Design and synthesis of a gonadotropin-releasing hormone (GnRH) analogue, [Tyr(OMe)5,d-Glu6,Aze9]GnRH: Receptor binding, gonadotropin release and ovulation studies

Keramida, Maria; Matsoukas, John; Panagiotopoulos, Dimitris; Alexopoulos, Kostas; Matsoukas, Elizabeth; Cladas, John; Tzingounis, V.; Cardamakis, E.; Maia, Hernâni L. S.; Pati, Debananda; Habibi, Hamid R.

doi:10.1007/bf00128117

Cited by 7 publications

(4 citation statements)

References 11 publications

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“…GnRH agonists were developed to increase potency over naturally occurring GnRH through enhanced binding affinity to the GnRH receptor and decrease enzymatic proteolysis . Despite the clinical success of the pharmacological application of GnRH derivatives, radiolabelled peptides are used for molecular imaging and radionuclide therapy of tumors . Many reports are available on the developing radiolabelled GnRH analogues.…”

Section: Introductionmentioning

confidence: 99%

Preclinical evaluation of new GnRH‐I receptor radionuclide therapy with ¹⁷⁷Lu‐peptide tracer

Zoghi

Nosrati

Rogni

et al. 2019

Labelled Comp Radiopharmac

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The purpose of this study was to develop preclinical evaluation of a novel radiolabeled gonadotropin-releasing hormone (GnRH) receptor targeting peptide for prostate cancer therapy. The new antiproliferative agent of GnRH-I analogue was developed on the basis of the D-Trp 6 -GnRH-I scaffold, and in vivo pharmacokinetics and receptor binding affinity were enhanced by the substitution of Gly-NHNH 2 for Gly-NH 2 at position 10 in D-Trp 6 -GnRH-I. To evaluate 177 Lu-DOTA-triptorelin-hydrazide as radionuclide therapy of tumor, the quality control tests and preclinical stage assessment were carried out.Solid-phase method was used to synthesize new peptide. Characterization and purity of peptide were done by mass spectroscopy and high-performance liquid chromatography (HPLC). In order to be utilized in targeted therapy, the new GnRH-I agonist was coupled with pSCN-Bn-DOTA. The precipitate crude of DOTA-triptorelin-hydrazide was then purified via preparative HPLC. At optimal conditions of time, temperature, ligand amount, and lutetium content, DOTA-triptorelin-hydrazide was labeled with 177 Lu (specific activity not less than 925 GBq/mg). Investigation of the in vivo biodistribution and in vitro studies for 177 Lu-DOTA-TRPHYD was performed in three different ways, and the binding of radiopeptide to GnRH receptors was expressed on the human cell lines using 125 I-labeled D-TRP 6 GnRH-I as a tracer, respectively.Synthesized novel GnRH-I was obtained with purity greater than 98%. Paper chromatography was found to be the most suitable with R f of the complex and observed radiochemical purity of RTLC and HPLC greater than 97%. For in vivo studies, 177 Lu-DOTA-triptorelin-hydrazide showed promising results with fast clearance from the blood and resulted in good T/NT ratios at 1, 4, and 24 hours postinjection and satisfactory biodistribution with no significant activity seen in normal tissue. The values of internalization efficiency and receptor affinity of new radiopeptide binding were IC 50 = 0.47 ± 0.06 vs 0.13 ± 0.01 nM for triptorelin and cellular uptake: 3.4 ± 0.7% at 1 hour and 6.8 ± 1.17% at 4 hours of the internal reference. The results showed a good stability and radiochemical purity of the obtained radioconjugate. For in vivo and in vitro studies, new radiopeptide showed a high uptake of 177 Lu conjugate in tumor and rapid clearance from the blood stream almost entirely via the

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Section: Introductionmentioning

confidence: 99%

Preclinical evaluation of new GnRH‐I receptor radionuclide therapy with ¹⁷⁷Lu‐peptide tracer

Zoghi

Nosrati

Rogni

et al. 2019

Labelled Comp Radiopharmac

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“…GnRH agonists have the same effect on gonadotropin release after binding the type Ιreceptor as native GnRH . GnRH agonists were developed to increase potency over naturally occurring GnRH through enhanced binding affinity to the GnRH receptor and decreased enzymatic proteolysis . Despite the clinical success of the pharmacological application of GnRH derivatives, radiolabeled peptides are used for molecular imaging and radionuclide therapy of tumors .…”

Section: Introductionmentioning

confidence: 99%

Preparation of a radiolabeled GnRH‐I analogue derivative with ¹¹¹In as a new anti‐proliferative agent

