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

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.

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

“…In our previous report, we summarized ramatroban-based GPR44 ligands containing a fluorine group and assessed their potential as targets for the development of novel 18 F-labeled PET tracers [60]. The present paper aims to continue to summarize current indole-based potential GPR44 analogues and cyclopentenylindole-based potential GPR44 analogues containing a fluorine group and evaluate their potential as treatment targets, to provide a more complete map of current GPR44 analogues containing a fluorine group as options for cancer-related inflammation PET tracer development.…”

“…In this section, we evaluate a series of known analogues containing an isolated indole group not fused with other rings, with the exception of those already discussed as ramatroban ( Figure 1 ) and ramatroban-based analogues [ 60 ]. These compounds could be considered as analogues of the well-characterized GPR44 antagonist indomethacin ( Figure 1 ), a nonsteroidal anti-inflammatory drug (NSAID) commonly used to reduce fever, pain, stiffness, and swelling from inflammation [ 61 ].…”

One-Step Automatic Radiosynthesis and Evaluation of [18F]TM-30089 as GPR44 Radiotracer

“…There existed a number of GPR44 ligands containing fluorine groups that could serve as a source for the development of potentially 18 F-labeled GPR44 radiotracers [30,31]. ramatroban (Figure 1), also known as BAY-u 3405, was first described as an antagonist of the thromboxane receptor (TP) and was later shown to selectively bind as an antagonist to GPR44 as well [33].…”

“…Moreover, by the radioisotopic replacement, they ideally preserved their pharmacokinetic properties. In the scope of our present study, TM-30089 ({3-[(4-fluoro-benzenesulfonyl)methyl-amino]-1,2,3,4-tetrahydro-carbazol-9-yl}acetic acid) containing a fluorine nuclide, was selected from an initial pool [30,31]. TM-30089 as a GPR44 antagonist (Figure 1), exhibited the optimal measures of high affinity, specificity, lipophilicity, intrinsic clearance, and bioavailability levels [32].…”

“…TM-30089 as a GPR44 antagonist (Figure 1), exhibited the optimal measures of high affinity, specificity, lipophilicity, intrinsic clearance, and bioavailability levels [32]. The potent binding and negligible off-target activity of TM-30089 made it an especially ideal candidate for developing a GRP44 radiotracer [30]. A challenge arose from the presence of a carboxylic acid group in a number of GPR44 antagonists containing a fluorine nuclide (such as TM-30089), culminating in notably diminished radiochemical yield.…”