Mechanistic Positron Emission Tomography Studies: Demonstration of a Deuterium Isotope Effect in the Monoamine Oxidase‐Catalyzed Binding of [¹¹C]l‐Deprenyl in Living Baboon Brain

Abstract

The application of positron emission tomography (PET) to the study of biochemical transformations in the living human and animal body requires the development of highly selective radiotracers whose concentrations in tissue provide a record of a discrete metabolic process. L-N-[11C-methyl]Deprenyl ([11C]L-deprenyl), a suicide inactivator of monoamine oxidase (MAO) type B, has been developed as a radiotracer for mapping MAO B in the living human and animal brain. In this investigation, [11C]L-deprenyl (1) and [11C]L-deprenyl-alpha, alpha-2H2 (2) have been compared in three different baboons by PET measurement of carbon-11 uptake and retention in the brain and the measurement of the amount of unchanged tracer in the arterial plasma over a 90-min time interval. For one baboon, N-[11C-methyl-2H3]L-deprenyl (3) was also studied. Kinetic parameters calculated using a three-compartment model revealed a deuterium isotope effect of 3.8 +/- 1.1. Comparison of the two tracers (1 and 2) in mouse brain demonstrated that deuterium substitution significantly reduced the amount of radioactivity bound to protein. HPLC and GLC analysis of the soluble radioactivity in mouse brain after injection of [11C]L-deprenyl showed the presence of [11C]methamphetamine as a major product along with unidentified labeled products. Sodium dodecyl sulfate-polyacrylamide electrophoresis with carbon-14-labeled L-deprenyl showed that a protein of molecular weight 58,000 was labeled. These results establish that MAO-catalyzed cleavage of the alpha carbon-hydrogen bond on the propargyl group is the rate limiting (or a major rate contributing) step in the retention of carbon-11 in brain and that the in vivo detection of labeled products in brain after the injection of [11C]L-deprenyl provides a record of MAO activity.

In Vivo and In Vitro Characterization of a Novel MAO-B Inhibitor Radioligand, 18F-Labeled Deuterated Fluorodeprenyl

“…Indeed, 18 F-fluorodeprenyl showed in vivo kinetic behavior similar to that of 11 C-deprenyl (20). It has been reported that MAO-B-catalyzed cleavage of the carbon-hydrogen bond of the propargyl group at the carbon is the rate-limiting step in the retention of radioligand in the brain (27). The energy required to cleave the C-D bond is higher than that required to cleave the C-H bond, and the substitution of hydrogen atoms with deuterium atoms reduces the rate of cleavage.…”

Graphical analysis of PET data applied to reversible and irreversible tracers

“…that they can both be determined trapping. This is an example of the kinetic isotope effect in which the increased mass of the atom involved in the reaction slows the reaction rate [15].…”

Kinetic Modeling of the Monoamine Oxidase B Radioligand [11C]SL25.1188 in Human Brain with High-Resolution Positron Emission Tomography

“…Several MAO-B radiotracers for PET have been developed but only [ 11 C]L-deprenyl 7 and its derived [ 11 C]L-deprenyl-D2 8 have been evaluated in vivo in humans. These radioligands are irreversible and selective for MAO-B.…”