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.

Keywords: 18F-labeling; CRTH2; G-protein coupled receptor 44 (GPR44); PET probes; beta cell imaging; beta cell mass (BCM); diabetes; pancreatic islets; positron emission tomography (PET); ramatroban analogues.

Figure 1

Molecular structures of fevipiprant, TM-30089, ramatroban, [¹¹C]AZ12204657 and [¹¹C]MK-7246.

Figure 2

Molecular structures of compounds 1–6.

Figure 3

Molecular structures of compounds 7–19.

Figure 4

Molecular structures of compounds 20–24.

Figure 5

Molecular structures of TM-30642, TM-30643 and TM-30089.

Figure 6

Molecular structure and synthesis of MK-7246 from ramatroban.

Figure 7

Molecular structures of compounds 25 and 26.

Figure 8

Molecular structures of compounds 27 and 28.

Figure 9

Molecular structures of compounds 29–39.

Figure 10

Molecular structures of compounds 40 and 41.

Figure 11

Molecular structures of compounds 42–47.

Figure 12

Molecular structures of compounds 48–55.

Figure 13

Molecular structures of compounds 56–61.

Figure 14

Metabolites of setipiprant [83]. The asterisk (*) denotes the position of the ¹⁴C atom in [¹⁴C]setipiprant.

Figure 15

Molecular structures of setipiprant and compounds 64–74.

Figure 16

Molecular structure of CT-133 (compound 45).

Scheme 1

Radiosynthesis of [¹⁸F]-TM-30089.