Revisiting [¹⁸F]FHMP for imaging MAO-B

Objectives Fluorine-18 labelled N-(6-fluorohexyl)-N-methylpropargylamine ([¹⁸F]FHMP) was developed as a promising imaging agent for monoamine oxidase B (MAO-B) (Mukherjee, J. et al, Nucl. Med. Biol., 1999, 26, 111). We here report the synthesis of a new stable precursor, an automated radiosynthesis procedure, and our preliminary biological evaluations of [¹⁸F]FHMP in conscious rats.

Methods N-(6-tosyloxyhexyl)-N-methylpropargylamine was prepared in three steps by reaction of N-methylpropargylamine with ethyl-6-bromohexanoate (84%), followed by reduction with LiAlH₄ (95%), and tosylation of the resulting alcohol (58%). Automated radiosynthesis of [¹⁸F]FHMP was carried out by reaction of the tosyloxy precursor with [K₂₂₂][¹⁸F] in DMSO at 90 ^oC for 5 min, followed by HPLC purification. Ex vivo biodistributions, as well as metabolite analyses of plasma and brain homogenates, were conducted in male Sprague-Dawley rats.

Results Synthesis of the previously described radiolabelling precursor, N-(6-bromohexyl)-N-methylpropargylamine, was unsuccessful in our hands and resulted in an azepanium bromide salt as the major product, confirmed by X-ray crystallography. The propargylamine was efficiently labelled via the new precursor in 29 +/-5% (n=3) uncorrected radiochemical yield based on starting [¹⁸F]fluoride and had a specific activity of 1-2 Ci/μmol at the end of synthesis. Formulated [¹⁸F]FHMP was radiochemically pure (>99%) and prepared within 35 min. Tail-vein injection of [¹⁸F]FHMP in rats showed relatively low brain uptake (<0.25% i.d./g in all regions) and rapid metabolism to hydrophilic metabolites in the plasma as previously reported. In addition, a hydrophilic radioactive metabolite (>60% at 60 min post-injection) was detected in the brain.

Conclusions A new precursor was developed and used in an automated procedure to efficiently prepare [¹⁸F]FHMP. Low brain uptake in the rodent brain will likely preclude its use for CNS imaging. Our continued efforts to develop radiotracers for MAO-B will also be presented.

Research Support Ontario Ministry of Research and Innovatio