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International Union of Basic and Clinical Pharmacology. CV. Somatostatin Receptors: Structure, Function, Ligands, and New Nomenclature

Thomas Günther, Giovanni Tulipano, Pascal Dournaud, Corinne Bousquet, Zsolt Csaba, Hans-Jürgen Kreienkamp, Amelie Lupp, Márta Korbonits, Justo P. Castaño, Hans-Jürgen Wester, Michael Culler, Shlomo Melmed and Stefan Schulz
Eliot H. Ohlstein, ASSOCIATE EDITOR
Pharmacological Reviews October 2018, 70 (4) 763-835; DOI: https://doi.org/10.1124/pr.117.015388

Article Figures & Data

Figures

  • Fig. 1.
    Fig. 1.

    Historical perspective of somatostatin and somatostatin receptor research.

  • Fig. 2.
    Fig. 2.

    Primary and secondary amino acid structure of mammalian SRIF and CST isoforms. Color code: brown, binding motif; blue, identical in SRIF and CST; red, different in CST compared with SRIF; green, not present in rat/mouse CST-14.

  • Fig. 3.
    Fig. 3.

    Structure of human SST1. The primary and secondary amino acid structure of the human SST1 (UniProtKB - P30872) is shown in a schematic serpentine format. Glycosylation sites are colored in purple; the DRY motif is highlighted in green; the human SST motif is in light blue; potential phosphorylation sites are in gray; the PDZ ligand motif is in dark blue; the disulfide-forming cysteines are in pale blue; and the potential palmitoylation site is in orange. UMB-7 is a rabbit monoclonal antibody, which detects the carboxyl-terminal tail of SST1 in a phosphorylation-independent manner.

  • Fig. 4.
    Fig. 4.

    SST1 signaling leading to inhibition of hormone secretion, cell proliferation and migration, and angiogenesis. By coupling to Gi protein, SRIF-bound SST1 inhibits adenylate cyclase and reduces cAMP accumulation, as well as intracellular Ca2+ concentrations by regulating GIRK channels, which results in membrane hyperpolarization and subsequent reduction of Ca2+ influx through VOCC. This results in decreased hormone secretion. Inhibition of cell proliferation by SST1 involves upregulation of expression of the cyclin-dependent kinase inhibitor p21 (cip1/WAF1) and sequential activation through Src activity of tyrosine phosphatases (PTPη and SHP-2). Whereas p21 blocks cell cycling, tyrosine phosphatases block mitogenic signals through dephosphorylation (and inactivation) of effectors. Both PI3K–mTOR and MAPK pathways are inhibited, resulting in decreased cell growth and proliferation through inhibition of mRNA transcription and translation. SST1 also reduces endothelial NOS activation, resulting in reduced guanylate cyclase activity, cGMP production, and protein kinase G activity. Additionally, SST1 inhibits the NHE1 activity, resulting in a decrease of extracellular acidification rate. This involves inhibition of Rho activity through activation of Gα12 protein by SST1.

  • Fig. 5.
    Fig. 5.

    SST1 expression pattern in normal human tissues. Immunohistochemistry (red-brown color), counterstaining with hematoxylin; primary antibody: UMB-7; scale bar, 50 µm. SST1 displays both membranous and cytoplasmic expression.

  • Fig. 6.
    Fig. 6.

    Structures of synthetic SST1 ligands. L-797,591, SST1 agonist; SRA880, SST1 antagonist.

  • Fig. 7.
    Fig. 7.

    Structure of human SST2. The primary and secondary amino acid structure of the human SST2 (UniProtKB - P30874) is shown in a schematic serpentine format. Glycosylation sites are colored in purple; the DRY motif is highlighted in green; the human SST motif is in light blue; potential phosphorylation sites are in gray; identified GRK2/3 phosphorylation sites are in red; identified GRK2/3 or PKC phosphorylation sites are in dark green; the PDZ ligand motif is in dark blue; the disulfide-forming cysteines are in pale blue; and the potential palmitoylation site is in orange. UMB-1 is a rabbit monoclonal antibody, which detects the carboxyl-terminal tail of SST2 in a phosphorylation-independent manner.

  • Fig. 8.
    Fig. 8.

