Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
European Journal of Nuclear Medicine and Molecular Imaging
Published in: European Journal of Nuclear Medicine and Molecular Imaging 10/2003

01-10-2003 | Original Article

DOTA-NOC, a high-affinity ligand of somatostatin receptor subtypes 2, 3 and 5 for labelling with various radiometals

Published in: European Journal of Nuclear Medicine and Molecular Imaging | Issue 10/2003

Login to get access

Abstract

Earlier studies have shown that modification of the octapeptide octreotide in positions 3 and 8 may result in compounds with increased somatostatin receptor affinity that, if radiolabelled, display improved uptake in somatostatin receptor-positive tumours. The aim of a recent research study in our laboratory was to employ the parallel peptide synthesis approach by further exchanging the amino acid in position 3 of octreotide and coupling the macrocyclic chelator DOTA(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) to these peptides for labelling with radiometals like gallium-67 or -68, indium-111, yttrium-90 and lutetium-177. The purpose was to find radiopeptides with an improved somatostatin receptor binding profile in order to extend the spectrum of targeted tumours. A first peptide, [111In,90Y-DOTA]-1-Nal3-octreotide (111In,90Y-DOTA-NOC), was isolated which showed an improved profile. InIII-DOTA-NOC exhibited the following IC50 values (nM) when studied in competition with [125I][Leu8, d-Trp22, Tyr25]somatostatin-28 (values for YIII-DOTA-NOC are shown in parentheses): sstr2, 2.9±0.1 (3.3±0.2); sstr3, 8±2 (26±1.9); sstr5, 11.2±3.5 (10.4±1.6). Affinity towards sstr1 and 4 was very low or absent. InIII-DOTA-NOC is superior to all somatostatin-based radiopeptides having this particular type of binding profile, including DOTA-lanreotide, and has three to four times higher binding affinity to sstr2 than InIII,YIII-DOTA-Tyr3-octreotide (InIII,YIII-DOTA-TOC). In addition, [111In]DOTA-NOC showed a specific and high rate of internalization into AR4-2J rat pancreatic tumour cells which, after 4 h, was about two times higher than that of [111In]DOTA-TOC and three times higher than that of [111In]DOTA-octreotide ([111In]DOTA-OC). The internalized radiopeptides were externalized intact upon 2 h of internalization followed by an acid wash. After 2–3 h of externalization a plateau is reached, indicating a steady-state situation explained by reactivation of the receptors followed by re-endocytosis. Biodistribution studies in CA 20948 tumour-bearing rats showed rapid clearance from all sstr-negative tissues except the kidneys. At 4 h the uptake of [111In]DOTA-NOC in the tumour and sstr-positive tissues, such as adrenals, stomach and pancreas, was three to four times higher than that of [111In]DOTA-TOC. Differential blocking studies indicate that this is at least partially due to the uptake mediated by sstr3 and sstr5. These very promising preclinical data justify the use of this new radiopeptide for imaging and potentially internal radiotherapy studies in patients.
Literature
1.
Behr TM, Béhé M, Becker W. Diagnostic applications of radiolabeled peptides in nuclear endocrinology. Q J Nucl Med 1999; 43:268–280.
2.
Breeman WAP, de Jong M, Kwekkeboom DJ, et al. Somatostatin receptor-mediated imaging and therapy: basic science, current knowledge, limitations and future perspectives. Eur J Nucl Med 2001; 28:1421–1429.PubMed
3.
