Dataset Information

Synthesis and Evaluation of ¹⁸F-Labeled Peptide for Gonadotropin-Releasing Hormone Receptor Imaging.

ABSTRACT: The gonadotropin-releasing hormone (GnRH) receptor is overexpressed in the majority of tumors of the human reproductive system. The purpose of this study was to develop an ¹⁸F-labeled peptide for tumor GnRH receptor imaging. In this study, the GnRH (pGlu¹-His²-Trp³-Ser⁴-Tyr⁵-Gly⁶-Leu⁷-Arg⁸-Pro⁹-Gly¹⁰-NH₂) peptide analogues FP-d-Lys⁶-GnRH (FP?=?2-fluoropropanoyl) and NOTA-P-d-Lys⁶-GnRH (P?=?ethylene glycol) were designed and synthesized. The IC₅₀ values of FP-d-Lys⁶-GnRH and NOTA-P-d-Lys⁶-GnRH were 2.0?nM and 56.2?nM, respectively. 4-Nitrophenyl-2-[¹⁸F]fluoropropionate was conjugated to the ?-amino group of the d-lysine side chain of d-Lys⁶-GnRH to yield the new tracer [¹⁸F]FP-d-Lys⁶-GnRH with a decay-corrected yield of 8?±?3% and a specific activity of 20-100?GBq/µmol (n=6). Cell uptake studies of [¹⁸F]FP-d-Lys⁶-GnRH in GnRH receptor-positive PC-3?cells and GnRH receptor-negative CHO-K1 cells indicated receptor-specific accumulation. Biodistribution and PET studies in nude mice bearing PC-3 xenografted tumors showed that [¹⁸F]FP-d-Lys⁶-GnRH was localized in tumors with a higher uptake than in surrounding muscle and heart tissues. Furthermore, the metabolic stability of [¹⁸F]FP-d-Lys⁶-GnRH was determined in mouse blood and PC-3 tumor homogenates at 1?h after tracer injection. The presented results indicated a potential of the novel tracer [¹⁸F]FP-d-Lys⁶-GnRH for tumor GnRH receptor imaging.

SUBMITTER: Huang S

PROVIDER: S-EPMC6431521 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Synthesis and Evaluation of 18F-Labeled Peptide for Gonadotropin-Releasing Hormone Receptor Imaging.

Huang Shun S Li Hongsheng H Han Yanjiang Y Fu Lilan L Ren Yunyan Y Zhang Yin Y Li Youcai Y Sun Penghui P Wang Meng M Wu Hubing H Wang Quanshi Q Hu Kongzhen K

Contrast media & molecular imaging 20190307

The gonadotropin-releasing hormone (GnRH) receptor is overexpressed in the majority of tumors of the human reproductive system. The purpose of this study was to develop an 18F-labeled peptide for tumor GnRH receptor imaging. In this study, the GnRH (pGlu1-His2-Trp3-Ser4-Tyr5-Gly6-Leu7-Arg8-Pro9-Gly10-NH2) peptide analogues FP-d-Lys6-GnRH (FP = 2-fluoropro ...[more]

