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

111In-Dimeric [Tyr3]octreotide
, PhD
National Center for Biotechnology Information, NLM, NIH
Corresponding author.

Created: ; Last Update: December 28, 2010.

Chemical name:111In-Labeled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-conjugated dimeric [Tyr3]octreotide
Abbreviated name:111In-Dimeric [Tyr3]octreotide
Agent Category:Peptides
Target:Somatostatin receptors (SSTRs)
Target Category:Receptors
Method of detection:Single-photon emission computed tomography (SPECT) and planar imaging
Source of signal / contrast:111In
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For structures of octreotide analogues, click on PubChem.



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.



DOTA-conjugated dimeric [Tyr3]octreotide was synthesized with a two-stage ligation procedure that combined the Cu(I)-catalyzed “click” reaction between dendrimeric alkynes and peptidic azides and the subsequent copper-free thio acid/azide “sulfo-click” amidation reaction between the obtained dendrimeric peptide thio acids and a DOTA-derived sulfonyl azide (1). The 111In-labeling was achieved in NH4OAc buffer (pH 5.5) with 111InCl3 by heating the reaction mixture for 10–15 min at 95ºC. The radiochemical yield of the 111In-dimeric [Tyr3]octreotide was >98% with a specific activity of 22.7 GBq/μmol (0.61 Ci/μmol). Its lipophilicity, expressed as log(D) value, was −1.79 ± 0.11, more lipophilic than that of [111In-DOTA0,Tyr3]octreotide (−3.59 ± 0.14). This could be attributed to the aromatic character of the dendrimer-derived linker moiety.

In Vitro Studies: Testing in Cells and Tissues


Binding affinity of the dimeric [Tyr3]octreotide for SSTRs was determined using SSTR2-expressing AR42J tumor cells in a competitive binding assay (1). [111In-DOTA0,Tyr3]octreotide was used as a radiotracer, and commercially available [DOTA0,Tyr3]octreotide was included as a competing ligand. The dimeric [Tyr3]octreotide had a 50% inhibition concentration (IC50) of 2.45 nM, comparable to that of the reference [DOTA0,Tyr3]octreotide (IC50 = 2.45 nM). The IC50 values for the monomeric and tetrameric [Tyr3]octreotide conjugates were 1.32 nM and 14.0 nM, respectively. These results showed a decreased binding affinity with increased valency. The hypothesized increase in receptor affinity due to multimerization was not observed, especially in the case of tetrameric [Tyr3]octreotide, which may be attributed to the limited water solubility of the [Tyr3]octreotide conjugates. The IC50 values for all 111In-labeled conjugates improved by a factor of 1.4–2.9, compared to unlabeled counterparts.

Animal Studies



In vivo biodistribution and tumor targeting of 111In-dimeric [Tyr3]octreotide (0.37 MBq (0.01 mCi), 0.1 µg) were investigated in BALB/c nude mice bearing subcutaneous AR42J tumors (n = 5 mice/time point) (1). [111In-DOTA0,Tyr3]octreotide was used as the reference compound, with a tumor uptake of 19.5 ± 4.84% injected dose per gram tissue (ID/g) at 2 h and 7.47 ± 0.78% ID/g at 24 h after tail vein injection. 111In-Dimeric [Tyr3]octreotide exhibited a specific and high tumor uptake of 25.31 ± 5.86% ID/g at 2 h, 30.91 ± 6.61% ID/g at 6 h, and 10.75 ± 2.98% ID/g at 24 h after injection. High activity at 6 h after injection indicates a prolonged retention of this compound in the tumors. The tumor uptake could be blocked with co-injection of excess octreotide (50 µg, n = 3 mice) (decreased to 5.55 ± 0.43% ID/g at 2 h). The blood clearance of 111In-dimeric [Tyr3]octreotide was relatively fast (1.52 ± 0.36% ID/g at 2 h and 0.17 ± 0.01% ID/g at 24 h), with the tumor/blood ratios increasing from 16.7 at 2 h to 35.9 at 6 h and to 71 at 24 h after injection. Among the organs, the kidney had the highest uptake with 92.20 ± 13.08% ID/g, 65.61 ± 9.71% ID/g, and 11.74 ± 3.31% ID/g at 2 h, 6 h, and 24 h, respectively. Low uptake was observed in the pancreas, stomach, and colon. The higher tumor uptake of 111In-dimeric [Tyr3]octreotide compared to [111In-DOTA0,Tyr3]octreotide emphasizes the importance of the implemented sulfonamide linker and dendrimer-derived core for tumor targeting.

111In-Monomeric [Tyr3]octreotide (refer to MICAD chapter for details) exhibited behavior similar to 111In-dimeric [Tyr3]octreotide, whereas 111In-tetrameric [Tyr3]octreotide behaved differently than its monomeric and dimeric counterparts. 111In-Tetrameric [Tyr3]octreotide had high uptake in the liver and spleen, but negligible tumor accumulation. Tetramerization of the [Tyr3]octreotide had profound implications on its lipophilicity and consequently on receptor affinity and tumor uptake.