Fischman A, Babich J, Strauss H. A ticket to ride: peptide radiopharmaceuticals. J Nucl Med 1993; 34:2253–2263.PubMed
4.
Heppeler A, Froidevaux S, Eberle A, Maecke H. Receptor targeting for tumor localization and therapy with radiopeptides. Curr Med Chem 2000; 7:971–994.
5.
Lamberts SW, Van der Lely AJ, De Herder WW, Hofland LJ. Octreotide. N Engl J Med 1996; 25:246–254.CrossRef
6.
Lister-James J, Moyer B, Dean T. Small peptides radiolabeled with99mTc. Q J Nucl Med 1996; 40:221–233.
7.
Liu S, Edwards D.99mTc-labeled small peptides as diagnostic radiopharmaceuticals. Chem Rev 1999; 99:2235–2268.CrossRefPubMed
8.
Reubi JC. Neuropeptide receptors in health and disease: the molecular basis for in vivo imaging. J Nucl Med 1995; 36:1825–1835.PubMed
9.
Thakur M. Radiolabelled peptides: now and the future. Nucl Med Comm 1995; 16:724–732.
10.
Krenning EP, Kwekkeboom DJ, Bakker WH, et al. Somatostatin receptor scintigraphy with [111In-DTPA-d-Phe1]- and [123I-Tyr3]-octreotide: the Rotterdam experience with more than 1000 patients. Eur J Nucl Med 1993; 20:716–731.PubMed
11.
Gibril F, Reynolds JC, Doppman JL, et al. Somatostatin receptor scintigraphy: its sensitivity compared with that of other imaging methods in detecting primary and metastatic gastrinomas—a prospective study. Ann Intern Med 1996; 125:24–26.
12.
Blum JE, Handmaker H, Rinne NA. The utility of a somatostatin-type receptor binding peptide radiopharmaceutical (P829) in the evaluation of solitary pulmonary nodules. CHEST 1999; 115:224–232.PubMed
13.
Virgolini I, Leimer M, Handmaker H, et al. Somatostatin receptor subtype specificity and in vivo binding of a novel tumor tracer,99mTc-P829. Cancer Res 1998; 58:1850–1859.PubMed
14.
Lebtahi R, Le Cloirec J, Houzard C, et al. Detection of neuroendocrine tumors:99mTc-P829 scintigraphy compared with 111In-pentetreotide scintigraphy. J Nucl Med 2002; 43:889–895.
15.
de Jong M, Bakker WH, Krenning EP, et al. Yttrium-90 and indium-111 labelling, receptor binding and biodistribution of [DOTA0,d-Phe1,Tyr3]octreotide, a promising somatostatin analogue for radionuclide therapy. Eur J Nucl Med 1997; 24:368–371.
16.
Stolz B, Weckbecker G, Smith-Jones PM, Albert R, Raulf F, Bruns C. The somatostatin receptor-targeted radiotherapeutic [90Y-DPTA-dPhe1,Tyr3]octreotide (90Y-SMT 487) eradicates experimental rat pancreatic CA 20948 tumours. Eur J Nucl Med 1998; 25:668–674.
17.
Otte A, Herrmann R, Heppeler A, et al. Yttrium-90-DOTATOC: first clinical results. Eur J Nucl Med 1999; 26:1439–1447.PubMed
18.
Otte A, Mueller-Brand J, Dellas S, Nitzsche E, Herrmann R, Maecke H. Yttrium-90-labelled somatostatin-analogue for cancer treatment. Lancet 1998; 351:417–418.PubMed
19.
Cremonesi M, Ferrari M, Zoboli S, et al. Biokinetics and dosimetry in patients administered with111In-DOTA-Tyr3-octreotide: implications for internal radiotherapy with 90Y-DOTATOC. Eur J Nucl Med 1999; 26:877–886.PubMed
20.
Waldherr C, Pless M, Maecke H, et al. Tumor response and clinical benefit in neuroendocrine tumors after 7.4 GBq90Y-DOTATOC. J Nucl Med 2002; 43:610–616.
21.
Paganelli G, Zoboli S, Cremonesi M, et al. Receptor-mediated radiotherapy with90Y-DOTA-Phe1-Tyr3-octreotide. Eur J Nucl Med 2001; 28:426–434.PubMed
22.
Waldherr C, Pless M, Maecke H, Haldemann A, Mueller-Brand J. The clinical value of [90Y-DOTA]-d-Phe1-Tyr3-octreotide (90Y-DOTATOC) in the treatment of neuroendocrine tumours: a clinical phase II study. Ann Oncol 2001; 12:942–945.CrossRef
23.
