Somatostatin Receptor 1 Selective Analogues:  3. Dicyclic Peptides

Rivier, Jean; Kirby, Dean A.; Érchegyi, Judit; Waser, Beatrice; Eltschinger, Véronique; Cescato, Renzo; Reubi, Jean Claude

doi:10.1021/jm049519m

Cited by 10 publications

(17 citation statements)

References 61 publications

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“…The longer side chain in 4 led to higher binding affinity compared to that of 2 and 3. 2 The strong sequential d RN (i,i + 1) NOEs and the d RN (i,i + 2) NOE between D-Trp 8 and Thr 10 confirm the type-III β-turn around D-Trp 8 and IAmp 9 (Figure 2 and Table 3). The structure is further stabilized as evidenced by the presence of some long range d RN (3,14), d RN (6,13), d RR (6,11), and d RN (7,11) NOEs.…”

Section: Resultsmentioning

confidence: 81%

“…In this section, the chemical shift assignment and the structure determination by NMR of each SRIF analogue 1-6 given in Table 1 are presented. These six sst 1selective analogues were selected to cover the chemical diversity uncovered in the two preceding papers 1,2 and judged necessary and sufficient to elucidate the corresponding pharmacophore.…”

Section: Resultsmentioning

confidence: 99%

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Somatostatin Receptor 1 Selective Analogues: 4. Three-Dimensional Consensus Structure by NMR

et al. 2004

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The three-dimensional NMR structures of six analogues of somatostatin (SRIF) are described. These analogues with the amino acid 4-(N-isopropyl)-aminomethylphenylalanine (IAmp) at position 9 exhibit potent and highly selective binding to human SRIF subtype 1 receptors (sst(1)). The conformations reveal that the backbones of these analogues have a hairpin-like structure similar to the sst(2)-subtype-selective analogues. This structure serves as a scaffold for retaining a unique arrangement of the side chains of d-Trp(8), IAmp(9), Phe(7), and Phe(11) or m-I-Tyr(11) (m-I-Tyr = mono-iodo-tyrosine). The conformational preferences and results from biological analyses of these analogues(1,2) allow a detailed study of the structure-activity relationship of SRIF. The proposed consensus pharmacophore of the sst(1)-selective analogues requires a unique set of distances between an indole/2-naphthyl ring, an IAmp side chain, and two aromatic rings. This motif is necessary and sufficient to explain the binding affinities of all of the analogues studied and is distinct from the existing models suggested for sst(4) as well as sst(2)/sst(5) selectivity.

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Section: Resultsmentioning

confidence: 81%

Section: Resultsmentioning

confidence: 99%

Somatostatin Receptor 1 Selective Analogues: 4. Three-Dimensional Consensus Structure by NMR

et al. 2004

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“…Intuitively, the introduction of conformational constraints should lead to subtype selectivity. This subtype selectivity was shown in a study by Rivier et al examining short-chain somatostatin analogs at sst 1 -sst 5 to identify sterically constrained sst 1 selective scaffolds (17). They found a large affinity dependence on the ring size but also highly selective sst 1 agonists if they used 4-(N-isopropyl)-aminomethylphenylalanine to replace lysine.…”

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confidence: 68%

“…They were studied as cold peptides by Veber et al (13)(14)(15), mainly to increase the metabolic stability but also to better understand the structural parameters necessary for functional activity. Later, Rivier et al and the Peptor group along with Falb et al used this strategy to introduce conformational constraints for sst subtype selectivity (16,17). In a first family of peptides, we partially followed the approach of Veber et al by keeping the 20-atom sequence of the N-and C-terminally amino acid-deleted octreotide as an inner cycle and by adding a 16-atom ring composed of the 2 amino acids Arg and GABA head-to-tail.…”

Section: Discussionmentioning

confidence: 99%

Radiolabeled Bicyclic Somatostatin-Based Analogs: A Novel Class of Potential Radiotracers for SPECT/PET of Neuroendocrine Tumors