    SST2 signaling leading to inhibition of hormone secretion, cell proliferation and migration, and angiogenesis. By coupling to Gi proteins, SST2 inhibits adenylate cyclase and reduces cAMP accumulation, and reduces intracellular Ca2+ concentrations by activating GIRK channels, which results in membrane hyperpolarization and subsequent reduction of Ca2+ influx through VOCC. This results in decreased hormone secretion. By coupling to a pertussis toxin–independent G protein, SST2 activates PLC, triggering inositol-1,4,5-trisphosphate (IP3) production and subsequent Ca2+ release into the cytoplasm from the endoplasmic reticulum. Major downstream effectors of SST2 are the tyrosine phosphatases SHP-1 and SHP-2 and the tyrosine kinase Src, which subsequently inhibit the PI3K-mTOR, MAPK, JAK2, and neuronal NOS pathways, thereby decreasing cell growth and proliferation. SST2-dependent inhibition of cell proliferation involves upregulation of the transcription factor ZAC1, triggering cell cycle inhibition.

  • Fig. 9.
    Fig. 9.

    SST2 expression pattern in normal human and neoplastic tissues. Immunohistochemistry (red-brown color), counterstaining with hematoxylin; primary antibody: UMB-1; scale bar, 50 µm. Note that SST2 is predominantly expressed at the plasma membrane.

  • Fig. 10.
    Fig. 10.

    Structures of synthetic SST2 ligands. L-779,976 and BIM-23120, SST2 agonists; JR-11, SST2 antagonist.

  • Fig. 11.
    Fig. 11.

    Structure of human SST3. The primary and secondary amino acid structure of the human SST3 (UniProtKB - P32745) is shown in a schematic serpentine format. Glycosylation sites are colored in purple; the DRY motif is highlighted in green; the human SST motif is in light blue; potential phosphorylation sites are in gray; identified GRK2/3 phosphorylation sites are in red; the PDZ ligand motif is in dark blue; the cilia localization motif is in dark red; and the disulfide-forming cysteines are in pale blue. UMB-5 is a rabbit monoclonal antibody, which detects the carboxyl-terminal tail of SST3 in a phosphorylation-independent manner.

  • Fig. 12.
    Fig. 12.

    SST3 signaling leading to inhibition of hormone secretion, proliferation, and induction of apoptosis. By coupling to Gi proteins, SST3 inhibits adenylate cyclase and reduces cAMP accumulation and reduces intracellular Ca2+ concentrations by activating GIRK channels, which results in membrane hyperpolarization and subsequent reduction of Ca2+ influx through VOCC. This results in decreased hormone secretion. By coupling to a pertussis toxin–independent G protein (probably Gq), SST3 activates PLC, triggering inositol-1,4,5-trisphosphate (IP3) production and subsequent Ca2+ release into the cytoplasm from endoplasmic reticulum. SST3-dependent induction of apoptosis involves p53 and Bax.

  • Fig. 13.
    Fig. 13.

    SST3 expression pattern in human pituitary adenomas, human pancreatic islets, and rat neuronal cilia. Immunohistochemistry (red-brown color), counterstaining with hematoxylin; primary antibody: UMB-5; scale bar, 50 µm. SST3 displays both membranous and cytoplasmic expression. NFPA, clinically nonfunctioning pituitary adenoma.

  • Fig. 14.
    Fig. 14.

    Structures of synthetic SST3 ligands. L-796,776, SST3 agonist; ACQ090, sst3-ODN-8, and MK-4256, SST3 antagonists.

  • Fig. 15.
    Fig. 15.

    Structure of human SST4. The primary and secondary amino acid structure of the human SST4 (UniProtKB - P31391) is shown in a schematic serpentine format. The glycosylation site is colored in purple; the DRY motif is highlighted in green; the human SST motif is in light blue; potential phosphorylation sites are in gray; the PDZ ligand motif is in dark blue; the disulfide-forming cysteines are in pale blue; and the potential palmitoylation site is in orange.

  • Fig. 16.
    Fig. 16.

    SST4 signaling leading to inhibition of hormone secretion, proliferation, and migration. By coupling to Gi proteins, SST4 inhibits adenylate cyclase and reduces cAMP accumulation, and reduces intracellular Ca2+ concentrations by activating GIRK and M channels, which results in membrane hyperpolarization and subsequent reduction of Ca2+ and Na+ influx through VOCC and TRPV1. In addition, SST4 inhibits the NHE1 activity, resulting in a decrease of extracellular acidification rate. Another major effector of SST4 is the tyrosine phosphatase SHP-2, which mediates antiproliferative effects. SST4 also mediates a prolonged ERK activation and subsequent signal transducer and activator of transcription 3 phosphorylation, which is Gi/Go and PI3K dependent. Activation of SST4 can induce cell cycle arrest by upregulation of the cyclin-dependent kinase inhibitor p21 (cip1/WAF1).

