Dynamics of the Ghrelin/Growth Hormone Secretagogue Receptor System in the Human Heart Before and After Cardiac Transplantation

Sullivan, Rebecca; Randhawa, Varinder K.; Stokes, Anne; Wu, Daniel; Lalonde, Tyler; Kiaii, Bob; Luyt, Leonard G.; Wisenberg, Gerald; Dhanvantari, Savita

doi:10.1101/362525

Cited by 2 publications

(2 citation statements)

References 37 publications

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“…GHSR expression in healthy, developing, and diseased heart models, as well as human hearts. 78,79 The increasing promise of fluorescently labeled ghrelin analogues contributed to a desire to develop ghrelin imaging probes with improved metabolic stability. Recently, ghrelin (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) was cyclized through a lactam bridge between Glu 12 and Lys 16 for improved stability of secondary structure, and labeled with the SulfoCy5 dye off the C-terminal lysine residue (Figure 5).…”

Section: Molecular Imaging Agents Based On Ghrelinmentioning

confidence: 99%

A Decade’s Progress in the Development of Molecular Imaging Agents Targeting the Growth Hormone Secretagogue Receptor

Childs

Luyt

2020

Mol Imaging

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The growth hormone secretagogue receptor 1a (GHSR), also called the ghrelin receptor, is a G protein-coupled receptor known to play an important metabolic role in the regulation of various physiological processes, including energy expenditure, growth hormone secretion, and cell proliferation. This receptor has been implicated in numerous health issues including obesity, gastrointestinal disorders, type II diabetes, and regulation of body weight in patients with Prader-Willi syndrome, and there has been growing interest in studying its mechanism of behavior to unlock further applications of GHSR-targeted therapeutics. In addition, the GHSR is expressed in various types of cancer including prostate, breast, and testicular cancers, while aberrant expression has been reported in cardiac disease. Targeted molecular imaging of the GHSR could provide insights into its role in biological processes related to these disease states. Over the past decade, imaging probes targeting this receptor have been discovered for the imaging modalities PET, SPECT, and optical imaging. High-affinity analogues of ghrelin, the endogenous ligand for the GHSR, as well as small molecule inhibitors have been developed and evaluated both in vitro and in pre-clinical models. This review provides a comprehensive overview of the molecular imaging agents targeting the GHSR reported to the end of 2019.

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Section: Molecular Imaging Agents Based On Ghrelinmentioning

confidence: 99%

A Decade’s Progress in the Development of Molecular Imaging Agents Targeting the Growth Hormone Secretagogue Receptor

Childs

Luyt

2020

Mol Imaging

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“…Ghrelin actions are mediated via activation of the G protein coupled receptor (GPCR) growth hormone secretagogue receptor type 1a (GHS‐R1a) . It was originally reported that GHS‐R1a was found within the pituitary gland and hypothalamus, but recent work has revealed a more widespread expression in other tissues, including the brain and heart . GHS‐R1a is also reported to be differentially expressed in certain cancer cells.…”

Section: Figurementioning

confidence: 99%

Single Amino Acid Replacement in G‐7039 Leads to a 70‐fold Increase in Binding toward GHS‐R1a

et al. 2019

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The growth hormone secretagogue receptor type 1a (GHS‐R1a) is a class A rhodopsin‐like G protein coupled receptor (GPCR) that is expressed in a variety of human tissues and is differentially expressed in benign and malignant prostate cancer. Previously, the peptidomimetic [1‐Nal4,Lys5(4‐fluorobenzoyl)]G‐7039 was designed as a molecular imaging tool for positron emission tomography (PET). However, this candidate was a poor binder (IC50=69 nm), required a lengthy four‐step radiosynthesis, and had a cLogP above 8. To address these challenges, we now report on changes targeted at the 4th position of G‐7039. A 2‐fluoropropionic acid (2‐FPA) group was added on to Lys5 to determine the potential binding affinity of the [18F]‐2‐FP radiolabeled analogue, which could be prepared by simplified radiochemistry. Lead candidate [Tyr4,Lys5(2‐fluoropropionyl)]G‐7039 exhibited an IC50 of 0.28 nm and low picomolar activity toward GHS‐R1a. Molecular docking revealed a molecular basis for this picomolar affinity.

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Dynamics of the Ghrelin/Growth Hormone Secretagogue Receptor System in the Human Heart Before and After Cardiac Transplantation

Abstract: we examined tissue ghrelin-GHSR levels as specific markers of cardiac dysfunction in patients 8 who underwent cardiac transplantation. 9 Methods and Results 10

Cited by 2 publications

References 37 publications

A Decade’s Progress in the Development of Molecular Imaging Agents Targeting the Growth Hormone Secretagogue Receptor

A Decade’s Progress in the Development of Molecular Imaging Agents Targeting the Growth Hormone Secretagogue Receptor

Single Amino Acid Replacement in G‐7039 Leads to a 70‐fold Increase in Binding toward GHS‐R1a

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