Synthesis and evaluation of an [18F] labelled imidazopyridine, for the study of the peripheral benzodiazepine binding sites using PET

Abstract

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Objectives: The purpose of this study was to synthesise and evaluate the F-18 imidazopyridine 2-(2-(4-(3-fluoropropoxy)phenyl)-6,8-dichloroimidazo[1,2-a]pyridin-3-yl)-N-methyl-N-phenylacetamide 1 as a potential tracer for the study of PBBS using PET. Methods: [18F]1 has been prepared by nucleophilic substitution of the tosylethyloxy precursor with 18F-fluoride in the presence of K222, K2CO3 in ACN at 100°C for 5 mins followed by RP-HPLC purification. The biodistribution of [18F]1 was performed in SD rats and brain and peripheral tissues were analysised at 15, 30 min, 1, and 4 h p.i. The specificity and selectivity of the tracer was assessed by pre-treatment with the PBBS ligands PK11195 and Ro 5-4864 and with Flumazenil for CBR at 1 mg/kg 5 min prior to injection of [18F]1. Results: In vitro binding of 1 indicated an IC50 of 7.4 nM for PBBS and >4000 nM for the CBR. [18F]1 was synthesised in 40-55 % radiochemical yield non-decay corrected and with > 95 % radiochemical purity. The specific activity ranged from 37-80 GBq/μmol (non optimised). Biodistribution studies indicated uptake of [18F]1 in tissue expressing PBBS. The adrenals showed high uptake, increasing from 9% ID/g at 30 min p.i to 11% at 4 h. In the kidneys the activity peaked at 15 min p.i.(5%) and decreased over time to 3.6% at 4h. In the heart the uptake was maintained at 7% througout the experiment (15 min to 4 h). Bone uptake ranged from 1% (at 15 min) to 2.9% at 4h. [18F]1 readily penetrated the blood-brain barrier with uptake in the olfactory regions ranging from an initial 0.66% at 15 min to 0.26% at 4 h p.i. The concentration in the blood was significantly lower than the brain regions (0.7% at 15 min to 0.15% at 4 h). Pre-treatment with PK 11195, Ro 5-4864 and non radioactive analogue 1 significantly decreased the uptake in the brain and peripheral organs except in the adrenals which showed a modest increase or no change in uptake. Flumazenil had no effect in the uptake of [18F]1 in the brain or peripheral organs. Conclusions: These results demonstrate the specific PBBS uptake of [18F]1 in vivo. Therefore [18F]1 warrants further investigation as a potential PET tracer for the PBBS.