  • Fig. 17.
    Fig. 17.

    Structures of synthetic SST4 ligands. J-2156 and L-803,087, SST4 agonists.

  • Fig. 18.
    Fig. 18.

    Structure of human SST5. The primary and secondary amino acid structure of the human SST5 (UniProtKB - P35346) as well as its truncated variants SST5TMD4 and SST5TMD5 are shown in a schematic serpentine format. Glycosylation sites are colored in purple; the DRY motif is highlighted in green; the human SST motif is in light blue; potential phosphorylation sites are in gray; identified GRK2/3 phosphorylation site is in red; constitutive phosphorylation site is in black; the PDZ ligand motif is in dark blue; the disulfide-forming cysteines are in pale blue; and the potential palmitoylation site is in orange. UMB-4 is a rabbit monoclonal antibody, which detects the carboxyl-terminal tail of SST5 in a phosphorylation-independent manner.

  • Fig. 19.
    Fig. 19.

    SST5 signaling leading to inhibition of hormone secretion and proliferation. By coupling to Gi proteins, SST5 inhibits adenylate cyclase and reduces cAMP accumulation, and reduces intracellular Ca2+ concentrations by activating GIRK channels, which results in membrane hyperpolarization and subsequent reduction of Ca2+ influx through VOCC. This results in decreased hormone secretion. By coupling to a pertussis toxin–independent G protein, SST5 activates PLC, triggering inositol-1,4,5-trisphosphate (IP3) production and subsequent Ca2+ release into the cytoplasm from endoplasmic reticulum. Major downstream effectors of SST5 are the tyrosine phosphatases SHP-1 and SHP-2, which subsequently inhibit mTOR pathway, thereby decreasing cell growth and proliferation. In addition, SST5 inhibits NHE1 activity, resulting in a decrease of extracellular acidification rate.

  • Fig. 20.
    Fig. 20.

    Differential trafficking of somatostatin receptors. Agonist activation of SSTs triggers activation of the associated heterotrimeric G protein that in turn stimulates a second messenger system. Quenching of this signal involves phosphorylation of the receptor by GRKs. Phosphorylation by GRKs increases the affinity for arrestins, which uncouple the receptor from the G protein and target the receptor to clathrin-coated pits for internalization. Return to its resting state requires dissociation or degradation of the agonist, dephosphorylation, and dissociation of arrestin. For SST5, the catalytic PP1γ subunit was identified to catalyze S/T dephosphorylation at the plasma membrane within seconds to minutes after agonist removal. SST5 forms unstable complexes with arrestins that are rapidly disrupted. After dephosphorylation, SST5 is either resensitized at the plasma membrane or recycled back through an endosomal pathway. For SST2, the catalytic PP1β subunit was identified to catalyze S/T dephosphorylation. SST2 forms stable complexes with arrestins that cointernalize into the same endocytic vesicles. This dephosphorylation process is initiated at the plasma membrane and continues along the endosomal pathway. PP1β-mediated dephosphorylation promotes dissociation of arrestins and, hence, facilitates quenching of arrestin-dependent signaling. Subsequently, SST2 is recycled back through an endosomal pathway to the plasma membrane. For SST3, the catalytic PP1α/β subunits were identified to catalyze S/T dephosphorylation at the plasma membrane within seconds to minutes after agonist removal. SST3 forms unstable complexes with arrestins that are rapidly disrupted. After dephosphorylation, SST3 is either subject to lysosomal degradation or recycled back to the plasma membrane through an endosomal pathway.

  • Fig. 21.
    Fig. 21.

    SST5 expression pattern in human normal and neoplastic tissues. Immunohistochemistry (red-brown color), counterstaining with hematoxylin; primary antibody: UMB-4; scale bar, 50 µm. SST5 displays a predominant membranous expression.

  • Fig. 22.
    Fig. 22.

    Structures of synthetic SST5 ligands. L-817,818 and BIM-23268, SST5 agonists; S5A1, SST5 antagonist.

  • Fig. 23.
    Fig. 23.

