Radiosynthesis and Early Evaluation of a Positron Emission Tomography Imaging Probe [ 18 F]AGAL Targeting Alpha-Galactosidase A Enzyme for Fabry Disease.

Autor: Lohith, Talakad G., Kaittanis, Charalambos, Belanger, Anthony P., Ahn, Shin Hye, Sandoval, Phil, Cohen, Lawrence, Rajarshi, Girija, Ruangsiriluk, Wanida, Islam, Rizwana, Winkelmann, Christopher T., McQuade, Paul
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Zdroj: Molecules; Oct2023, Vol. 28 Issue 20, p7144, 13p
Abstrakt: Success of gene therapy relies on the durable expression and activity of transgene in target tissues. In vivo molecular imaging approaches using positron emission tomography (PET) can non-invasively measure magnitude, location, and durability of transgene expression via direct transgene or indirect reporter gene imaging in target tissues, providing the most proximal PK/PD biomarker for gene therapy trials. Herein, we report the radiosynthesis of a novel PET tracer [18F]AGAL, targeting alpha galactosidase A (α-GAL), a lysosomal enzyme deficient in Fabry disease, and evaluation of its selectivity, specificity, and pharmacokinetic properties in vitro. [18F]AGAL was synthesized via a Cu-catalyzed click reaction between fluorinated pentyne and an aziridine-based galactopyranose precursor with a high yield of 110 mCi, high radiochemical purity of >97% and molar activity of 6 Ci/µmol. The fluorinated AGAL probe showed high α-GAL affinity with IC50 of 30 nM, high pharmacological selectivity (≥50% inhibition on >160 proteins), and suitable pharmacokinetic properties (moderate to low clearance and stability in plasma across species). In vivo [18F]AGAL PET imaging in mice showed high uptake in peripheral organs with rapid renal clearance. These promising results encourage further development of this PET tracer for in vivo imaging of α-GAL expression in target tissues affected by Fabry disease. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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