to increase massively its binding affinity in contrast to the Ga-DOTA analog. The 3 NODAGA analogs are antagonists in functional tests. In vivo biodistribution studies comparing 68Ga-DOTATATE agonist with 68Ga-DOTA-JR11 and 68Ga-NODAGA-JR11 showed not only that the JR11 antagonist radioligands were superior to the agonist ligands but also that 68Ga-NODAGA-JR11 was the tracer of choice and preferable to 68Ga-DOTA-JR11 in transplantable HEK293-hsst2 tumors in mice. One may therefore generalize that somatostatin receptor 2 antagonists are sensitive to radiometal modifications and may preferably be coupled with a 68Ga-NODAGA chelator–radiometal complex.