    Structures of SRIF ligands currently used in clinical practice.

  • Fig. 24.
    Fig. 24.

    Structures of SST ligands used for scintigraphy. [123I]Tyr3-octroeotide, the very first compound for SST-targeted scintigraphy. Conjugation of DTPA to octreotide and labeling with indium-111 resulted in Octreoscan (Mallinckrodt), the first approved SST agent for SPECT imaging. Advanced Accelerator Application recently received market authorization for 68Ga-labeled DOTA-TOC (SomatoKit TOC) by the European Medicines Agency and for 68Ga-DOTA-TATE (Netspot) by the FDA. It is expected that [177Lu]DOTATATE will soon be approved by FDA and European Medicines Agency as first agent for peptide receptor radiotherapy.

  • Fig. 25.
    Fig. 25.

    Representative examples of clinical PRRT images. PRRT in a 73-year-old patient with metastasized neuroendocrine cancer (G1). Pretherapeutic 68Ga-DOTANOC PET/computed tomography images show extensive metastases in the liver and additional abdominal lymph node metastases (A). Post-therapeutic whole-body scintigraphy after application of 177Lu-DOTATATE confirms uptake in metastatic lesions (B). After four cycles of 177Lu-DOTATATE, 68Ga-DOTANOC PET/computed tomography demonstrates considerable response of liver and abdominal lymph node metastases (C). Images courtesy of M. Eiber, Department of Nuclear Medicine, Technical University Munich, Germany.

Tables

  • TABLE 1

    Nomenclature and properties of somatostatin receptors

    SST1SST2SST3SST4SST5
    Gennomic location14q1317q2422q13.120p11.216p13.3
    Amino acids391369418388364
    Naturally occurring agonistsSRIF-14, SRIF-28SRIF-14, SRIF-28SRIF-14, SRIF-28SRIF-14, SRIF-28SRIF-14, SRIF-28
    CST-17, CST-29CST-17, CST-29CST-17, CST-29CST-17, CST-29CST-17, CST-29
    G protein couplingGαi/oGαi/oGαi/oGαi/oGαi/o
    Primary signal transductioncAMP↓cAMP↓cAMP↓cAMP↓cAMP↓
    VOCC ↓VOCC ↓VOCC ↓VOCC ↓VOCC ↓
    GIRK↑GIRK↑GIRK↑GIRK↑GIRK↑
    NHE1↓PTP↑NHE1↓NHE1↓PTP↑
    PTP↑PTP↑PTP↑
    Expression in human normal tissueBrainBrainBrainBrain
    Anterior pituitary Pancreatic isletsAnterior pituitaryAnterior pituitaryRetinaAnterior pituitary
    Gastrointestinal tractPancreatic isletsPancreatic isletsDorsal root gangliaPancreatic islets
    Dorsal root gangliaGastrointestinal tractPlacentaGastrointestinal tract
    Gastrointestinal tractLymphatic tissueLymphatic tissue
    Lymphatic tissueAdrenalsAdrenals
    Adrenals
    Expression in human tumorsaGH-Adenomas NETGH-AdenomasGH-AdenomasGH-Adenomas
    TSH-AdenomasACTH-AdenomasACTH-Adenomas
    NETNF-AdenomasNET
    Pheochromocytomas
    Paragangliomas
    Phenotype of mice lacking receptorAltered insulin homeostasisHigh basal acid secretionImpaired novel object recognitionIncreased seizure susceptibilityIncreased insulin secretion
    Inhibition of glucagon releaseIncreased anxietyBasal hypoglycemia
    Impaired motor coordination

    • ↵a Expression in >50% of cases.

  • TABLE 2

    Sequences of human receptors were aligned using the BLAST algorithm, and the percentages of sequence identity (upper right) and similarity (i.e., the presence of similar amino acids; lower left) were determined

    Sequence comparisons are limited to the core regions of receptors (i.e., sequences encompassing the seven-helix bundle plus adjacent segments), whereas no significant similarities were detected in the N-terminal and C-terminal tails.

