111In-Labeled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-conjugated dimeric [Tyr3]octreotide (2010)

The 111In-labeled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-conjugated dimeric [Tyr3]octreotide, abbreviated as 111In-dimeric [Tyr3]octreotide, is an octreotide-based agent developed by Yim et al. for somatostatin receptor (SSTR)–targeted imaging and radionuclide therapy (1).The human SSTR family is a group of G-protein–coupled receptors with five members (SSTR1–SSTR5). All receptor members have seven α-helical transmembrane domains and possess a highly conserved sequence motif (YANSCANPI/VLY) in the seventh topology, which serves as a signature sequence for this family (2-4). Overall, there is 39%–57% sequence identity among the members, with the highest homology between SSTR1 and SSTR4, and among SSTR2, SSTR3, and SSTR5, respectively. The two groups of receptors also differ in their interactions with somatostatin (SST) and its analogs. SSTR2, SSTR3, and SSTR5 have a high affinity for octreotide and seglitide, whereas SSTR1 and SSTR4 exhibit a very low affinity for them (1-3). With the exception of SSTR2, the precise contributions of other members remain to be elucidated. This is largely due to the lack of highly selective ligands and the co-expression of different subtypes in single cells. SSTRs are distributed widely in cells both in the nervous system and periphery, and they have been shown to be overexpressed in a large number of malignancies, with particularly high density in neuroendocrine tumors (5-7).As the targets of SST radiopharmaceuticals, SSTRs are of considerable clinical relevance for tumor imaging and radionuclide therapy (4, 6, 8, 9). Because the native SST has a very short biological half-life (<2 min), various analogs have been synthesized, including octreotide, lanreotide, vapreotide, and their derivatives (6, 8, 10). In general, these analogs have a high affinity to SSTR2, somewhat lower affinity to SSTR3 and SSTR5, and almost no affinity to SSTR1 and SSTR4. Treatment with the radiolabeled analogs results in reduced hormonal overproduction and symptomatic relief in most patients with neuroendocrine tumors; however, it is much less successful in tumor size reduction (11, 12). Imaging with 111In-, 90Y-, or 177Lu-labeled [DOTA0,Tyr3]octreotide analogs has proven the usefulness of octreotide conjugates in the diagnosis and staging of neuroendocrine tumors (8, 9, 13).There is growing interest in the development of polyvalent ligands for dual imaging and therapeutic purposes, considering that polyvalent ligands may have a higher binding affinity than monovalent analogs. Yim et al., synthesized mono-, di-, and tetrameric [Tyr3]octreotide conjugates with a two-stage metal-free ligation procedure (1). The investigators characterized these conjugates and compared them with 111In-labeled [DOTA0,Tyr3]octreotide ([111In-DOTA0,Tyr3]octreotide), a chemically engineered and long-acting analog. [111In-DOTA0,Tyr3]octreotide has been applied for imaging and treatment in patients with neuroendocrine tumors (6, 11, 12). Yim et al. have shown that the 111In-labeled monomeric and dimeric [Tyr3]octreotides, but not the tetrameric [Tyr3]octreotide, have a similar binding affinity for SSTRs and a longer tumor retention time when compared with [111In-DOTA0,Tyr3]octreotide (1). This chapter describes the results obtained with 111In-dimeric [Tyr3]octreotide.