Ramatroban-Based Analogues Containing Fluorine Group as Potential 18F-Labeled Positron Emission Tomography (PET) G-Protein Coupled Receptor 44 (GPR44) Tracers.

Lina A Huang,Fouad Kandeel,Jui Tu,Kelly X Huang,Junfeng Li

doi:10.3390/molecules26051433

Abstract

Diabetes remains one of the fastest growing chronic diseases and is a leading source of morbidity and accelerated mortality in the world. Loss of beta cell mass (BCM) and decreased sensitivity to insulin underlie diabetes pathogenesis. Yet, the ability to safely and directly assess BCM in individuals with diabetes does not exist. Measures such as blood glucose provide only a crude indirect picture of beta cell health. PET imaging could, in theory, allow for safe, direct, and precise characterization of BCM. However, identification of beta cell-specific radiolabeled tracers remains elusive. G-protein coupled receptor 44 (GPR44) is a transmembrane protein that was characterized in 2012 as highly beta cell-specific within the insulin-positive islets of Langerhans. Accordingly, radiolabeling of existing GPR44 antagonists could be a viable method to accelerate PET tracer development. The present study aims to evaluate and summarize published analogues of the GPR44 antagonist ramatroban to develop 18F-labeled PET tracers for BCM analysis. The 77 corresponding ramatroban analogues containing a fluorine nuclide were characterized for properties including binding affinity, selectivity, and pharmacokinetic and metabolic profile, and 32 compounds with favorable properties were identified. This review illustrates the potential of GPR44 analogues for the development of PET tracers.

Highlights

Type 1 diabetes (T1D) and type 2 diabetes (T2D) are two primary diagnoses, and pathology of both is caused by insulin dysregulation and subsequent hyperglycemia
The present paper aims to summarize current ramatroban-based G-protein coupled receptor 44 (GPR44) ligands containing a fluorine group and evaluate their potential as targets for the development of novel 18F-labeled Positron Emission Tomography (PET) tracers
Of note is that FLIPR assays against mouse, rat, guinea pig, and dog GPR44 revealed that all compounds exhibited antagonistic effects when binding to GPR44 with comparable potencies, except for compound 68, which were identified as partial agonists on the mouse and the guinea pig receptor

Summary

Introduction

Diabetes is a chronic disease characterized by the disruption of glucose homeostasis and a major cause of limb amputation, stroke, renal failure, and heart disease. Compound 3, which contained a 2-F phenyl group, had the lowest Ki value but still displayed an undesirable binding affinity (Figure 2) Overall, these compounds did not exhibit optimal properties desirable for a selective GPR44 PET tracer. The modifications of ramatroban included decreasing the chain length by one carbon to replace the propanoic acid group with an acetic acid group (compound 12), adding a methyl group to the cyclohexane group (compound 20), adding a phenyl group to the cyclohexane group (compound 21), and adding one carbon to the cyclohexane group to create a 7-membered ring (compound 24) These compounds can be considered for further development as GPR44 PET tracers. Due to favorable selectivity for GPR44 over TP and DP1, TM-30642, TM-30643, and TM-30089 can all be considered promising candidates for developing GPR44 PET tracers

Merck Analogues MK-7246

Radiosynthesis Strategies for 18F-Labeled Ramatroban-Based Analogues

Findings

Conclusions