    SST1SST2SST3SST4SST5
    SST110055526949
    SST274100535356
    SST369691004856
    SST482736610053
    SST564746970100
  • TABLE 3

    Rabbit monoclonal SST antibodies

    CloneEpitopeSpecies ReactivityReference
    SST1UMB-7377ENLESGGVFRNGTCTSRITTL391HumanLupp et al. (2013)
    SST2UMB-1355ETQRTLLNGDLQTSI369Mouse, rat humanFischer et al. (2008)
    SST3UMB-5398QLLPQEASTGEKSSTMRISYL418HumanLupp et al. (2012)
    SST5UMB-4344QEATPPAHRAAANGLMQTSKL364HumanLupp et al. (2011)
  • TABLE 4

    Ligand-binding affinities of SST1-selective ligands

    SST1SST2SST3SST4SST5
    L-797/591a1.4187522401703600
    BIM-23926b3.6>1000>1000833788
    SRA880c7.6>1000>1000>1000954

    • ↵a Data from Rohrer et al. (1998).

    • ↵b Data from Zatelli et al. (2002).

    • ↵c Data from Hoyer et al. (2004), Cammalleri et al. (2009).

  • TABLE 5

    Ligand-binding affinities of SST2-selective ligands

    SST1SST2SST3SST4SST5
    L-779/976a27600.057293104260
    BIM-23120b>10000.34412>1000213.5
    DOTA-JR11c>10000.58>1000>1000>1000

    • ↵a Data from Rohrer et al. (1998).

    • ↵b Data from Gruszka et al. (2012).

    • ↵c Data from Cescato et al. (2008).

  • TABLE 6

    Ligand-binding affinities of SST3-selective ligands

    SST1SST2SST3SST4SST5
    L-796/778a1255>10,0002486501200
    sst3-ODN-8b>10,000>10,0004.1>10,000>10,000
    ACQ090c5.685.318.136.815.93
    MK-4256d236240250.66384533

    • ↵a Data from Rohrer et al. (1998).

    • ↵b Data from Reubi et al. (2000a).

    • ↵c Data from Troxler et al. (2010).

    • ↵d Data from He et al. (2012).

  • TABLE 7

    Ligand-binding affinities of SST4-selective ligands

    SST1SST2SST3SST4SST5
    L-803,087a199472012800.73880
    J-2156b350>500013000.8460

    • ↵a Data from Rohrer et al. (1998).

    • ↵b Data from Engström et al. (2005).

  • TABLE 8

    Ligand-binding affinities of SST5-selective ligands

    SST1SST2SST3SST4SST5
    L-817/818a3.35264820.4
    BIM-23268b18.415.161.616.30.37
    S5A1c>5190>10,000>10,000—4.87

    • ↵a Data from Rohrer et al. (1998).

    • ↵b Data from Shimon et al. (1997a).

    • ↵c Data from Farb et al. (2017).

  • TABLE 9

    Ligand-binding affinities for approved and investigational SRIF ligands

    SST1SST2SST3SST4SST5
    Octreotidea>10000.44.4>10005.6
    Lanreotideb21290.759818265.2
    Pasireotidec9.311.5>1000.16
    Veldoreotided>10003>10076

    • ↵a Data from Reisine and Bell (1995), Patel (1999).

    • ↵b Data from Shimon et al. (1997b), Zatelli et al. (2001).

    • ↵c Data from Bruns et al. (2002).

    • ↵d Data from Afargan et al. (2001).

  • TABLE 10

    Approved and investigational SRIF analogs blocking GH secretion

    Data adapted from Melmed (2016).

    AgentDescriptionRegulatory Status
    Lanreotide autogelLong-acting lanreotideAvailable
    Administered via deep s.c. injection every 4–6 wk
    Octreotide LARLong-acting octreotideAvailable
    Administered via i.m. injection every 4 wk
    Pasireotide LARLong-acting pasireotideAvailable
    Administered via i.m. injection every 4 wk
    Octreotide capsulesOctreotide encapsulated with transient permeability enhancerCompleted phase 3
    Administered orally twice daily
    CAM2029Octreotide bound in liquid crystal matrixIn phase II
    Administered via s.c. injection at a frequency not yet determined but likely to be every 4 wk
    Veldoreotide (COR-005)SRIF analog highly selective for GH suppressionIn phase II
    Administered via i.m. injection at a frequency not yet determined but likely to be every 4 wk
  • TABLE 11

    Markers of somatostatin receptor ligand responsiveness in GH-secreting pituitary adenomas

    Data adapted from Cuevas-Ramos et al. (2015).

