NODAGATOC, a new chelator-coupled somatostatin analogue labeled with [67/68Ga] and [111In] for SPECT, PET, and targeted therapeutic applications of somatostatin receptor (hsst2) expressing tumors

Klaus Peter Eisenwiener, M. I.M. Prata, I. Buschmann, Han Wen Zhang, A. C. Santos, Sandra Wenger, Jean Claude Reubi, Helmut R. Mäcke

Research output: Contribution to journalArticlepeer-review

186 Scopus citations

Abstract

A monoreactive NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid) derived prochelator (1-(1-carboxy 3-carbo-tert-butoxypropyl)-4,7-(carbo-tert-butoxymethyl)-1,4,7- triazacyclononane (NODAGA(tBu)3)) was synthesized in five steps with an overall yield of 21%. It is useful for the coupling to the N-terminus of peptides on solid phase and in solution; it was coupled to [Tyr3]-octreotide (TOC) on solid phase, and the resulting peptide, NODAGA-Tyr3-octreotide (NODAGATOC), was labeled with the radiometals rain and 67Ga in high yields and good specific activities. [67Ga] - and [111In] - NODAGA-Tyr3-octreotide appear to be useful to visualize primary tumors and metastases which express somatostatin receptors subtype 2 (sstr2), such as neuroendocrine tumors, because of their high affinity to this receptor subtype with IC50 = 3.5 ± 1.6 nM and 1.7 ± 0.2 nM, respectively. NODAGATOC could be used as a SPECT and PET tracer, when labeled with 111In, 67Ga, or 68Ga, and even for therapeutic applications. Surprisingly, [111In] - NODAGATOC shows 2 times higher binding affinity to sstr2, but also a factor of 4 higher affinity to sstr5 compared to [67Ga] - NODAGATOC. [67Ga] - NODAGATOC is very stable in serum and rat liver homogenate. There is no difference in the rate of internalization into AR4-2J rat pancreatic tumor cells; both radioligands are highly internalized, at 4 h a 3 times higher uptake compared to [111In] - DOTA-Tyr3-octreotide ([111In] - DOTATOC) was found. The biodistribution of [67Ga] - NODAGATOC in AR4-2J tumor bearing nude mice is very favorable at short times after injection; there is fast excretion from all nontarget organs except the kidneys and high uptake in sst receptor rich organs and in the AR4-2J tumor. Again it is superior to [111In] - DOTATOC in this respect. The results indicate an improved biological behavior which is likely due to the fact that an additional spacer group separates the chelate from the pharmacophoric part of the somatostatin analogue.

Original languageEnglish
Pages (from-to)530-541
Number of pages12
JournalBioconjugate Chemistry
Volume13
Issue number3
DOIs
StatePublished - 2002

Fingerprint

Dive into the research topics of 'NODAGATOC, a new chelator-coupled somatostatin analogue labeled with [67/68Ga] and [111In] for SPECT, PET, and targeted therapeutic applications of somatostatin receptor (hsst2) expressing tumors'. Together they form a unique fingerprint.

Cite this