RT Journal Article
SR Electronic
T1 Unexpected Sensitivity of sst<sub>2</sub> Antagonists to N-Terminal Radiometal Modifications
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 1481
OP 1489
DO 10.2967/jnumed.112.102764
VO 53
IS 9
A1 Fani, Melpomeni
A1 Braun, Friederike
A1 Waser, Beatrice
A1 Beetschen, Karin
A1 Cescato, Renzo
A1 Erchegyi, Judit
A1 Rivier, Jean E.
A1 Weber, Wolfgang A.
A1 Maecke, Helmut R.
A1 Reubi, Jean Claude
YR 2012
UL http://jnm.snmjournals.org/content/53/9/1481.abstract
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.