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Daniel Storch, Joerg S. Schmitt, Christian Waldherr, Beatrice Waser, Jean-Claude Reubi, Helmut R. Maecke
Preclinical evaluation of somatostatin analogs bearing two macrocyclic chelators for high specific activity labeling with radiometals
Keywords: Somatostatin analogues, Octreotate, DOTA, Pentasarcosine, Indium-111
Radiometallated analogues of the regulatory peptide somatostatin are of interest in the in vivo localization and targeted radiotherapy of somatostatin receptor-overexpressing tumors. An important aspect of their use in vivo is a fast and efficient labeling (complexation) protocol for radiometals along with a high specific activity.
We describe in this manuscript synthetic methods for the coupling of two chelators (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid=DOTA) to the bioactive peptide [Tyr3,Thr8]-octreotide (TATE) in order to increase the specific activity (radioactivity in Bq per mole peptide). The full chelator-linker-peptide conjugate was assembled on solid support using standard Fmoc chemistry. Two DOTA-chelators were linked to the peptide using lysine or N,N′-bis(3-aminopropyl)-glycine (Apg); in addition, pentasarcosine (Sar5) was used as a spacer between the chelators and the peptide to probe its influence on biology and pharmacology. Complexation rates with In3+ and Y3+ salts and the corresponding radiometals were high, the bis-DOTA-derivatives showed higher complexation rates and gave higher specific activity than DOTA-TATE.
Pharmacological and biological data of the complexed molecules did not show significant differences if compared to the parent peptide [111/natIn-DOTA]-TATE except for [(111/natIn-DOTA)2-Apg]-TATE which showed a lower binding affinity and rate of internalization into tumor cells. The biodistribution of [(111/natIn-DOTA)-Lys(111/natIn-DOTA)]-TATE in the rat tumor model (AR4-2J) showed a high and specific (as shown by a blocking experiment) tracer uptake in somatostatin receptor-positive tissue but a lower tumor uptake compared to [111/natIn-DOTA]-TATE.
Radiochimica Acta, Oldenbourg Wissenschaftsverlag
Print ISSN: 0033-8230
Volume: 95, 06/2007
Pages: 359 - 369