    GH GranulationDense vs. Sparse Using CAM5.2 Cytokeratin Immunostaining
    SST2, SST5Positive vs. negative expression
    SST2:SST5High vs. low ratio of average SST2 to SST5
    SST5TMD4Low vs. high expression
    AIPLack vs. presence of mutation or high vs. low protein expression
    β-arrestinLow vs. high score based on intensity and expression pattern
    Filamin AHigh vs. low score based on intensity and expression pattern
    GspPresence vs. absence of mutation
    E-cadherinHigh vs. low score based on intensity and expression pattern
  • TABLE 12

    Ligand-binding affinities of SRIF-based radiochemicals

    SST1SST2SST3SST4SST5Regulatory Status
    Agonists with Predominant SST2 Affinity
    DTPA-octreotidea>10,00012 ± 2376 ± 84>1000299 ± 50
    DOTA-lanreotidea>10,00026 ± 3.4771 ± 229>10,00073 ± 12
    In-DTPA-OCa>10,00022 ± 3.6182 ± 13>1000237 ± 52FDA approved
    DOTA-TOCa>10,00014 ± 2.6880 ± 324>1000393 ± 84
    Y-DOTA-TOCa>10,00011 ± 1.7389 ± 135>10,000114 ± 29Phase II studies
    DOTA-OCa>10,00014 ± 327 ± 9>1000103 ± 39
    Y-DOTA-OCa>10,00020 ± 227 ± 8>10,00057 ± 22
    Ga-DOTA-TOCa>10,0002.5 ± 0.5613 ± 140>100073 ± 21EMA approved
    Ga-DOTA-OCa>10,0007.3 ± 1.9120 ± 45>100060 ± 14
    DTPA-TATEa>10,0003.9 ± 1>10,000>1000>1000
    In-DTPA-TATEa>10,0001.3 ± 0.2>10,000433 ± 16>1000
    DOTA-TATEa>10,0001.5 ± 0.4>1000453 ± 176547 ± 160
    Y-DOTA-TATEa>10,0001.6 ± 0.4>1000523 ± 239187 ± 50
    In-DOTA-TOCb>10,0004.6 ± 0.2120 ± 26230 ± 82130 ± 17
    Ga-DOTA-TATEa>10,0000.2 ± 0.04>1000300 ± 140377 ± 18FDA approved
    Lu-DOTATATEc>10002.0 ± 0.8162 ± 16>1000>1000Phase III completed
    I-Gluc-TOCd—2.2 ± 0.7357 ± 22—64 ± 24
    I-Gluc-TTEd—2.0 ± 0.5>1000—521 ± 269
    I-Gluc-S-TATEd—2.0 ± 0.7398 ± 19—310 ± 156
    I-Gal-S-TATEd—2.0 ± 0.8491 ± 63—413 ± 167
    Gluc-Lys(FP)-TATEe>10,0002.8 ± 0.4>1000437 ± 84123 ± 8.8
    Agonists with Pansomatostatin-Like Binding Profile
    Ga-DOTA-NOCf>10,0001.9 ± 0.440.0 ± 5.8260 ± 747.2 ± 1.6Phase II studies
    In-DOTA-NOCg>10003.3 ± 0.326 ± 1.9>100010.4 ± 1.6
    In-DOTA-BOCg>10,0003.1 ± 0.312 ± 1.0455 ± 656 ± 1.8
    NOC-ATEb>10003.6 ± 1.6302 ± 137260 ± 9516.7 ± 9.9
    BOC-ATEb>10000.8 ± 0.433 ± 5.580 ± 203.6 ± 1.5
    In-DOTA-NOC-ATEb>10,0002 ± 0.3513 ± 4160 ± 3.84.3 ± 0.5
    Lu-DOTA-NOC-ATEd—3.6 ± 0.331 ± 2—15 ± 1
    In-DOTA-BOC-ATEb>10001.4 ± 0.375.5 ± 0.8135 ± 323.9 ± 0.2
    Lu-DOTA-BOC-ATEd—2.4 ± 0.311 ± 1—8.3 ± 0.4
    KE108h0.96 ± 0.150.4 ± 0.040.44 ± 0.060.6 ± 0.030.26 ± 0.04
    KE121h1.6 ± 0.70.5 ± 0.20.3 ± 0.10.4 ± 0.20.2 ± 0.1
    Y-DOTA-K121h (Y-KE88)2 ± 0.84.3 ± 0.80.7 ± 0.20.5 ± 0.20.7 ± 0.2
    Ga-DOTA-K121h (Ga-KE88)3.5 ± 1.61.8 ± 1.60.8 ± 0.31.8 ± 0.50.9 ± 0.2
    Y-DOTAGA-KE121h (Y-KE87)6.7 ± 2.12.7 ± 2.40.6 ± 0.11.6 ± 0.61.3 ± 0.4
    Antagonists
    In-DOTA-BASSi>10009.4 ± 0.4>1000380 ± 57>1000Pilot study
    In-DOTA-JR11j>10003.8 ± 0.7>1000>1000>1000Pilot study
    Ga-DOTA-JR11j (Ga-OPS201)>100029 ± 2.7>1000>1000>1000Pilot study
    Ga-NODAGA-JR11j (Ga-OPS202)>10001.2 ± 0.2>1000>1000>1000Phase I/II study
    Lu-DOTA-JR11j (Lu-OPS201)>10000.73 ± 0.15>1000>1000>1000
    sst3-ODN-8d—>10006.7 ± 2.6>1000
    DOTA-sst3-ODN-8g>1000>10005.2 ± 1.3>1000>1000
    In-DOTA-sst3-ODN-8g>1000>100015 ± 5.2>1000>1000