PMID: 30983920

Similar Datasets

Project description:Gonadotropin-releasing hormone acts via cell surface receptors but most human (h) GnRH receptors (GnRHRs) are intracellular. A membrane-permeant nonpeptide antagonist [(2S)-2-[5-[2-(2-axabicyclo[2.2.2]oct-2-yl)-1,1-dimethy-2-oxoethyl]-2-(3,5-dimethylphenyl)-1H-indol-3-yl]-N-(2-pyridin-4-ylethyl)propan-1-amine (IN3)] increases hGnRHR expression at the surface, apparently by facilitating its exit from the endoplasmic reticulum. Here we have quantified GnRHR by automated imaging in HeLa cells transduced with adenovirus expressing hemagglutinin-tagged GnRHR. Consistent with an intracellular site of action, IN3 increases cell surface hGnRHR, and this effect is not blocked or mimicked by membrane-impermeant peptide antagonists [Ac-D2Nal-D4Cpa-D3Pal-Ser-Tyr-d-Cit-Leu-Arg-Pro-d-Ala-NH(2) (cetrorelix) and antide]. However, when the C-terminal tail of a Xenopus (X) GnRHR was added (h.XGnRHR) to increase expression, both peptides further increased cell surface GnRHR. Cetrorelix also synergized with IN3 to increase expression of hGnRHR and a G-protein coupling-deficient mutant (A261K-hGnRHR). Cetrorelix also increased cell surface expression of hGnRHR, h.XGnRHR, and mouse GnRHR in gonadotrope-lineage LbetaT2 cells, and in HeLa cells it slowed h.XGnRHR internalization (measured by receptor-mediated antihemagglutinin uptake). Thus cetrorelix has effects other than GnRHR blockade; it acts as an inverse agonist in internalization assays, supporting the potential importance of ligand-biased efficacy at GnRHR. We also developed an imaging assay for GnRH function based on Ca(2+)-dependent nuclear translocation of a nuclear factor of activated T cells reporter. Using this in HeLa and LbetaT2 cells, IN3 and cetrorelix behaved as competitive antagonists when coincubated with GnRH, and long-term pretreatment (16 h) with IN3 reduced its effectiveness as an inhibitor whereas pretreatment with cetrorelix increased its inhibitory effect. This distinction between peptide and nonpeptide antagonists may prove important for therapeutic applications of GnRH antagonists.

Project description:PurposeMetabotropic glutamate receptor 2 (mGluR2) has been implicated in various psychiatric and neurological disorders, such as schizophrenia and Alzheimer's disease. We have previously developed [11C]7 as a PET radioligand for imaging mGluR2. Herein, [18F]JNJ-46356479 ([18F]8) was synthesized and characterized as the first 18F-labeled mGluR2 imaging ligand to enhance diagnostic approaches for mGluR2-related disorders.ProceduresJNJ-46356479 (8) was radiolabeled via the copper (I)-mediated radiofluorination of organoborane 9. In vivo PET imaging experiments with [18F]8 were conducted first in C57BL/6 J mice and Sprague-Dawley rats to obtain whole body biodistribution and brain uptake profile. Subsequent PET studies were done in a cynomolgus monkey (Macaca fascicularis) to investigate the uptake of [18F]8 in the brain, its metabolic stability, as well as pharmacokinetic properties.ResultsJNJ-46356479 (8) exhibited excellent selectivity against other mGluRs. In vivo PET imaging studies showed reversible and specific binding characteristic of [18F]8 in rodents. In the non-human primate, [18F]8 displayed good in vivo metabolic stability, excellent brain permeability, fast and reversible kinetics with moderate heterogeneity across brain regions. Pre-treatment studies with compound 7 revealed time-dependent decrease of [18F]8 accumulation in mGluR2 rich regions based on SUV values with the highest decrease in the nucleus accumbens (18.7 ± 5.9%) followed by the cerebellum (18.0 ± 7.9%), the parietal cortex (16.9 ± 7.8%), and the hippocampus (16.8 ± 6.9%), similar to results obtained in the rat studies. However, the volume of distribution (VT) results derived from 2T4k model showed enhanced VT from a blocking study with compound 7. This is probably because of the potentiating effect of compound 7 as an mGluR2 PAM as well as related non-specific binding in the tissue data.Conclusions[18F]8 readily crosses the blood-brain barrier and demonstrates fast and reversible kinetics both in rodents and in a non-human primate. Further investigation of [18F]8 on its binding specificity would warrant translational study in human.

Dataset Information

Synthesis and Evaluation of ¹⁸F-Labeled Peptide for Gonadotropin-Releasing Hormone Receptor Imaging.

Publications

Synthesis and Evaluation of <sup>18</sup>F-Labeled Peptide for Gonadotropin-Releasing Hormone Receptor Imaging.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets