NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.

Cover of Molecular Imaging and Contrast Agent Database (MICAD)

Molecular Imaging and Contrast Agent Database (MICAD) [Internet].

Show details

68Ga-1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid-Cpa-cyclo(d-Cys-amino-Phe-hydroorotic acid-D-4-amino-Phe(carbamoyl)-Lys-Thr-Cys)-D-Tyr-NH2 (JR11)

68Ga-DOTA-JR11
, PhD
National for Biotechnology Information, NLM, NIH, Bethesda, MD

Created: ; Last Update: January 3, 2013.

Chemical name:68Ga-1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid-Cpa-cyclo(d-Cys-amino-Phe-hydroorotic acid-D-4-amino-Phe(carbamoyl)-Lys-Thr-Cys)-D-Tyr-NH2 (JR11)
Abbreviated name:68Ga-DOTA-JR11
Synonym:
Agent category:Peptide
Target:Somatostatin receptor (SSTR2)
Target category:Receptor
Method of detection:Positron emission tomography (PET)
Source of signal:68Ga
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
Click on protein, nucleotide (RefSeq), and gene for more information about somatostatin.

Background

[PubMed]

Somatostatin (SST) is an inhibitor of the release of somatotropin, glucagon, insulin, gastrointestinal hormones, and other secretory proteins (1). SST is also known as the somatotropin release-inhibiting factor (SRIF). SST is a cyclic polypeptide with two biologically active isoforms, SRIF-14 and SRIF-28, of 14 and 28 amino acids, respectively. SRIF has a short plasma half-life of <3 min (2). SST receptors (SSTRs) (G-protein–coupled) have been found on a variety of neuroendocrine tumors and cells of the immune system, and five individual subtypes (SSTR1–SSTR5) have been identified and subsequently cloned from animal and human tissues (3, 4). SST also inhibits cell proliferation and promotes apoptosis through binding to specific cell-surface SSTRs (5).

111In-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-Octreotate (111In-DOTA-TATE) is an SST analog used in single-photon emission computed tomography (SPECT). Octreotate (d-Phe-c[Cys-d-Tyr-Trp-Lys-Thr-Cys]-Thr) is a cyclic peptide with eight amino acids. 111In-DOTA-TATE binds with high affinity to SSTR2, with little or no binding to other SSTRs. A large number of radiolabeled SST analogs have been reported using different radionuclides and different linkers. Most targeting SSTR peptides currently in use are SSTR2 agonists. Therefore, there is a need for SSTR2 antagonist radioligands because they tend to bind to both high and low affinity receptors (6). SSTR antagonists bind to a higher number of receptors than the agonists (7). Cpa-cyclo(d-Cys-amino-Phe-hydroorotic acid-D-4-amino-Phe(carbamoyl)-Lys-Thr-Cys)-D-Tyr-NH2 (JR11) is a novel selective SSTR2 antagonist. Fani et al. (8) prepared 68Ga-DOTA-JR11 as a positron emission tomography (PET) imaging agent for SSTR2.

Synthesis

[PubMed]

DOTA-JR11 was synthesized via standard solid-phase peptide synthesis (8). DOTA was incorporated at the N-terminus of the peptide. DOTA-JR11 was purified with high-performance liquid chromatography. 68Ga was complexed to DOTA-JR11 by reaction of DOTA-JR11 with 68Ga in ammonium acetate buffer (pH 5.0) for 8 min at 95°C. 68Ga-DOTA-JR11 had a >95% radiochemical purity and specific activity of 80–100 MBq/nmol (2.2–2.7 mCi/nmol), with a labeling yield >97%.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Fani et al. (8) reported that NODAGA-JR11, natGa-NODAGA-JR11, DOTA-JR11, and natGa-DOTA-JR11 had 50% inhibition concentration (IC50) values of 4.1 ± 0.2, 1.2 ± 0.2, 0.72 ± 0.12, and 29 ± 3 nM, respectively, for human SSTR2 in competition with 125I-SRIF-28. The four JR11 conjugates (1,000 nM) exhibited little inhibition of the other SSTR subtypes. Immunofluorescence studies showed that the agonist [Tyr3]octreotide (10 nM) triggers receptor internalization, whereas natGa-DOTA-JR11 at a much higher concentration (1,000 nM) does not stimulate receptor internalization in HEK-sst2 cells. This is another indication that JR11 is an antagonist. natGa-DOTA-JR11 (1,000 nM) was able to inhibit receptor internalization induced by [Tyr3]octreotide.

