Web Release Date: December 15,
Influence of Different Spacers on the Biological Profile of a DOTA-Somatostatin Analogue
and
Division of Radiological Chemistry, Department of Radiology, University Hospital Basel, and Divison of Cell Biology and Experimental Cancer Research, Institute of Pathology, University of Berne, Switzerland
Received June 13, 2006
Revised October 19, 2006
Abstract:
Radiolabeled somatostatin analogues have been successfully used for targeted radiotherapy and for imaging of
somatostatin receptor (sst1-5)-positive tumors. Nevertheless, these analogues are subject to improving their tumor-to-nontarget ratio to enhance their diagnostic or therapeutic properties, preventing nephrotoxicity. In order to
understand the influence of lipophilicity and charge on the pharmacokinetic profile of [1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)]-somatostatin-based radioligands such as [DOTA,1-Nal3]-octreotide
(DOTA-NOC), different spacers (X) based on 8-amino-3,6-dioxaoctanoic acid (PEG2), 15-amino-4,7,10,13-tetraoxapentadecanoic acid (PEG4), N-acetyl glucosamine (GlcNAc), triglycine, 
-alanine, aspartic acid, and lysine
were introduced between the chelator DOTA and the peptide NOC. All DOTA-X-NOC conjugates were
synthesized by Fmoc solid-phase synthesis. The partition coefficient (log D) at pH = 7.4 indicated that higher
hydrophilicity than [111In-DOTA]-NOC was achieved with the introduction of the mentioned spacers, except
with triglycine and -alanine. The high affinity of [InIII-DOTA]-NOC for human sst2 (hsst2) was preserved with
the structural modifications, while an overall drop for hsst3 affinity was observed, except in the case of [InIII-DOTA]--Ala-NOC. The new conjugates preserved the good affinity for hsst5, except for [InIII-DOTA]-Asn(GlcNAc)-NOC, which showed decreased affinity. A significant 1.2-fold improvement in the specific
internalization rate in AR4-2J rat pancreatic tumor cells (sst2 receptor expression) at 4 h was achieved with the
introduction of Asp as a spacer in the parent compound. In sst3-expressing HEK cells, the specific internalization
rate at 4 h for [111In-DOTA]-NOC (13.1% ± 0.3%) was maintained with [111In-DOTA]--Ala-NOC (14.0%
± 1.8%), but the remaining derivatives showed <2% specific internalization. Biodistribution studies were performed
with Lewis rats bearing the AR4-2J rat pancreatic tumor. In comparison to [111In-DOTA]-NOC (2.96% ± 0.48%
IA/g), the specific uptake in the tumor at 4 h p.i. was significantly improved for the 111In-labeled sugar analogue
(4.17% ± 0.46% IA/g), which among all the new derivatives presented the best tumor-to-kidney ratio (1.9).
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