    • EMA, European Medicines Agency.

    • ↵a Data from Reubi et al. (2000a).

    • ↵b Data from Ginj et al. (2005).

    • ↵c Data from Schottelius et al. (2015).

    • ↵d Data from Cescato et al. (2006).

    • ↵e Data from Wester et al. (2003).

    • ↵f Data from Antunes et al. (2007).

    • ↵g Data from Ginj et al. (2006a).

    • ↵h Data from Ginj et al. (2008).

    • ↵i Data from Ginj et al. (2006b).

    • ↵j Data from Fani et al. (2012).

  • TABLE 13

    Amino acid sequences of SRIF-based radiochemicals

    Amino acids: first letter capitalized: L-amino acid; first letter in lowercase: D-amino acid.

    LigandChelator/Prosthetic GroupAA1AA2AA3AA4AA5AA6AA7AA8AA9AA10
    Peptide Agonists with Predominantly SST2 Affinity
    Octreotide—pheCysPhetrpLysThrCysThr-ol
    Tyr3-octreotide (TOC)pheCysTyrtrpLysThrCysThr-ol
    RC160 (Vapreotide)pheCysTyrtrpLysValCysTrp-NH2
    Lanreotide (BIM-23014)2-nalCysTyrtrpLysValCysThr-NH2
    Radiopeptide Agonists and Precursors with Predominantly SST2 Affinity
    DTPA-octreotideDTPApheCysPhetrpLysThrCysThr-ol
    DOTA-lanreotideDOTA2-nalCysTyrtrpLysValCysThr-NH2
    In-DTPA-OCIn-DTPApheCysPhetrpLysThrCysThr-ol
    DOTA-TOCDOTApheCysTyrtrpLysThrCysThr-ol
    Y-DOTA-TOCY-DOTApheCysTyrtrpLysThrCysThr-ol
    DOTA-OCDOTApheCysPhetrpLysThrCysThr-ol
    Y-DOTA-OCY-DOTApheCysPhetrpLysThrCysThr-ol
    Ga-DOTA-TOCGa-DOTApheCysTyrtrpLysThrCysThr-ol
    Ga-DOTA-OCGa-DOTApheCysPhetrpLysThrCysThr-ol
    DTPA-TATEDTPApheCysTyrtrpLysThrCysThr
    In-DTPA-TATEIn-DTPApheCysTyrtrpLysThrCysThr
    DOTA-TATEDOTApheCysTyrtrpLysThrCysThr
    Y-DOTA-TATEY-DOTApheCysTyrtrpLysThrCysThr
    In-DOTA-TOCIn-DOTApheCysTyrtrpLysThrCysThr-ol
    Ga-DOTA-TATEGa-DOTApheCysTyrtrpLysThrCysThr
    Lu-DOTATATELu-DOTApheCysTyrtrpLysThrCysThr
    I-Gluc-TOCGlucosylpheCys3-I-TyrtrpLysThrCysThr-ol
    I-Gluc-TATEGlucosylpheCys3-I-TyrtrpLysThrCysThr
    I-Gluc-S-TATEGlucosyl-S-pheCys3-I-TyrtrpLysThrCysThr
    I-Gal-S-TATEGalactosyl-S-pheCys3-I-TyrtrpLysThrCysThr
    Gluc-Lys(FP)-TATEGlucosyl-Lys(fluoropropionyl)pheCys3-I-TyrtrpLysThrCysThr
    Agonists toward Pansomatostatin-Like Binding Profile
    Ga-DOTA-NOCGa-DOTApheCys1-NaltrpLysThrCysThr-ol
    In-DOTA-NOCIn-DOTApheCys1-NaltrpLysThrCysThr-ol
    In-DOTA-BOCIn-DOTApheCysBzThitrpLysThrCysThr-ol
