ABSTRACT
Nuclear Medicine has been playing an important role in the management of patients with neuroendocrine neoplasms (NEN). Radiolabeled somatostatin receptor analogs are currently the most advanced radiopharmaceuticals used for imaging and treatment of NENs. The clinical success of somatostatin receptor targeted radiolabeled somatostatin derivatives (agonists) have paved the way for the development of new radiopharmaceuticals for other radioligand-receptor systems. The Glucagon-Like Peptide-1 Receptor (GLP-1R)-radioligands, the cholecystokinin 2 (CCK2)/gastrin receptor-radioligands, glucose-dependent insulinotropic polypeptide receptor-radioligands are the examples of these systems. In addition, radiolabeled somatostatin antagonist, which are an alternative approach to radiolabeled somatostatin receptor agonist can be given as an example. Apart from these radiopharmaceuticals, several radiopharmaceuticals (F-18 DOPA, C-11 5-HTP, I-123 MIBG, F-18 FDG) are used for metabolic imaging of NENs. In this review the aim is to present the status of the most innovative peptide-based radiopharmaceuticals (beyond sstr agonists) for the diagnosis and treatment of NENs’ receptors.
References
1Fani M, Peitl PK, Velikyan I. Current Status of Radiopharmaceuticals for the Theranostics of Neuroendocrine Neoplasms. Pharmaceuticals (Basel) 2017;10:30.
2Carollo A, Papi S, Grana CM, Mansi L, Chinol M. State of the Art and Recent Developments of Radiopharmaceuticals for Pancreatic Neuroendocrine Tumors Imaging. Curr Radiopharm 2019;12:107-125.
3Eychenne R, Bouvry C, Bourgeois M, Loyer P, Benoist E, Lepareur N. Overview of Radiolabeled Somatostatin Analogs for Cancer Imaging and Therapy. Molecules 2020;25:4012.
4Ginj M, Zhang H, Waser B, et al. Radiolabeled somatostatin receptor antagonists are preferable to agonists for in vivo peptide receptor targeting of tumors. Proc Natl Acad Sci U S A 2006;103:16436-16441.
5Bass RT, Buckwalter BL, Patel BP, et al. Identification and characterization of novel somatostatin antagonists. Mol Pharmacol 1996;50:709-715.
6Reubi JC, Schaer JC, Wenger S, et al. SST3-selective potent peptidic somatostatin receptor antagonists. Proc Natl Acad Sci U S A 2000;97:13973-13978.
7Fani M, Del Pozzo L, Abiraj K, et al. PET of somatostatin receptor-positive tumors using 64Cu- and 68Ga-somatostatin antagonists: the chelate makes the difference. J Nucl Med 2011;52:1110-1118.
8Fani M, Braun F, Waser B, et al. Unexpected sensitivity of sst2 antagonists to N-terminal radiometal modifications. J Nucl Med 2012;53:1481-1489.
9Antunes P, Ginj M, Zhang H, et al. Are radiogallium-labelled DOTA-conjugated somatostatin analogues superior to those labelled with other radiometals? Eur J Nucl Med Mol Imaging 2007;34:982-993.
10Reubi JC, Schär JC, Waser B, et al. Affinity profiles for human somatostatin receptor subtypes SST1-SST5 of somatostatin radiotracers selected for scintigraphic and radiotherapeutic use. Eur J Nucl Med 2000;27:273-282.
11Dalm SU, Nonnekens J, Doeswijk GN, et al. Comparison of the Therapeutic Response to Treatment with a 177Lu-Labeled Somatostatin Receptor Agonist and Antagonist in Preclinical Models. J Nucl Med 2016;57:260-265.
12Wild D, Fani M, Behe M, et al. First clinical evidence that imaging with somatostatin receptor antagonists is feasible. J Nucl Med 2011;52:1412-1417.
13Wild D, Fani M, Fischer R, et al. Comparison of somatostatin receptor agonist and antagonist for peptide receptor radionuclide therapy: a pilot study. J Nucl Med 2014;55:1248-1252.
14Reidy DL, Pandit-Taskar N, Krebs S, et al. Theranostic trial of well differentiated neuroendocrine tumors (NETs) with somatostatin antagonists 68Ga-OPS202 and 177Lu-OPS201. J Clin Oncol 2017;35(15_suppl):4094.
15Cescato R, Waser B, Fani M, Reubi JC. Evaluation of 177Lu-DOTA-sst2 antagonist versus 177Lu-DOTA-sst2 agonist binding in human cancers in vitro. J Nucl Med 2011;52:1886-1890.
16Reubi JC, Waser B, Mäcke H, Rivier J. Highly Increased 125I-JR11 Antagonist Binding In Vitro Reveals Novel Indications for sst2 Targeting in Human Cancers. J Nucl Med 2017;58:300-306.
17Mansi R, Fani M. Design and development of the theranostic pair 177 Lu-OPS201/68 Ga-OPS202 for targeting somatostatin receptor expressing tumors. J Labelled Comp Radiopharm 2019;62:635-645.