In conclusion, the IC50 values of mono- and multimeric [Tyr3]octreotide conjugates are all in the low nanomolar range. Monomeric [Tyr3]octreotide has the highest binding affinity for SSTRs, followed by dimeric [Tyr3]octreotide and tetrameric [Tyr3]octreotide. In mouse models, 111In-monomeric [Tyr3]octreotide shows the highest tumor uptake, better than that of the [111In-DOTA0,Tyr3]octreotide, whereas 111In-dimeric [Tyr3]octreotide exhibits the longest tumor retention, probably due to the bivalency effect. Both monomeric and dimeric [Tyr3]octreotide conjugates exhibit interesting properties for imaging and therapeutic applications (1).

Other Non-Primate Mammals


No references are currently available.

Non-Human Primates


No references are currently available.

Human Studies


No references are currently available.


Yim C.B., Dijkgraaf I., Merkx R., Versluis C., Eek A., Mulder G.E., Rijkers D.T., Boerman O.C., Liskamp R.M. Synthesis of DOTA-conjugated multimeric [Tyr3]octreotide peptides via a combination of Cu(I)-catalyzed "click" cycloaddition and thio acid/sulfonyl azide "sulfo-click" amidation and their in vivo evaluation. J Med Chem. 2010;53(10):3944–53. [PubMed: 20411957]
Tulipano G., Schulz S. Novel insights in somatostatin receptor physiology. Eur J Endocrinol. 2007;156 Suppl 1:S3–11. [PubMed: 17413186]
Lesche S., Lehmann D., Nagel F., Schmid H.A., Schulz S. Differential effects of octreotide and pasireotide on somatostatin receptor internalization and trafficking in vitro. J Clin Endocrinol Metab. 2009;94(2):654–61. [PubMed: 19001514]
van der Hoek J., Hofland L.J., Lamberts S.W. Novel subtype specific and universal somatostatin analogues: clinical potential and pitfalls. Curr Pharm Des. 2005;11(12):1573–92. [PubMed: 15892663]
Strowski M.Z., Blake A.D. Function and expression of somatostatin receptors of the endocrine pancreas. Mol Cell Endocrinol. 2008;286(1-2):169–79. [PubMed: 18375050]
Froidevaux S., Eberle A.N. Somatostatin analogs and radiopeptides in cancer therapy. Biopolymers. 2002;66(3):161–83. [PubMed: 12385036]
Kwekkeboom D.J., Kam B.L., van Essen M., Teunissen J.J., van Eijck C.H., Valkema R., de Jong M., de Herder W.W., Krenning E.P. Somatostatin-receptor-based imaging and therapy of gastroenteropancreatic neuroendocrine tumors. Endocr Relat Cancer. 2010;17(1):R53–73. [PubMed: 19995807]
de Jong M., Breeman W.A., Kwekkeboom D.J., Valkema R., Krenning E.P. Tumor imaging and therapy using radiolabeled somatostatin analogues. Acc Chem Res. 2009;42(7):873–80. [PubMed: 19445476]
Bal C.S., Gupta S.K., Zaknun J.J. Radiolabeled somatostatin analogs for radionuclide imaging and therapy in patients with gastroenteropancreatic neuroendocrine tumors. Trop Gastroenterol. 2010;31(2):87–95. [PubMed: 20862981]
Ferone D., Saveanu A., Culler M.D., Arvigo M., Rebora A., Gatto F., Minuto F., Jaquet P. Novel chimeric somatostatin analogs: facts and perspectives. Eur J Endocrinol. 2007;156 Suppl 1:S23–8. [PubMed: 17413184]
Hofland, L.J., J. van der Hoek, R. Feelders, A.J. van der Lely, W. de Herder, and S.W. Lamberts, Pre-clinical and clinical experiences with novel somatostatin ligands: advantages, disadvantages and new prospects. J Endocrinol Invest, 2005. 28(11 Suppl International): p. 36-42. [PubMed: 16625843]
Kwekkeboom D.J., Mueller-Brand J., Paganelli G., Anthony L.B., Pauwels S., Kvols L.K. M. O'Dorisio T, R. Valkema, L. Bodei, M. Chinol, H.R. Maecke, and E.P. Krenning, Overview of results of peptide receptor radionuclide therapy with 3 radiolabeled somatostatin analogs. J Nucl Med. 2005;46 Suppl 1:62S–6S. [PubMed: 15653653]
Gerasimou G., Moralidis E., Gotzamani-Psarrakou A. Somatostatin receptor imaging with (111)In-pentetreotide in gastro-intestinal tract and lung neuroendocrine tumors-Impact on targeted treatment. Hell J Nucl Med. 2010;13(2):158–62. [PubMed: 20808990]
Mintzer, M.A. and M.W. Grinstaff, Biomedical applications of dendrimers: a tutorial. Chem Soc Rev, 2010. [PubMed: 20877875]


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