    NOC-ATEpheCys1-NaltrpLysThrCysThr
    BOC-ATEpheCysBzThitrpLysThrCysThr-ol
    In-DOTA-NOC-ATEIn-DOTApheCys1-NaltrpLysThrCysThr
    Lu-DOTA-NOC-ATELu-DOTApheCys1-NaltrpLysThrCysThr
    In-DOTA-BOC-ATEIn-DOTApheCysBzThitrpLysThrCysThr-ol
    Lu-DOTA-BOC-ATELu-DOTApheCysBzThitrpLysThrCysThr-ol
    KE108Y-DOTATyrdabArgPhePhetrpLysThrPhe
    KE121dabArgPhePhetrpLysThrPhe
    Y-DOTA-K121 (Y-KE88)Y-DOTAdabArgPhePhetrpLysThrPhe
    Ga-DOTA-K121 (Ga-KE88)Y-DOTAdabArgPhePhetrpLysThrPhe
    Y-DOTAGA-KE121 (Y-KE87)Y-DOTAdabArgPhePhetrpLysThrPhe
    Antagonists
    In-DOTA-BASSIn-DOTApNO2−PhecysTyrtrpLysThrCystyr-NH2
    In-DOTA-JR11In-DOTACpacysAph(Hor)Aph(Cbm)LysThrCystyr-NH2
    Ga-DOTA-JR11 (Ga-OPS201)Ga-DOTACpacysAph(Hor)Aph(Cbm)LysThrCystyr-NH2
    Ga-NODAGA-JR11 (Ga-OPS202)Ga-NODAGACpacysAph(Hor)Aph(Cbm)LysThrCystyr-NH2
    Lu-DOTA-JR11 (Lu-OPS201)Lu-DOTACpacysAph(Hor)Aph(Cbm)LysThrCystyr-NH2
    sst3-ODN-8NH2COcysPheTyrDAgl8(Me,2-naphthoyl)LysThrPheCys
    DOTA-sst3-ODN-8DOTANH2COcysPheTyrDAgl8(Me,2-naphthoyl)LysThrPheCys
    DOTA-TOCDOTAd-PheCysPhed-TrpLysThrCysThr(ol)

    • AgI, α-Aminoglycyl; Aph(Cbm), 4-aminocarbamoylphenylalanine; Aph(Hor), 4-amino-L-hydroorotylphenylalanine; BOC, [BzThi3]-octreotide; BOC-ATE, [BzThi3]-octreotate; BzThi, 3-benzothienylalanine; Cpa, 4-Cl-phenylalanine; Dab, α,γ-diaminobutyryl; DOTA, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid; DOTAGA, 1-(1-carboxy-3-carboxy-propyl)-4,7,10(carboxymethyl)-1,4,7,10-tetraazacyclo-dodecane; DTPA, diethylenetriaminepentaacetic acid; Gal-S, galactosyl-mercaptopropionyl; Gluc, glucosyl; Gluc-S, glucosyl-mercaptopropionyl; Gluc-Lys(FP), Nα-glucosyl-Nε-(2-fluoropropionyl)Lys; 1-Nal, 1-naphthylalanine; NOC, [1-Nal3]-octreotide; TATE, [Tyr3,Thr8]-octreotide; TOC, [Tyr3]-octreotide.

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Nomenclature of Somatostatin Receptors

Thomas Günther, Giovanni Tulipano, Pascal Dournaud, Corinne Bousquet, Zsolt Csaba, Hans-Jürgen Kreienkamp, Amelie Lupp, Márta Korbonits, Justo P. Castaño, Hans-Jürgen Wester, Michael Culler, Shlomo Melmed and Stefan Schulz
Pharmacological Reviews October 1, 2018, 70 (4) 763-835; DOI: https://doi.org/10.1124/pr.117.015388
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