Radioactive N,N‐Dimethylphenylethylamine: A Selective Radiotracer for In Vivo Measurement of Monoamine Oxidase‐B Activity in the Brain

Abstract

N-[methyl-14C]N,N-dimethylphenylethylamine (DMPEA) was synthesized and its availability as a selective radiotracer for in vivo measurement of mouse brain monoamine oxidase (MAO) activity was examined. Relatively high incorporation of labelled DMPEA into brain (about 10% of the injected dose/per gram of brain) was observed just after its injection; however, radioactive dimethylamine, a metabolite produced from labelled DMPEA in the brain 1 h after DMPEA injection, was reduced in a dose-dependent manner by pretreatment with various doses of a specific MAO-B inhibitor, 1-deprenyl, but was not reduced appreciably by pretreatment with a specific MAO-A inhibitor, clorgyline. Pretreatment with 1-deprenyl did not affect significantly the rate of incorporation of the radiotracer DMPEA into the brain, suggesting that reduction of the radioactivity in brain by this compound might be due to a decrease in the rate of production of the radioactive metabolite dimethylamine by brain MAO-B. The amount of the radioactive metabolite trapped in the brain was found to be proportional to the brain MAO-B activity remaining after pretreatment with 1-deprenyl. In vitro deamination of DMPEA by mouse brain MAO showed a higher sensitivity to inhibition by 1-deprenyl than that by clorgyline. These results indicate that DMPEA is a selective substrate for mouse brain MAO-B both in vivo and in vitro and that the positron emitter [11C]DMPEA might be used instead of [14C]DMPEA as a radiotracer for in vivo measurement of MAO-B activity in human brain.

Synthesis and Evaluation of Two Positron-Labeled Nitric Oxide Synthase Inhibitors, S-[11C]Methylisothiourea and S-(2-[18F]Fluoroethyl)isothiourea, as Potential Positron Emission Tomography Tracers

“…The second approach involves the use of a labeled enzyme inhibitor bound to the enzyme either covalently or noncovalently with relatively slow dissociation. Several enzymes, including angiotensin-converting enzyme, monoamine oxidase, − and dopamine decarboxylase, have been successfully probed with PET using either the radiolabeled inhibitor or the radiolabeled substrate approach. These results have provided valuable information about enzyme activities in normal and diseased states, as well as the effects of novel pharmaceuticals on these enzymatic systems in vivo .…”

Positron emission tomography and its use to image the occupancy of drug binding sites

“…Both [Bergstrom et al, 1997a,b]. [ 11 C]Dimethyl phenylethylamine has been evaluated as a reversible inhibitor selective for MAO-B [Inoue et al, 1985]. Structures of monoamine oxidase tracers are shown in Figure 5.…”

Gas phase production of [11C]methyl iodide‐d3. Synthesis and biological evaluation of S‐[N‐methyl‐11C]citalopram and deuterated analogues

“…Accordingly, in a PET study with S-[N-methyl- 11 ]dimethylamine due to their limited lipophilicity do not really leave the brain within the time window of a PET study and might therefore result in non-specific binding. [29][30][31] There are, to the best of our knowledge, no reports on the in vivo metabolism of citalopram (3) applied in tracer doses, which could be different from the pharmacokinetic data obtained after treatment with pharmacological doses. [32][33][34] In this paper, we report the synthesis of S-desmethylcitalopram-a,a-d 2 (11) and the radiosynthesis of S-[N-methyl - 11 …”