Monoamine oxidases (MAO-A and MAO-B) are important
enzymes regulating the
levels of monoaminergic neurotransmitters. Selectiv
e and irreversible MAO-B
inhibitors such as
L
-deprenyl and rasagiline are clinically used for the t
reatment of
psychiatric and neurological disorders. Positron em
ission tomography (PET) is a non-
invasive imaging technique which has widely been util
ized to visualize the localization
of MAO-B in monkey and human brains and thereby has b
een useful for studying
neurodegenerative diseases and epilepsy. This thesi
s deals with the synthesis and
evaluation of novel fluorine-18 labeled PET radioligan
ds for detection of MAO-B
activity.
The present thesis demonstrates that nine fluorinat
ed propargyl amines were
synthesized and tested for inhibition of MAO-B. In o
rder to label those compounds
with fluorine-18 seven chloro-precursors and two sulph
amidate-precursors were also
synthesized by multi step organic synthesis. Radiola
beling of six chloro-precursors
with fluorine-18 was accomplished by a one-step nucl
eophilic substitution reaction.
Radiolabeling of two sulphamidate-precursors with fl
uorine-18 was performed in two
steps, compromising a nucleophilic substitution foll
owed by the removal of the
protecting group. The incorporation yield of the fluo
rination reactions varied from 40-
70%. The radiochemical purity was >99% and the specif
ic radioactivities were in a
range of 190-240 GBq/μmol at the time of administrat
ion.
In vitro
MAO inhibition and/or autoradiography (ARG) experimen
ts demonstrated a
high selectivity for MAO-B over MAO-A for five of the
compounds namely
[
18
F]fluorodeprenyl, [
18
F]fluororasagiline, [
18
F]fluoro-
N
,4-dimethyl-
N
-(prop-2-ynyl)
pentan-2-amine, [
18
F]fluorodeprenyl-D
2
and [
18
F]fluororasagiline-D
2
. All five
compounds
were examined by PET and
showed a high initial brain uptake in known
MAO-B rich regions in cynomolgus monkey. [
18
F]Fluorodeprenyl showed a kinetic
behavior similar to [
11
C]deprenyl where its fast irreversible binding to th
e enzyme
renders the distribution of this radioligand in tissue
limited by blood flow rather than
the MAO-B enzyme concentration. [
18
F]Fluororasagiline and [
18
F]fluoro-
N
,4-dimethyl-
N
-(prop-2-ynyl)pentan-2-amine showed continuous increase
of the radioactivity
throughout the PET measurement that might be an indic
ation of a blood-brain barrier
penetrating radiometabolite which might in turn compl
icate a reliable quantification.
Only [
18
F]fluorodeprenyl-D
2
and [
18
F]fluororasagiline-D
2
showed fast wash-out from
the brain and less accumulation in cortical and sub-
cortical regions. Radiometabolite
studies demonstrated that both deuterated analogues
were more stable measured in
monkey plasma when compared to the non-deuterated a
nalogues.
These results together suggest that both
[
18
F]fluorodeprenyl-D
2
and
[
18
F]fluororasagiline-D
2
may be improved PET radioligands and potential mole
cular
imaging biomarker candidates for PET studies in neuroi
nflammation and
neurodegeneration, accompanied with astrocyte activat
ion