de Jong M, Breeman WA, Bernard BF, et al. Tumor response after [90Y-DOTA0,Tyr3]octreotide radionuclide therapy in a transplantable rat tumor model is dependent on tumor size. J Nucl Med 2001; 42:1841–1846.
24.
Reubi J, Schaer J, Waser B, et al. Affinity profiles for human somatostatin receptor sst1–sst5 of somatostatin radiotracers selected for scintigraphic and radiotherapeutic use. Eur J Nucl Med 2000; 27:273–282.PubMed
25.
Kwekkeboom DJ, Bakker WH, Kooij PP, et al. [177Lu-DOTA0,Tyr3]octreotate: comparison with [111DTPA0]octreotide in patients. Eur J Nucl Med 2001; 28:1319–1325.PubMed
26.
Reubi JC, Waser B, Schaer J, Laissue JA. Somatostatin receptor sst1–sst5 expression in normal and neoplastic human tissues using receptor autoradiography with subtype-selective ligands. Eur J Nucl Med 2001; 28:836–846.PubMed
27.
Halmos G, Sun B, Schally AV, Hebert F, Nagy A. Human ovarian cancers express somatostatin receptors. J Clin Endocrinol Metab 2000; 85:3509–3512.
28.
Reubi JC, Schaer J, Waser B, Mengod G. Expression and localization of somatostatin receptor sstr1, sstr2, and sstr3 messenger RNAs in primary human tumors using in situ hybridization. Cancer Res 1994; 54:3455–3459.PubMed
29.
Forssell-Aronsson E, Nilsson O, Benjegard SA, et al.111In-DTPA-d-Phe1-octreotide binding and somatostatin receptor subtypes in thyroid tumors. J Nucl Med 2000; 41:636–642.
30.
Raderer M, Pangerl T, Leimer M, et al. Expression of human somatostatin receptor subtype 3 in pancreatic cancer in vitro and in vivo. J Nat Cancer Inst 1998; 90:1666–1668.
31.
Traub T, Petkov V, Ofluoglu S, et al.111In-DOTA-lanreotide scintigraphy in patients with tumors of the lung. J Nucl Med 2001; 42:1309–1315.PubMed
32.
Heppeler A, Froidevaux S, Maecke HR, et al. Radiometal-labelled macrocyclic chelator-derivatised somatostatin analogue with superb tumour targeting properties and potential for receptor-mediated internal radiotherapy. Chem Eur J 1999; 5:1974–1981.
33.
Atherton E, Sheppard R. Fluorenylmethoxycarbonyl-polyamide solid phase peptide synthesis. General principles and development. Oxford: Oxford Information Press, 1989.
34.
Oberg K. Established clinical use of octreotide and lanreotide in oncology. Chemotherapy 2001; 47:40–53.
35.
Chiti A, Fanti S, Savelli G, et al. Comparison of somatostatin receptor imaging, computed tomography and ultrasound in the clinical management of neuroendocrine gastro-entero-pancreatic tumours. Eur J Nucl Med 1998; 25:1396–1403.
36.
Lebtahi R, Cadiot G, Sarda L, et al. Clinical impact of somatostatin receptor scintigraphy in the management of patients with neuroendocrine gastroenteropancreatic tumors. J Nucl Med 1997; 38:853–858.
37.
Cadiot G, Bonnaud G, Lebtahi R, et al. Usefulness of somatostatin receptor scintigraphy in the management of patients with Zollinger-Ellison syndrome. Gut 1997; 41:107–114.
38.
Termanini B, Gibril F, Reynolds JC, et al. Value of somatostatin receptor scintigraphy: a prospective study in gastrinoma of its effect on clinical management. Gastroenterology 1997; 112:335–347.
39.
Gibril F, Doppman JL, Reynolds JC, et al. Bone metastases in patients with gastrinomas: a prospective study of bone scanning, somatostatin receptor scanning, and MRI in their detection, their frequency, location and effect of their detection on management. J Clin Oncol 1998; 16:1040–1053.
40.
Krenning EP, de Jong M, Kooij PP, et al. Radiolabelled somatostatin analogue(s) for peptide receptor scintigraphy and radionuclide therapy. Ann Oncol 1999; 10 (Suppl 2):S23–S29.
