Unexpected sensitivity of sst2 antagonists to N-terminal radiometal modifications

Fani, Melpomeni; Braun, Friederike; Waser, Beatrice; Beetschen, Karin; Cescato, Renzo; Erchegyi, Judit; Rivier, Jean E; Weber, Wolfgang A; Maecke, Helmut R; Reubi, Jean-Claude (2012). Unexpected sensitivity of sst2 antagonists to N-terminal radiometal modifications. Journal of nuclear medicine, 53(9), pp. 1481-9. New York, N.Y.: Society of Nuclear Medicine 10.2967/jnumed.112.102764

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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-NO(2)-Phe-c[D-Cys-Tyr-D-Aph(Cbm)-Lys-Thr-Cys]-D-Tyr-NH(2), DOTA-Cpa-c[D-Cys-Aph(Hor)-D-Aph(Cbm)-Lys-Thr-Cys]-D-Tyr-NH(2) (DOTA-JR11), and DOTA-p-Cl-Phe-c[D-Cys-Tyr-D-Aph(Cbm)-Lys-Thr-Cys]-D-Tyr-NH(2), 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 (68)Ga-DOTATATE agonist with (68)Ga-DOTA-JR11 and (68)Ga-NODAGA-JR11 showed not only that the JR11 antagonist radioligands were superior to the agonist ligands but also that (68)Ga-NODAGA-JR11 was the tracer of choice and preferable to (68)Ga-DOTA-JR11 in transplantable HEK293-hsst(2) tumors in mice. One may therefore generalize that somatostatin receptor 2 antagonists are sensitive to radiometal modifications and may preferably be coupled with a (68)Ga-NODAGA chelator-radiometal complex.

Item Type:

Journal Article (Original Article)


04 Faculty of Medicine > Service Sector > Institute of Pathology
04 Faculty of Medicine > Department of Radiology, Neuroradiology and Nuclear Medicine (DRNN) > Clinic of Nuclear Medicine

UniBE Contributor:

Cescato, Renzo and Reubi-Kattenbusch, Jean-Claude


500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health




Society of Nuclear Medicine




Factscience Import

Date Deposited:

04 Oct 2013 14:32

Last Modified:

05 Dec 2022 14:10

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https://boris.unibe.ch/id/eprint/12489 (FactScience: 218841)

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