Animal Studies

Rodents

[PubMed]

Fani et al. (8) performed ex vivo biodistribution studies with 5–8 MBq (0.14–0.22 mCi) 68Ga-DOTA-JR11 in nude mice (n = 3–5/group) bearing HEK-sst2 xenografts at 1 h and 2 h after injection. The accumulation of radioactivity in the SSTR2 tumor was 23.8 ± 3.7% injected dose per gram (% ID/g) and 22.4 ± 7.6% ID/g at 1 h and 2 h, respectively. The kidney had the highest accumulation at 1 h (12.7% ID/g), followed by the adrenal (2.6% ID/g), bone (1.4% ID/g), and lung (1.0% ID/g). Low radioactivity levels (< 1% ID/g) were found in the other tissues and the SSTR2-positive tissues, such as the pancreas and stomach. The concentration in the blood was 0.6% ID/g at 1 h. The tumor/blood, tumor/liver, tumor/kidney, and tumor/muscle ratios at 1 h were 41.1, 50.7, 1.9, and 33.5, respectively. Co-injection with 1,500-fold excess DOTA-JR11 inhibited the SSTR2-positive tumor and adrenal radioactivity accumulation by 95% and 85% at 1 h, respectively. Little inhibition was observed in the SSTR2-negative tissues. At 1 h after injection, accumulation of 68Ga-DOTA-JR11 in the kidney was 20% higher and 22% lower in the tumor than that of 68Ga-NODAGA-JR11 in the same organs (P < 0.05). 68Ga-DOTA-JR11 exhibited 34% higher tumor and 144% higher kidney accumulation than the agonist 68Ga-DOTA-TATE (P < 0.05). 68Ga-DOTA-JR11 has a lower binding affinity (IC50 = 29 nM) to SSTR2 than 68Ga-DOTA-TATE (IC50 = 0.2 nM) yet exhibits higher binding to SSTR2-positive tumor. The higher number of binding sites for 68Ga-DOTA-JR11 (antagonist) versus68Ga-DOTA-TATE (agonist) more than compensates for the affinity difference.

Whole-body PET imaging visualized the SSTR2 tumor at 1 h and 2 h after injection of 5–8 MBq (0.14–0.22 mCi) 68Ga-DOTA-JR11 (8). The visualization was abrogated by co-injection of excess unlabeled DOTA-JR11.

Other Non-Primate Mammals

[PubMed]

No publication is currently available.

Non-Human Primates

[PubMed]

No publication is currently available.

Human Studies

[PubMed]

No publication is currently available.

References

1.
Weckbecker G., Lewis I., Albert R., Schmid H.A., Hoyer D., Bruns C. Opportunities in somatostatin research: biological, chemical and therapeutic aspects. Nat Rev Drug Discov. 2003;2(12):999–1017. [PubMed: 14654798]
2.
Patel Y.C., Wheatley T. In vivo and in vitro plasma disappearance and metabolism of somatostatin-28 and somatostatin-14 in the rat. Endocrinology. 1983;112(1):220–5. [PubMed: 6128222]
3.
Corleto V.D., Nasoni S., Panzuto F., Cassetta S., Delle Fave G. Somatostatin receptor subtypes: basic pharmacology and tissue distribution. Dig Liver Dis. 2004;36 Suppl 1:S8–16. [PubMed: 15077906]
4.
Moller L.N., Stidsen C.E., Hartmann B., Holst J.J. Somatostatin receptors. Biochim Biophys Acta. 2003;1616(1):1–84. [PubMed: 14507421]
5.
Barnett P. Somatostatin and somatostatin receptor physiology. Endocrine. 2003;20(3):255–64. [PubMed: 12721505]
6.
Reubi J.C., Schar J.C., Waser B., Wenger S., Heppeler A., Schmitt J.S., Macke H.R. Affinity profiles for human somatostatin receptor subtypes SST1-SST5 of somatostatin radiotracers selected for scintigraphic and radiotherapeutic use. Eur J Nucl Med. 2000;27(3):273–82. [PubMed: 10774879]
7.
Ginj M., Zhang H., Waser B., Cescato R., Wild D., Wang X., Erchegyi J., Rivier J., Macke H.R., Reubi J.C. Radiolabeled somatostatin receptor antagonists are preferable to agonists for in vivo peptide receptor targeting of tumors. Proc Natl Acad Sci U S A. 2006;103(44):16436–41. [PMC free article: PMC1618814] [PubMed: 17056720]
8.
Fani M., Braun F., Waser B., Beetschen K., Cescato R., Erchegyi J., Rivier J.E., Weber W.A., Maecke H.R., Reubi J.C. Unexpected Sensitivity of sst2 Antagonists to N-Terminal Radiometal Modifications. J Nucl Med. 2012;53(9):1481–9. [PubMed: 22851637]
PubReader format: click here to try

Views

  • PubReader
  • Print View
  • Cite this Page
  • PDF version of this page (585K)
  • MICAD Summary (CSV file)

Search MICAD

Limit my Search:


Related information

  • PMC
    PubMed Central citations
  • PubMed
    Links to pubmed

Related citations in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...