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

Abstract

Recently, growing evidence of the relationship between G-protein coupled receptor 44 (GPR44) and the inflammation-cancer system has garnered tremendous interest, while the exact role of GPR44 has not been fully elucidated. Currently, there is a strong and urgent need for the development of non-invasive in vivo GPR44 positron emission tomography (PET) radiotracers that can be used to aid the exploration of the relationship between inflammation and tumor biologic behavior. Accordingly, the choosing and radiolabeling of existing GPR44 antagonists containing a fluorine group could serve as a viable method to accelerate PET tracers development for in vivo imaging to this purpose. The present study aims to evaluate published (2000-present) indole-based and cyclopentenyl-indole-based analogues of the GPR44 antagonist to guide the development of fluorine-18 labeled PET tracers that can accurately detect inflammatory processes. The selected analogues contained a crucial fluorine nuclide and were characterized for various properties including binding affinity, selectivity, and pharmacokinetic and metabolic profile. Overall, 26 compounds with favorable to strong binding properties were identified. This review highlights the potential of GPR44 analogues for the development of PET tracers to study inflammation and cancer development and ultimately guide the development of targeted clinical therapies.

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].…”

“…This strategy has been validated as a feasible and successful approach. Based on this efficient and effective screening method, we summarized and recommended a series of 19 F GPR44 ligands as a potential pool for future PET radiotracer development in our previous review paper [30,31]. However, we addressed a significant concern in the previous section: the presence of one carboxyl acid group in a number of these GPR44 analogues, which could cause diminished radiochemical yields and even indirect nucleophilic radiofluorination (such as [ 18 F]TM30089 and [ 18 F]MK-7246).…”

“…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].…”

Monofluoromethylation of N-Heterocyclic Compounds

“…The introduction of fluorine atoms is an effective approach to the development of new drugs and agrochemicals [9][10][11][12][13][14][15][16]. Fluorine atoms increase resistance to biological processes and permeability through cell membranes, provide good binding to enzyme targets and increase target selectivity.…”