18Reubi JC, Schaer JC, Waser B. Cholecystokinin(CCK)-A and CCK-B/gastrin receptors in human tumors. Cancer Res 1997;57:1377-1386.
19Reubi JC, Waser B. Unexpected high incidence of cholecystokinin-B/gastrin receptors in human medullary thyroid carcinomas. Int J Cancer 1996;67:644-647.
20Kebebew E, Kikuchi S, Duh QY, Clark OH. Long-term results of reoperation and localizing studies in patients with persistent or recurrent medullary thyroid cancer. Arch Surg 2000;135:895-901.
21Pacini F, Castagna MG, Cipri C, Schlumberger M. Medullary thyroid carcinoma. Clin Oncol (R Coll Radiol) 2010;22:475-485.
22Moley JF. Medullary thyroid cancer. Surg Clin North Am 1995;75:405-420.
23Gotthardt M, Béhé MP, Beuter D, et al. Improved tumour detection by gastrin receptor scintigraphy in patients with metastasised medullary thyroid carcinoma. Eur J Nucl Med Mol Imaging 2006;33:1273-1279.
24Gotthardt M, Béhé MP, Grass J, et al. Added value of gastrin receptor scintigraphy in comparison to somatostatin receptor scintigraphy in patients with carcinoids and other neuroendocrine tumours. Endocr Relat Cancer 2006;13:1203-1211.
25de Jong M, Bakker WH, Bernard BF, et al. Preclinical and initial clinical evaluation of 111In-labeled nonsulfated CCK8 analog: a peptide for CCK-B receptor-targeted scintigraphy and radionuclide therapy. J Nucl Med 1999;40:2081-2087.
26Kwekkeboom DJ, Bakker WH, Kooij PP, et al. Cholecystokinin receptor imaging using an octapeptide DTPA-CCK analogue in patients with medullary thyroid carcinoma. Eur J Nucl Med 2000;27:1312-1317.
27Behr TM, Béhé M, Angerstein C, et al. Cholecystokinin-B/gastrin receptor binding peptides: preclinical development and evaluation of their diagnostic and therapeutic potential. Clin Cancer Res 1999 Oct;5(10 Suppl):3124s-3138s.
28Behr TM, Jenner N, Béhé M, et al. Radiolabeled peptides for targeting cholecystokinin-B/gastrin receptor-expressing tumors. J Nucl Med 1999;40:1029-1044.
29Béhé M, Behr TM. Cholecystokinin-B (CCK-B)/gastrin receptor targeting peptides for staging and therapy of medullary thyroid cancer and other CCK-B receptor expressing malignancies. Biopolymers 2002;66:399-418.
30Béhé M, Kluge G, Becker W, Gotthardt M, Behr TM. Use of polyglutamic acids to reduce uptake of radiometal-labeled minigastrin in the kidneys. J Nucl Med 2005;46:1012-1015.
31Kolenc Peitl P, Tamma M, Kroselj M, et al. Stereochemistry of amino acid spacers determines the pharmacokinetics of (111)In-DOTA-minigastrin analogues for targeting the CCK2/gastrin receptor. Bioconjug Chem 2015;26:1113-1119.
32Good S, Walter MA, Waser B, et al. Macrocyclic chelator-coupled gastrin-based radiopharmaceuticals for targeting of gastrin receptor-expressing tumours. Eur J Nucl Med Mol Imaging 2008;35:1868-1877.
33Mather SJ, McKenzie AJ, Sosabowski JK, Morris TM, Ellison D, Watson SA. Selection of radiolabeled gastrin analogs for peptide receptor-targeted radionuclide therapy. J Nucl Med 2007;48:615-622.
34Fröberg AC, de Jong M, Nock BA, et al. Comparison of three radiolabelled peptide analogues for CCK-2 receptor scintigraphy in medullary thyroid carcinoma. Eur J Nucl Med Mol Imaging 2009;36:1265-1272.
35Aloj L, Aurilio M, Rinaldi V, et al. Comparison of the binding and internalization properties of 12 DOTA-coupled and ¹¹¹In-labelled CCK2/gastrin receptor binding peptides: a collaborative project under COST Action BM0607. Eur J Nucl Med Mol Imaging 2011;38:1417-1425.
36Laverman P, Joosten L, Eek A, et al. Comparative biodistribution of 12 ¹¹¹In-labelled gastrin/CCK2 receptor-targeting peptides. Eur J Nucl Med Mol Imaging 2011;38:1410-1416.
37Ocak M, Helbok A, Rangger C, et al. Comparison of biological stability and metabolism of CCK2 receptor targeting peptides, a collaborative project under COST BM0607. Eur J Nucl Med Mol Imaging 2011;38:1426-1435.
38Konijnenberg MW, Breeman WA, de Blois E, et al. Therapeutic application of CCK2R-targeting PP-F11: influence of particle range, activity and peptide amount. EJNMMI Res 2014;4:47.
