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ABSTRACT: A simple synthesis of the dopamine transporter ligand [(18)F]FECNT with high radiochemical yield and short synthesis time, suitable for routine production is reported. Reaction of 2β-carbomethoxy-3β-(4-chlorophenyl)nortropane with [(18)F]2-fluoroethyl triflate ([(18)F]FEtOTf) at room temperature for 4min provided [(18)F]FECNT in 84% decay corrected radiochemical yield. Since [(18)F]FEtOTf was prepared from [(18)F]2-fluoroethyl bromide that was isolated from its starting material, formation of unwanted side products and the amount of expensive precursor used could be greatly reduced. The overall radiochemical yields of [(18)F]FECNT were 40% (n=29) and the total synthesis time was ca. 100min. The average specific activity of [(18)F]FECNT was 377.4GBq/μmol (10.2Ci/μmol).
Applied radiation and isotopes: including data, instrumentation and methods for use in agriculture, industry and medicine 10/2012; 72C:128-132. · 1.09 Impact Factor
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ABSTRACT: The aromatic L-amino acid decarboxylase (AAAD) is involved in the de novo synthesis of dopamine, a neurotransmitter crucial in cognitive, neurobehavioral and motor functions. The goal of this study was to assess the in vivo turnover rate of AAAD enzyme protein in the rhesus macaque striatum by monitoring, using microPET imaging with the tracer [(18)F]fluoro-m-tyrosine (FMT), the recovery of enzyme activity after suicide inhibition. Results showed the AAAD turnover half-life to be about 86 h while total recovery was estimated to be 16 days after complete inhibition. Despite this relatively slow AAAD recovery, the animals displayed normal movement and behavior within 24 h. Based on the PET results, at 24 h, the animals have recovered about 20% of normal AAAD function. These findings show that normal movement and behavior do not depend on complete recovery of AAAD function but likely on pre-synaptic and post-synaptic compensatory mechanisms.
Brain Research 09/2005; 1054(1):55-60. · 2.73 Impact Factor
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Synapse 05/2005; 56(1):54-6. · 2.94 Impact Factor
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ABSTRACT: The aromatic L-amino acid decarboxylase (AAAD) enzyme is significantly upregulated in neuroendocrine tumors and, thus, would be a good target for PET imaging agents. Alpha-fluoromethyl-DOPA (FMDOPA) is one of the most potent irreversible AAAD inhibitor and its non-catechol derivative, alpha-fluoromethyl-m-tyrosine (FMmT), is a promising AAAD imaging agent. We synthesized FMmT and its direct electrophilic fluorination provided a mixture of products identified by NMR analysis after HPLC purification as 6-fluoro-, 2-fluoro- and 2,6-difluoro-derivatives of FMmT. Using rat striatal homogenates, alpha-fluoromethyl-6-fluoro-m-tyrosine (FM-6-FmT) was found to have AAAD inhibitory activity comparable to that of FMDOPA. Electrophilic radiofluorination of FMmT using [18F]AcOF gave 18F labeled 6-fluoro-, 2-fluoro- and 2,6-difluoro-FMmT derivatives in 22.0%, 21.9% and 8.5% radiochemical yields, respectively. Based on its proposed mechanism of inhibition, FM-6-[18F]FmT is expected to irreversibly bind to AAAD and, hence, could be used as a PET agent to image tumors of endocrine origin containing high concentrations of AAAD. Since FM-6-FmT lacks the catechol moiety, it is expected to be better than FMDOPA since it is not a substrate for catechol-O-methyltransferase.
Applied Radiation and Isotopes 11/2003; 59(4):237-43. · 1.17 Impact Factor
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ABSTRACT: The effect of aging on aromatic L-amino acid decarboxylase (AAAD) activity in rhesus monkey striatum was assessed in vivo using PET imaging. Two analogs of L-DOPA, 6-fluoro-m-tyrosine (FMT) and 6-fluoro-L-DOPA (FDOPA), were used to image rhesus monkeys of various ages. Results show that when the animals were grouped between young (3-11 years) and aged (25-37 years), FDOPA uptake in the older animals showed a 21% decline (P < 0.0005), while FMT uptake in young and older animals were not different. On the other hand, when individual uptake values were plotted vs. age, linear regression analysis showed FDOPA uptake similarly declined with age (r = -0.84, P < 0.001) while FMT uptake increased with age (r = 0.66, P < 0.05). Since FMT pharmacokinetics has been shown to be unaffected by metabolic steps occurring after the AAAD step, while FDOPA traces all the steps involved in L-DOPA metabolism, FMT is a suitable tracer to assess AAAD activity while FDOPA traces dopamine turnover. Based on these tracer characteristics, this study found that AAAD activity is maintained or increased in the aging rhesus monkey striatum while the FDOPA uptake decreases with age consistent with age-related declines in neuronal mechanisms whose overall effect is increased striatal dopamine turnover and clearance. Furthermore, comparison of results of this study with previous studies support the notion that the effect of aging in the dopamine system is different from that of MPTP-induced parkinsonism.
