A bicyclic and hsst2 selective somatostatin analogue: design, synthesis, conformational analysis and binding

Falb, Eliezer; Salitra, Yoseph; Yechezkel, Tamar; Bracha, Moshe; Litman, Pninit; Olender, Roberto; Rosenfeld, Rakefet; Senderowitz, Hanoch; Jiang, Sanyuan; Goodman, Murray

doi:10.1016/s0968-0896(01)00234-6

Cited by 27 publications

(40 citation statements)

References 25 publications

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“…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%

“…The inner cycle comprised the octreotide sequence, and backbone cyclization was through lactamization via the N and C terminus of the 2 cysteines. Falb et al (16) found a high degree of sst 2 selectivity, which they explained with the large hydrophobicity of the lactam ring Phe side chains. Intuitively, the introduction of conformational constraints should lead to subtype selectivity.…”

mentioning

confidence: 98%

“…The bicyclic peptide cyclo(Aha,cyclo(Cys-Phe-D-Trp-Lys-Thr-Cys)) showed higher potency than SRIF-14 and longer duration of biologic activity. In 2001, Falb et al looked for selectivity toward receptor subtypes (16). They synthesized a backbone and disulfide-bridged bicyclic somatostatin analog.…”

mentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

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confidence: 98%

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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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“…Backbone cyclization is a synthetic method that allows formation of rigid cyclic peptides, synthesized using building units consisting of N-alkylated amino acids bearing a variable-length alkyl arm [17][18][19][20][21].…”

Section: Introductionmentioning

confidence: 99%

Targeting small-cell lung cancer with novel fluorescent analogs of somatostatin

Kostenich

Livnah²,

Bonasera³

et al. 2005

Lung Cancer

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“…As part of our efforts to design and synthesize compounds displaying an increased selectivity to the somatostatin subtype receptors and enhanced in vivo stability, [1][2][3][4][5] we were interested in a heterocyclic scaffold-based approach to somatostatin analogs.…”

mentioning

confidence: 99%

Utilizing the intramolecular Fukuyama–Mitsunobu reaction for a flexible synthesis of novel heterocyclic scaffolds for peptidomimetic drug design

Zapf

Valle

Goodman

2005

Bioorganic & Medicinal Chemistry Letters

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A bicyclic and hsst2 selective somatostatin analogue: design, synthesis, conformational analysis and binding

Cited by 27 publications

References 25 publications

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

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

Targeting small-cell lung cancer with novel fluorescent analogs of somatostatin

Utilizing the intramolecular Fukuyama–Mitsunobu reaction for a flexible synthesis of novel heterocyclic scaffolds for peptidomimetic drug design

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