Objectives:  Upon binding succinate, the G-protein coupled receptor GPR91 initiates a signal cascade leading to the activation of the renin-angiotensin system (RAS). This mechanism of RAS activation may contribute to the progression of renovascular hypertension and diabetic nephropathy. A radiotracer targeting GPR91 will allow investigators to probe these disease processes in vivo and potentially develop novel diagnostic or therapeutic strategies. In the presented work, our goal was to further the development of the first GPR91 radiotracer by designing and preparing a series of fluorine-containing compounds based on high-affinity GPR91 inhibitors (Bhuniya, et al.; Bioorg Med Chem Lett, 2011 , p. 3596).Methods:  The steric and electronic properties of high-affinity GPR91 ligands were examined (Avogadro 1.1.0) to assist the design of fluorine-containing compounds with comparable pharmacological properties. The development of an appropriate synthetic pathway for the target compounds focused on the inclusion of a final 18F labeling step and the purification of the radioactive products.Results:  A small series of fluorine-containing compounds was designed. A 6-step synthetic pathway was developed to conclude with an 18F radiolabeling reaction (nucleophilic aromatic substitution of a nitro group with tetrabutylammonium fluoride). An HPLC method for the purification and characterization of 18F species was developed using a nonradioactive 19F analog. Each prepared fluorine compound was obtained in high purity and fully characterized by NMR, HRMS, EA, and HPLC.Conclusion:  Candidates for the first GPR91 radiotracer have been designed and synthesized. Radiolabeling and purification methods required for 18F radiotracer preparation for in vivo studies have been established. Results from consequent in vitro studies will identify the best candidate of this series for 18F radiolabeling and in vivo evaluation.

Development of an <sup>18</sup>F radiotracer targeting GPR91

248th National Meeting (2014)

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Development of an 18F radiotracer targeting GPR91

Development of an ¹⁸F radiotracer targeting GPR91