Fani¹,

Mueller²,

Tamma³

et al. 2010

J Nucl Med

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A variety of radiolabeled somatostatin analogs have been developed for targeting of somatostatin receptor (sst)-positive tumors. Bicyclic somatostatin-based radiopeptides have not been studied yet. Hypothesizing that the introduction of conformational constraints may lead to receptor subtype selectivity or may help to delineate structural features determining pansomatostatin potency, we developed and evaluated first examples of this new class of potential radiotracers for imaging or therapy of neuroendocrine tumors. Methods: The bicyclic peptides were synthesized by standard solid-phase peptide synthesis. DOTA was coupled to the resin-assembled peptide for labeling with 177 Lu and 68 Ga. Binding affinity and receptor subtype profile were determined using human ssts. Ca 21 flux, internalization, and efflux were studied in human embryonic kidney (HEK)-sst 2 and HEK-sst 3 cell lines. Biodistribution and PET/CT studies were performed in corresponding nude mice models. Results: Some of the new analogs showed high affinity for sst 2 and sst 3 and moderate affinity for sst 1 , sst 4 , and sst 5 , while exhibiting agonistic properties. The analog AM3, comprising an octreotide ring and a head-to-tail-coupled Arg-diaminobutyric acid(DOTA) cycle, showed the highest receptor affinity and agonist potency. 177 Lu-AM3 showed high and receptor-mediated uptake in vivo in sst 2 and sst 3 tumors with low background. Kidneys were the only other tissue accumulating radioactivity that could be reduced by a preinjection of lysine. PET/CT studies of 68 Ga-AM3 at 1 h after injection were characterized by clear localization of the tumor, visualization of the kidneys, and negligible background. Conclusion: The high rigidity of these new bicyclic somatostatin-based radiopeptides led to agonistic ligands with good affinity for all 5 ssts. The pharmacokinetic data of 177 Lu/ 68 Ga-AM3 make this peptide an excellent candidate as an imaging-and especially as a PET-radiotracer.

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“…Their properties make them attractive and promising tools in the field of nuclear medicine [1]. Among the bicyclic peptides described in the literature, there are a number of reports on somatostatin (SST) analogues [2][3][4][5][6][7]. SST derivatives play an important role in the diagnosis and treatment of neuroendocrine tumors [8] and their complexes with radioactive isotopes are already used in peptide receptor radionuclide therapy [9][10][11][12].…”

Section: Introductionmentioning

confidence: 99%

Detailed Insight into the Interaction of Bicyclic Somatostatin Analogue with Cu(II) Ions

Marciniak

Witak

Sabatino

et al. 2020

IJMS

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Somatostatin analogues are useful pharmaceuticals in peptide receptor radionuclide therapy. In previous studies, we analyzed a new bicyclic somatostatin analogue (BCS) in connection with Cu(II) ions. Two characteristic sites were present in the peptide chain: the receptor- and the metal-binding site. We have already shown that this ligand can form very stable imidazole complexes with the metal ion. In this work, our aim was to characterize the intramolecular interaction that occurs in the peptide molecule. Therefore, we analyzed the coordination abilities of two cyclic ligands, i.e., P1 only with the metal binding site and P2 with both sites, but without the disulfide bond. Furthermore, we used magnetic circular dichroism (MCD) spectroscopy to better understand the coordination process. We applied this method to analyze spectra of P1, P2, and BCS, which we have described previously. Additionally, we analyzed the MCD spectra of P3 ligand, which has only the receptor binding site in its structure. We have unequivocally shown that the presence of the Phe-Trp-Lys-Thr motif and the disulfide bond significantly increases the metal binding efficiency.

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Somatostatin Receptor 1 Selective Analogues: 3. Dicyclic Peptides

Cited by 10 publications

References 61 publications

Somatostatin Receptor 1 Selective Analogues: 4. Three-Dimensional Consensus Structure by NMR

Somatostatin Receptor 1 Selective Analogues: 4. Three-Dimensional Consensus Structure by NMR

Radiolabeled Bicyclic Somatostatin-Based Analogs: A Novel Class of Potential Radiotracers for SPECT/PET of Neuroendocrine Tumors

Detailed Insight into the Interaction of Bicyclic Somatostatin Analogue with Cu(II) Ions

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