Two F-18 radiochemistry methods to synthesize a promising transient receptor potential canonical 5 (TRPC5) radioligand

Abstract

TRPC5 is a member of the mammalian transient receptor potential (TRP) channel superfamily and it has been implicated in various physiological and pathological mechanisms of neurological and psychiatric diseases. Fluorine-18 is one of the most widely used radionuclides for PET imaging due to its favorable chemical characteristics and nuclear-physical properties. Herein, we describe two complementary radiosynthetic approaches and preliminary in vivo evaluation for [¹⁸F]TZ78141 as a novel and promising fluorine-18 labeled radiotracer for imaging TRPC5. The latter strategy employed a ruthenium-mediated radiofluorination method, facilitating the rapid synthesis of the desired radiotracer with substantial advantages in simplicity and efficiency.

Keywords: Fluorine -18; PET tracer; Radiolabeling; TRPC5.

Fig. 1.

Representative structures of TRPC5 radiotracers.

Fig. 2.

Two different approaches for the radiosynthesis of [¹⁸F]TZ78141.

Fig. 3.

Radiosynthesis of [¹⁸F]TZ78141 by linear synthesis.

Fig. 4.

Radiosynthesis of [¹⁸F]TZ78141 by Ru-mediated deoxyfluorination.

Fig. 5.

Representative HPLC chromatogram for separating [¹⁸F]TZ78141 by Ru-mediated deoxyfluorination. Top: UV absorbance at 254 nm; Bottom: radioactivity detection. The retention time of the product was 30–32 min.

Fig. 6.

Time-activity curve of radiotracers for microPET study in the whole brain of a nonhuman primate. SUV: standardized uptake value.

Scheme 1.

Synthesis route of amine precursor 11 and phenol precursor 12, reference standard TZ78141.