Zoghi

Nosrati

Rogni

et al. 2018

Labelled Comp Radiopharmac

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The new GnRH-Ιanalogue developed in this paper was based on the D-Trp -GnRH-Ι-scaffold, and its potency was increased by the replacement Gly-NH by NH-NH binding to the Gly at position 10. Triptorelin-Hydrazide analogue was synthesized using solid phase. For In labeling, synthesized peptide was followed by conjugation with DOTA using pSCN-Bn-DOTA. The conjugated Triptorelin-Hydrazide was labeled with 500-550 MBq of In-chloride (in 0.2 M HCl). At optimized conditions after labeling, radio-chromatography showed radiochemical purity of approximately equal to 98% (RTLC) and greater than 95% (HPLC). The serum stability of the tracer was determined up to 24 hr. Binding affinities of Triptorelin-Hydrazide analogue were determined in a binding assay for both human and rat GnRH receptors. For in vivo studies, In-peptide was injected intravenously via the tail vein into rats and significant ovaries uptake consist with reported GnRH receptor mappings. In vitro radioligand binding assays performed with GnRHR-expressing human cell lines using I-Triptorelin as the standard radioligand. The quantities of internalization efficiency and receptor affinity of the new radioligand were IC = 0.20 ± 0.04 nM vs 0.13 ± 0.08 nM for Triptorelin and internalization: 3.5 ± 0.9% at 1 hr and 12.8 ± 1.8% at 4 hr of the internal reference.

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“…In this study we used linear salmon and chicken GnRH as control to test the activity of the synthesized GnRH analogue in goldfish in terms of gonadotropin subunit gene expression. This well characterized model system has previously been used to evaluate the activity of various GnRH analogues. − …”

mentioning

confidence: 99%

“…Furthermore, in this structure, important residues for activity such as Trp, His, Tyr remain intact and clustered for triggering agonist activity as native GnRH. Design was based on previous SAR studies and on the ring cluster conformational model suggested for this peptide. , …”

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confidence: 99%

Design, Synthesis, and Molecular Modeling of a Novel Amide-Linked Cyclic GnRH Analogue Cyclo(4−9)[Lys⁴,d-Trp⁶,Glu⁹]GnRH: Stimulation of Gonadotropin Gene Expression

et al. 2005

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This report describes the rational design, synthesis, and pharmacological properties of an amide-linked cyclic analogue of gonadotropin-releasing hormone (GnRH) namely Cyclo(4-9)[Lys(4),d-Trp(6),Glu(9)]GnRH. The conformationally restricted analogue is characterized by reduced flexibility of the peptide strand due to the introduction of a beta-turn mimetic through 4,9 residue amide cyclization. The cyclic analogue was found to stimulate gonadotropin gene expression in the goldfish pituitary with similar potency compared to two native forms of GnRH. Simulation studies based on ROE connectivities in linear GnRH and potency of cyclic analogue supports the His(2), Trp(3), Tyr(5) clustering considered important for triggering receptor activation.

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Design and synthesis of a gonadotropin-releasing hormone (GnRH) analogue, [Tyr(OMe)5,d-Glu6,Aze9]GnRH: Receptor binding, gonadotropin release and ovulation studies

Cited by 7 publications

References 11 publications

Preclinical evaluation of new GnRH‐I receptor radionuclide therapy with ¹⁷⁷Lu‐peptide tracer

Preclinical evaluation of new GnRH‐I receptor radionuclide therapy with ¹⁷⁷Lu‐peptide tracer

Preparation of a radiolabeled GnRH‐I analogue derivative with ¹¹¹In as a new anti‐proliferative agent

Design, Synthesis, and Molecular Modeling of a Novel Amide-Linked Cyclic GnRH Analogue Cyclo(4−9)[Lys⁴,d-Trp⁶,Glu⁹]GnRH: Stimulation of Gonadotropin Gene Expression

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Design and synthesis of a gonadotropin-releasing hormone (GnRH) analogue, [Tyr(OMe)5,d-Glu6,Aze9]GnRH: Receptor binding, gonadotropin release and ovulation studies

Cited by 7 publications

References 11 publications

Preclinical evaluation of new GnRH‐I receptor radionuclide therapy with 177Lu‐peptide tracer

Preclinical evaluation of new GnRH‐I receptor radionuclide therapy with 177Lu‐peptide tracer

Preparation of a radiolabeled GnRH‐I analogue derivative with 111In as a new anti‐proliferative agent

Design, Synthesis, and Molecular Modeling of a Novel Amide-Linked Cyclic GnRH Analogue Cyclo(4−9)[Lys4,d-Trp6,Glu9]GnRH: Stimulation of Gonadotropin Gene Expression

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Preclinical evaluation of new GnRH‐I receptor radionuclide therapy with ¹⁷⁷Lu‐peptide tracer

Preclinical evaluation of new GnRH‐I receptor radionuclide therapy with ¹⁷⁷Lu‐peptide tracer

Preparation of a radiolabeled GnRH‐I analogue derivative with ¹¹¹In as a new anti‐proliferative agent

Design, Synthesis, and Molecular Modeling of a Novel Amide-Linked Cyclic GnRH Analogue Cyclo(4−9)[Lys⁴,d-Trp⁶,Glu⁹]GnRH: Stimulation of Gonadotropin Gene Expression