Development of a ¹⁸F labeled acetylcholinesterase ligand as tracer as a radiopharmaceutical for diagnosis of Alzheimer`s disease.

Objectives Acetylcholinesterase (AChE) is a valuable CNS PET imaging target. The aim of this work is to develop a potential ¹⁸F labelled radiopharmaceutical as marker of the activity of acetylcholinesterase (AChE) in Alzheimer`s disease (AD).

Methods New AChE inhibitors were identified in vitro and compound 3-(benzyloxy)-1-(5-bromopentyl)-5-nitro-1H-indazole (IND) was selected for labeling. Labeling was performed by substitution of the Br in the IND by ¹⁸F for obtaining [¹⁸F]IND. The precursor, dissolved in DMSO was treated with K¹⁸F in presence of Kryptofix-222 in the nucleophilic synthesis module Tracerlab FXFN GE. The radiochemical purity was assessed by means of HPLC (the method was optimized). Bio-distribution studies were conducted in normal animals (Swiss female 2-month-old mice).

Results The best results were obtained in conditions 2 (see Table 1). The labelled compound was obtained with a yield of 25.0±5.5%(n = 5) (not decay corrected (NCD)) and radiochemical purity of 98.3±0.3%, (n=5). Residual solvents are below in the USP defined limit. The distribution in normal animals revealed the characteristic profile of a highly lipophilic compound, high hepatobiliar elimination (22.6 ± 0.3 after 30 minutes, n=3) and low urinary excretion (12.4 ± 3.5 30 minutes, n=3). The compound crossed the blood brain barrier (BBB ) and a uptake in the brain of 3.5 ± 0.3 % Administrated activity/gram (n=3) was observed at 30 minutes post-injection.

Conclusions [¹⁸F]IND cross the BBB and might be an interesting radioligand for in vivo comparative studies of the AChE brain activity in health animals and animals with AD.

Research Support Acknowledgements: ANII; PEDECIBA - Química; Proyecto CSIC(España)-UdelaR(Uruguay)