Comparison of radiation dosimetry estimates for [11C]L-Deprenyl and [11C]Clorgyline across species and with D for H isotopic substitution. (2016)

1931 Objectives MAO in peripheral organs represents a vast mechanism for detoxifying vasoactive compounds as well as for terminating the action of physiologically active amines. The monoamine oxidase A and B (MAO A and B) radiotracers [11C]clorgyline and [11C]L-deprenyl and their deuterium labeled counterparts have been used to access MAO A and MAO B availability in PET imaging studies. These compounds were compared to determine how internal radiation dosimetry estimates in humans were affected with D for H substitution. We also compare dosimetry estimates for these tracers between baboon and human using PET imaging. Methods Dynamic PET scans for both humans and baboons were acquired with a whole-body, high-resolution positron emission tomograph (Siemens/CTI ECAT HR+ in 3D dynamic acquisition mode. Regions of interest were drawn directly on the PET scans using an atlas for reference. Regions of interest were obtained for the following: heart (left ventricle), lungs, liver, kidneys, stomach, and spleen. Regions for each organ were identified on 2-3 planes and the weighted average was obtained. Time activity curves of percent injected dose per gram were obtained from these images and the residence times were calculated from these curves using standard organ weights for the respective species. The dosimetry estimates for the adult male were made using the program OLINDA from Oak Ridge National Laboratory. Results Both clorgyline and L-deprenyl are suicide enzyme inactivators for MAO in humans with high affinity and high selectivity for their respective enzyme subtypes. Both inhibit MAO by irreversible covalent attachment after enzyme catalyzed cleavage of the C-H bond on the methylene carbon of the propargyl group in the rate limiting step. The substitution of D for H in this methylene group accounts for the difference in kinetics and the corresponding difference in the organ dose for the isotopically substituted compound. The dose estimate for kidney in human with [11C]L-deprenyl was nearly twice as high with hydrogen as with deuterium substitution.
[11C]Clorgyline selectively binds to MAO A in the human brain, however, it has been demonstrated that this radiotracer does not bind to MAO A in the non-human primate brain. This difference in binding appears to affect dosimetry estimates in the peripheral organs as well since isotopic substitution made very little difference in radiotracer distribution. A kinetic isotope effect is observed in the baboon for [11C]L-deprenyl. Differences in dose estimates between species were species were substantial. Conclusions Depending on the mechanism of action of radiotracers, the simple isotopic substitution of D for H near the reactive site can have a very significant effect on the dose delivered to an organ. The kinetic isotope effect can alter the rate of reaction and therefore the biodistribution of the radiotracer. The dose estimates for radiotracers using the PET imaging in different species can be significantly different than the dose estimates obtained using human PET imaging.