Molecules (Oct 2023)

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

  • Talakad G. Lohith,
  • Charalambos Kaittanis,
  • Anthony P. Belanger,
  • Shin Hye Ahn,
  • Phil Sandoval,
  • Lawrence Cohen,
  • Girija Rajarshi,
  • Wanida Ruangsiriluk,
  • Rizwana Islam,
  • Christopher T. Winkelmann,
  • Paul McQuade

DOI
https://doi.org/10.3390/molecules28207144
Journal volume & issue
Vol. 28, no. 20
p. 7144

Abstract

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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.

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