39Roosenburg S, Laverman P, Joosten L, et al. PET and SPECT imaging of a radiolabeled minigastrin analogue conjugated with DOTA, NOTA, and NODAGA and labeled with (64)Cu, (68)Ga, and (111)In. Mol Pharm 2014;11:3930-3937.
40Kunikowska J, Ziemnicka K, Pawlak D, et al. Medullary thyroid carcinoma - PET/CT imaging with 68Ga-labelled gastrin and somatostatin analogues. Endokrynol Pol 2016;67:68-71.
41Körner M, Christ E, Wild D, Reubi JC. Glucagon-like peptide-1 receptor overexpression in cancer and its impact on clinical applications. Front Endocrinol (Lausanne) 2012;3:158.
42Körner M, Stöckli M, Waser B, Reubi JC. GLP-1 receptor expression in human tumors and human normal tissues: potential for in vivo targeting. J Nucl Med 2007;48:736-743.
43de Herder WW, Niederle B, Scoazec J-Y, et al. Well-differentiated pancreatic tumor/carcinoma: insulinoma. Neuroendocrinology 2006;84:183-188.
44Ademoğlu E, Candan Z, Tekçe H. Diagnosis and Treatment of Insulinoma: an up-to-date Overview. Abant Med J 2017;6:32-37.
45Reubi JC, Waser B. Concomitant expression of several peptide receptors in neuroendocrine tumours: molecular basis for in vivo multireceptor tumour targeting. Eur J Nucl Med Mol Imaging 2003;30:781-793.
46Wild D, Christ E, Caplin ME, et al. Glucagon-like peptide-1 versus somatostatin receptor targeting reveals 2 distinct forms of malignant insulinomas. J Nucl Med 2011;52:1073-1078.
47Wild D, Béhé M, Wicki A, et al. [Lys40(Ahx-DTPA-111In)NH2]exendin-4, a very promising ligand for glucagon-like peptide-1 (GLP-1) receptor targeting. J Nucl Med 2006;47:2025-2033.
48Sowa-Staszczak A, Pach D, Mikołajczak R, et al. Glucagon-like peptide-1 receptor imaging with [Lys40(Ahx-HYNIC- 99mTc/EDDA)NH2]-exendin-4 for the detection of insulinoma. Eur J Nucl Med Mol Imaging 2013;40:524-531.
49Brom M, Oyen WJG, Joosten L, Gotthardt M, Boerman OC. 68Ga-labelled exendin-3, a new agent for the detection of insulinomas with PET. Eur J Nucl Med Mol Imaging 2010;37:1345-1355.
50Eriksson O, Velikyan I, Selvaraju RK, et al. Detection of metastatic insulinoma by positron emission tomography with [(68)ga]exendin-4-a case report. J Clin Endocrinol Metab 2014;99:1519-1524.
51Wu Z, Liu S, Nair I, et al. (64)Cu labeled sarcophagine exendin-4 for microPET imaging of glucagon like peptide-1 receptor expression. Theranostics 2014;4:770-777.
52Kiesewetter DO, Gao H, Ma Y, et al. 18F-radiolabeled analogs of exendin-4 for PET imaging of GLP-1 in insulinoma. Eur J Nucl Med Mol Imaging 2012;39:463-473.
53Wild D, Mäcke H, Christ E, Gloor B, Reubi JC. Glucagon-like peptide 1-receptor scans to localize occult insulinomas. N Engl J Med 2008;359:766-768.
54Christ E, Wild D, Ederer S, et al. Glucagon-like peptide-1 receptor imaging for the localisation of insulinomas: a prospective multicentre imaging study. Lancet Diabetes Endocrinol 2013;1:115-122.
55Sowa-Staszczak A, Trofimiuk-Müldner M, Stefańska A, et al. 99mTc Labeled Glucagon-Like Peptide-1-Analogue (99mTc-GLP1) Scintigraphy in the Management of Patients with Occult Insulinoma. PLoS One 2016;11:e0160714.
56Christ E, Wild D, Antwi K, et al. Preoperative localization of adult nesidioblastosis using ⁶⁸Ga-DOTA-exendin-4-PET/CT. Endocrine 2015;50:821-823.
57Felber VB, Wester HJ. Small peptide-based GLP-1R ligands: an approach to reduce the kidney uptake of radiolabeled GLP-1R-targeting agents? EJNMMI Radiopharm Chem 2021;6:29.
58Waser B, Rehmann R, Sanchez C, Fourmy D, Reubi JC. Glucose-dependent insulinotropic polypeptide receptors in most gastroenteropancreatic and bronchial neuroendocrine tumors. J Clin Endocrinol Metab 2012;97:482-488.
59Eriksson O, Velikyan I, Haack T, et al. Drug Occupancy Assessment at the Glucose-Dependent Insulinotropic Polypeptide Receptor by Positron Emission Tomography. Diabetes 2021;70:842-853.
