Influence of Different Spacers on the Biological Profile of a DOTA−Somatostatin Analogue

• Published in: Bioconjugate chemistry 2007-01, Vol.18 (1), p.84-92
• Main Authors: Antunes, Patricia, Ginj, Mihaela, Walter, Martin A, Chen, Jianhua, Reubi, Jean-Claude, Maecke, Helmut R
• Format: Article
• Language: English
• Subjects: Animals; Cell Line; Growth hormones; Heterocyclic Compounds, 1-Ring - chemistry; Heterocyclic Compounds, 1-Ring - therapeutic use; Humans; Hydrophobic and Hydrophilic Interactions; Kidneys; Male; Molecular Structure; Neoplasms - drug therapy; Radiation therapy; Rats; Receptors, Somatostatin - metabolism; Serum; Somatostatin - analogs & derivatives; Somatostatin - chemistry; Somatostatin - metabolism; Statins; Toxins; Tumors
• ISSN: 1043-1802; 1520-4812
• DOI: 10.1021/bc0601673

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, β-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 β-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]−β-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]−β-Ala−NOC (14.0% ± 1.8%), but the remaining derivatives showed