Synthesis of Novel EP2 Prostaglandin Antagonists for Optimal Blood-Brain Barrier Permeation as Radioligands Restricted; Files Only

Morin, Emile (Spring 2022)

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The neuroinflammatory pathway regulated by the EP2 prostaglandin receptor is a key target in pharmacological studies. In order to demonstrate the mechanism of action in novel EP2 antagonist compounds, PET studies are utilized to showcase the binding to the target organ regions. Novel EP2 antagonists were synthesized to provide an optimal partition coefficient to permeate across the blood-brain barrier while containing fluorine that are accessible for PET studies. The synthesis of four derivative compounds based upon a model compound were developed in this study. The derivative synthesis was centered around the modification of key target function groups in locations that would minimally affect the reactivity and selectivity. The target compounds synthesized and partially synthesized were aimed with modifying functional groups to lower the Log P for optimal values in relation to membrane permeation. Resulting in two successfully synthesized possible EP2 receptor antagonists compounds with an experimental LogP value below 2.0.

Table of Contents

Abstract    1

Introduction  2

Methods 9 

Discussion 21 

Future Studies 25

Supplemental Information/Data 31 

Acknowledgements 40

References 41


Figure 1 - Target compounds for EP2 prostaglandin receptor inhibition 8

Figure 2 - LCMS data for TG13-154 38

Figure 3 - LCMS data for TG13-210 38

Figure 4 - HPLC purity analysis for final compounds 39


Scheme 1 - Target compound A reaction pathway 9

Scheme 2 - Target compound B reaction pathway 11

Scheme 3 - Target compound C reaction pathway 16

Scheme 4 - Target compound D reaction pathway 15

Scheme 5 - 4-fluoromethyl-piperidine reaction pathway 18


Table 1 - Calculated and experimental LogP values of target compounds 20

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