Decreased defluorination using the novel beta-cell imaging agent [(18)F]FE-DTBZ-d4 in pigs examined by PET

BACKGROUND: Fluorine-18 dihydrotetrabenazine [DTBZ] analogues, which selectively target the vesicular monoamine transporter 2 [VMAT2], have been extensively studied for in vivo quantification of beta cell mass by positron-emission tomography [PET]. This study describes a novel deuterated radioligand [(18)F]fluoroethyl [FE]-DTBZ-d4, aimed to increase the stability against in vivo defluorination previously observed for [(18)F]FE-DTBZ. METHODS: [(18)F]FE-DTBZ-d4 was synthesized by alkylation of 9-O-desmethyl-(+)-DTBZ precursor with deuterated [(18)F]FE bromide ([(18)F]FCD(2)CD(2)Br). Radioligand binding potential [BP] was assessed by an in vitro saturation homogenate binding assay using human endocrine and exocrine pancreatic tissues. In vivo pharmacokinetics and pharmacodynamics [PK/PD] was studied in a porcine model by PET/computed tomography, and the rate of defluorination was quantified by compartmental modeling. RESULTS: [(18)F]FE-DTBZ-d4 was produced in reproducible good radiochemical yield in 100 ± 20 min. Radiochemical purity of the formulated product was > 98% for up to 5 h with specific radioactivities that ranged from 192 to 529 GBq/μmol at the end of the synthesis. The in vitro BP for VMAT2 in the islet tissue was 27.0 ± 8.8, and for the exocrine tissue, 1.7 ± 1.0. The rate of in vivo defluorination was decreased significantly (k(defluorination )= 0.0016 ± 0.0007 min(-1)) compared to the non-deuterated analogue (k(defluorination )= 0.012 ± 0.002 min(-1)), resulting in a six fold increase in half-life stability. CONCLUSIONS: [(18)F]FE-DTBZ-d4 has similar PK and PD properties for VMAT2 imaging as its non-deuterated analogue [(18)F]FE-DTBZ in addition to gaining significantly increased stability against defluorination. [(18)F]FE-DTBZ-d4 is a prime candidate for future preclinical and clinical studies on focal clusters of beta cells, such as in intramuscular islet grafts.