TY - JOUR
T1 - Time profile of cerebral [18f]6-fluoro-L-DOPA metabolites in nonhuman primate
T2 - Implications for the kinetics of therapeutic L-DOPA
AU - Endres, Christopher J.
AU - DeJesus, Onofre T.
AU - Uno, Hideo
AU - Doudet, Doris J.
AU - Nickles, R. Jerome
AU - Holden, James E.
PY - 2004
Y1 - 2004
N2 - At least two rates of dopamine turnover have been demonstrated in vivo, including a slow turnover rate that is associated with synaptic vesicles, and a faster rate that leads to rapid production of dopamine metabolites. Similarly, [18F]6-fluorodopamine (FDA), the decarboxylation product of the PET tracer [18F]6-fluoro-L-DOPA (FDOPA), may have multiple turnover rates which could substantially affect the interpretation of FDOPA uptake. To better characterize FDA turnover in vivo, we measured the formation of FDOPA metabolites in primate brain following bolus FDOPA injection with carbidopa pretreatment. FDOPA was allowed to circulate for either 30 minutes or 90 minutes, prior to removal of brain samples. The primary metabolites in striatum were [18F]6-fluoro-3-methyl-L-DOPA (3-OMFD), FDA, [ 18F]6-fluoro- L-3,4-dihydroxyphenylacetic acid (FDOPAC), and [ 18F]O-fluorohomovanillic acid (FHVA). The percentages of total radioactivity in striatum at 30 minutes and 90 minutes were: FDOPA (5%, 2%), FDA (39%, 23%), FDOPAC (12%, 3%), FHVA (14%, 34%), and 3-OMFD (29%, 39%). In cortex and cerebellum most of the activity (73%, 80%) was 3-OMFD. These data were compared against the metabolite profiles predicted by two compartmental models of FDOPA metabolism. A model that assumes only a single slow rate of FDA turnover predicted much lower concentrations of FDA metabolites (FDOPAC, FHVA) in striatum than were found in the brain assay, while a model that includes both slow and fast FDA turnover was in much better agreement. These findings extend and confirm previous observations of FDOPA metabolites. The implications for the interpretation of FDOPA PET, particularly in terms of the availability of dopamine synthesized from therapeutic L-DOPA, are discussed.
AB - At least two rates of dopamine turnover have been demonstrated in vivo, including a slow turnover rate that is associated with synaptic vesicles, and a faster rate that leads to rapid production of dopamine metabolites. Similarly, [18F]6-fluorodopamine (FDA), the decarboxylation product of the PET tracer [18F]6-fluoro-L-DOPA (FDOPA), may have multiple turnover rates which could substantially affect the interpretation of FDOPA uptake. To better characterize FDA turnover in vivo, we measured the formation of FDOPA metabolites in primate brain following bolus FDOPA injection with carbidopa pretreatment. FDOPA was allowed to circulate for either 30 minutes or 90 minutes, prior to removal of brain samples. The primary metabolites in striatum were [18F]6-fluoro-3-methyl-L-DOPA (3-OMFD), FDA, [ 18F]6-fluoro- L-3,4-dihydroxyphenylacetic acid (FDOPAC), and [ 18F]O-fluorohomovanillic acid (FHVA). The percentages of total radioactivity in striatum at 30 minutes and 90 minutes were: FDOPA (5%, 2%), FDA (39%, 23%), FDOPAC (12%, 3%), FHVA (14%, 34%), and 3-OMFD (29%, 39%). In cortex and cerebellum most of the activity (73%, 80%) was 3-OMFD. These data were compared against the metabolite profiles predicted by two compartmental models of FDOPA metabolism. A model that assumes only a single slow rate of FDA turnover predicted much lower concentrations of FDA metabolites (FDOPAC, FHVA) in striatum than were found in the brain assay, while a model that includes both slow and fast FDA turnover was in much better agreement. These findings extend and confirm previous observations of FDOPA metabolites. The implications for the interpretation of FDOPA PET, particularly in terms of the availability of dopamine synthesized from therapeutic L-DOPA, are discussed.
KW - 6-fluorodopa
KW - Dopaminergic pathway
KW - L-DOPA
KW - Nonhuman primate
KW - Parkinson's disease
UR - http://www.scopus.com/inward/record.url?scp=2542485470&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=2542485470&partnerID=8YFLogxK
U2 - 10.2741/1224
DO - 10.2741/1224
M3 - Article
C2 - 14766386
AN - SCOPUS:2542485470
VL - 9
SP - 505
EP - 512
JO - Frontiers in Bioscience - Landmark
JF - Frontiers in Bioscience - Landmark
SN - 1093-9946
ER -