41.
Janson E, Eriksson B, Oberg K. Treatment with high dose [111In-DTPA-d-Phe1]-octreotide in patients with neuroendocrine tumors. Acta Oncol 1999; 38:373–377.PubMed
42.
Valkema R, de Jong M, Bakker WH, et al. Phase 1 study of peptide receptor radionuclide therapy with [111In-DTPA0]-octreotide: the Rotterdam experience. Semin Nucl Med 2002; 32:110–123.PubMed
43.
de Jong M, Breeman WA, Bernard BF, et al. [177Lu-DOTA0,Tyr3]Octreotate for somatostatin receptor-targeted radionuclide therapy. Int J Cancer 2001; 92:628–633.PubMed
44.
Lewis J, Lewis M, Srinivasan A, Schmidt MA, Wang J, Anderson CJ. Comparison of four64Cu-labeled somatostatin analogues in vitro and in tumor-bearing rat model: evaluation of new derivatives for positron emission tomography imaging and targeted radiotherapy. J Med Chem 1998; 42:1341–1347.CrossRef
45.
Froidevaux S, Heppeler A, Eberle A, et al. Preclinical comparison in AR4-2J tumor bearing-mice of four radiolabeled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-somatostatin analogs for tumor diagnosis and internal radiotherapy. Endocrinology 2000; 141:3304–3312.PubMed
46.
Reubi JC, Eisenwiener KP, Rink H, Waser B, Maecke H. A new peptide somatostatin agonist with high affinity to all five somatostatin receptors. Eur J Pharmacol 2002; 456:45–49.CrossRefPubMed
47.
Smith-Jones PM, Bischof C, Leimer M, et al. DOTA-lanreotide: a novel somatostatin analog for tumor diagnosis and therapy. Endocrinology 1999; 140:5136–5148.
48.
Maecke H, Scherer G, Heppeler A, Hennig M. Is In-111 an ideal surrogate for Y-90? If not why? Eur J Nucl Med 2001; 28:967.
49.
Eisenwiener KP, Prata MIM, Buschmann I, et al. NODAGATOC, a new chelator-coupled somatostatin analogue labeled with [67/68Ga] and [111In] for SPECT, PET, and targeted therapeutic applications of somatostatin receptor (hsst2) expressing tumors. Bioconj Chem 2002; 13:530–541.
50.
Koenig JA, Kaur R, Dodgeon I, Edwardson JM, Humphrey PPA. Fates of endocytosed somatostatin sst2 receptor and associated agonists. Biochem J 1998; 336:291–298.PubMed
51.
Raulf F, Pérez J, Joyer D, Bruns C. Differential expression of five somatostatin receptor subtypes, sstr1-5, in the CNS and peripheral tissue. Digestion 1994; 55 (Suppl 3):46–53.
Metadata
Title
DOTA-NOC, a high-affinity ligand of somatostatin receptor subtypes 2, 3 and 5 for labelling with various radiometals
Publication date
01-10-2003
Published in
European Journal of Nuclear Medicine and Molecular Imaging / Issue 10/2003
Print ISSN: 1619-7070
Electronic ISSN: 1619-7089
DOI
https://doi.org/10.1007/s00259-003-1255-5

Other articles of this Issue 10/2003

European Journal of Nuclear Medicine and Molecular Imaging 10/2003 Go to the issue

Original Article

Comparison of 16-frame and 8-frame gated SPET imaging for determination of left ventricular volumes and ejection fraction

Short Communication

[18F]FLT PET for diagnosis and staging of thoracic tumours

Occasional Survey

Use and risks of phosphorus-32 in the treatment of polycythaemia vera

OriginalPaper

In vitro evaluation of 213Bi-rituximab versus external gamma irradiation for the treatment of B-CLL patients: relative biological efficacy with respect to apoptosis induction and chromosomal damage

Original Article

The effects of 99mTc-HMPAO-labelled leucocyte scan on human karyotype

Original Article

Combined effect of gefitinib ('Iressa', ZD1839) and targeted radiotherapy with 211At-EGF