Research report6-[18F]Fluoro-l-m-tyrosine: metabolism, positron emission tomography kinetics, and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine lesions in primates
Introduction
6-[18F]Fluoro-l-DOPA (F-DOPA) has been widely used with positron emission tomography (PET) to study presynaptic dopaminergic function in animals and humans, e.g., 4, 29, 35, 38, 22, 48. However, its rapid methylation in peripheral tissues reduces its availability for brain uptake and yields fluorine-18 (F-18) labeled metabolites which enter the brain, contributing undesirable background noise to the F-DOPA signal. An improved tracer for this purpose would be equally selective for central dopaminergic activity but would not be susceptible to peripheral methylation. F-18 labeled m-tyrosine has many favorable characteristics in this respect. For example, 4-[18F]fluoro-l-m-tyrosine and 6-[18F]fluoro-l-m-tyrosine (FMT) have been used to successfully trace dopaminergic function in primates [39]and humans [44], respectively.
Within 1 h after F-DOPA injection, the majority of blood F-18 activity is associated with 3-[18F]-O-methyl-6-fluoro-l-dopa (3-OMFD) [41], formed by catechol-O-methyltransferase (COMT) in peripheral organs and erythrocytes [43]. Since 3-OMFD traverses the blood brain barrier, via the large neutral amino acid (LNAA) carrier, and has a slow rate of clearance, it adds profound background noise to the F-DOPA signal 14, 20, 52. In contrast, FMT has a minimal affinity for COMT [33]which prevents its methylation in the periphery. Significant metabolism does, however, appear to occur in peripheral tissues, since F-18 labeled forms of fluoro-m-hydroxyphenylethylamine-sulfate and fluoro-3-hydroxyphenylacetic acid have been identified in blood of monkeys and rats injected with FMT [39]. Nevertheless, despite bi-directional transfer of FMT across the blood brain barrier, via the LNAA carrier, uptake of FMT metabolites appears to be restricted, which limits their capacity to interfere with the parent tracer signal [39]. Recent PET studies with FMT demonstrated images of brain dopamine activity with a higher level of contrast compared to those typically reported with F-DOPA 39, 44. This lower level of non-specific tracer brain uptake simplifies dynamic PET data analysis and compartmental kinetic modeling of dopaminergic activity. PET images obtained using FMT show tracer accumulation in the striatum with good contrast, and a target to background ratio that is more than twice that for F-DOPA [44]suggesting FMT is a good tracer for imaging the dopaminergic system.
Validation of approaches to kinetic modeling of this tracer requires a complete knowledge of the biochemical form of the radioactivity during the time course of a PET experiment. For this reason, we examined FMT metabolism in brain regions of differing dopamine content at 60 and 120 min after FMT injection. Subsequently, we performed dynamic PET imaging with FMT in a different group of monkeys, before and after unilateral and intravenous (i.v.) 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) infusions, while simultaneously monitoring its metabolism in blood. Time activity kinetics of brain, blood and metabolite corrected blood FMT activity were fitted with a three compartment model for FMT uptake. A multiple time graphical approach [49]was also used as an alternative method of estimating regional FMT uptake rates.
Section snippets
Materials and methods
Two separate studies were performed — one to determine in vitro brain FMT metabolism and another to study the effect of systemic MPTP infusions upon brain FMT uptake kinetics. The first study used in vitro radiochemical analysis to evaluate regional brain FMT metabolism in four monkeys killed 60 or 120 min after FMT injection, PET scanning was not performed on these animals. The second study employed dynamic PET with simultaneous on-line arterial plasma F-18 sampling to respectively acquire
Brain and blood metabolism studies
At 60 and 120 min after FMT was injected, FMT, FMA and FPAC were detected in post-mortem caudate, putamen, nucleus accumbens, substantia nigra, frontal cortex and cerebellum (Table 1). These three radiolabeled species represented all of the F-18 radioactivity identified in each brain tissue sample. FPAC was the predominant species identified in all tissues except for the 60 min post-mortem cerebellum sample where FMT was the major labeled species (Fig. 2). At both post-mortem time points,
Discussion
The present study demonstrated the ability of FMT to provide high contrast dynamic PET images of brain dopaminergic function in normal and MPTP-lesioned primates. Prior to MPTP treatment the FMT signal appeared confined to dopaminergic areas, allowing F-18 activity to be clearly defined in caudate and putamen. A similar level of selective dopaminergic imaging has been reported with FMT in PET studies of monkey [39]and human [44]. Blood F-18 analysis revealed a gradual accumulation of labeled
Acknowledgements
This research was supported by the Laboratory Technology Applications Division (formerly ER LTT), Office of Energy Research, U.S. Department of Energy under a CRADA (Cooperative Research and Development Agreement) between Lawrence Berkeley National Laboratory and Somatix Therapy Corporation, Alameda, CA under US DOE Contract DE-AC03-76SF00098.
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