Synapse 02/2001; 39(1):58-63. · 2.94 Impact Factor
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ABSTRACT: 6-[(18)F]Fluoro-m-tyrosine (FMT) is a positron emission tomography (PET) imaging agent for the aromatic L-amino acid decarboxylase enzyme. Its parent compound, L-m-tyrosine (LMT) induces behavioral effects in rodents via dopamine release. To assess the potential pharmacologic effect of FMT, its role in dopamine release and metabolism in rat striatum was compared with LMT and L-DOPA using in vivo microdialysis. Results indicate that FMT will not have the same dopamine-induced behavioral effects as LMT.
Brain Research 12/2000; 884(1--2):192-5. · 2.73 Impact Factor
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ABSTRACT: 6-[18F]Fluoro-L-DOPA (FDOPA) is an imaging agent used in the study of dopamine terminals in the living brain using positron emission tomography (PET). To better understand the role of tracer metabolism in dynamic FDOPA PET studies, the pharmacokinetics of individual FDOPA metabolites in extracellular space in the striata of anesthetized rats was investigated using in vivo microdialysis. Brain tissues were also analysed to obtain FDOPA metabolite distribution in the combined intracellular and extracellular spaces. Total extracellular [18F] radioactivity in rat striata was observed to rise and peak at 30 min post-injection (p.i.) and declined with clearance half-life of 2 h. In the extracellular space, the dominant FDOPA metabolite at early times was FDOPAC, followed by FHVA at 50 min, then F-sulfoconjugates at 70 min and finally 3-O-methyl-6-Fluoro-L-DOPA (3OMFD) at later times. These results are consistent with the sequential metabolism and brain clearance of L-DOPA and its metabolites. Analysis of whole striatal tissue confirmed the intraneuronal localization of fluorodopamine most likely stored in vesicles. A new but not unexpected finding was the enrichment of 3OMFD in intraneuronal striatal space which is perhaps a factor in its slow cerebral clearance. Since FDOPA PET data reflects the overall pharmacokinetics of several [18F]-metabolites, the observed different rates of formation and clearance and also different neuronal localization of each metabolite contribute to the measures obtained in dynamic FDOPA PET studies. These metabolic steps and their role in tracer kinetics are, thus, important factors to consider in ascribing physiologic significance to PET-derived measures.
Brain Research 10/2000; 877(1):31-6. · 2.73 Impact Factor
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ABSTRACT: The purpose of this study was to address four major questions regarding 6-FMT, a noncatecholic PET tracer for AAAD: 1) Where is the specific uptake of 6-FMT? 2) Why does it accumulate where and to the degree that it does? 3) How does its uptake differ from that of fluoroDOPA globally? and 4) Does its regional uptake differ significantly from that of fluoroDOPA? High-resolution PET scans were obtained in three rhesus monkeys using 6-FMT and in two of them using fluoroDOPA. Anatomic distribution was analyzed visually and quantitative uptake of 6-FMT was compared with published regional decarboxylase activity and monoamine neurotransmitter concentrations. In addition to high uptake in the dopamine-rich striatal nuclei, there was specific uptake of 6-FMT in brain regions which have little dopaminergic innervation but which have other amines in significant concentration. 6-FMT uptake correlated best with regional AAAD activity (r = 0.97). It correlated slightly less well with the sum of catecholamine and indolamine neurotransmitter concentrations, but does not correlate with dopamine concentration. The uptake of 6-FMT is greater than that of fluoroDOPA, with only slight differences in their regional distributions. Radiolabeled analogs of DOPA are often implicitly or explicitly regarded as tracers for presynaptic dopaminergic function. However, localization of these tracers more broadly includes many regions with relatively high concentrations of norepinephrine and serotonin. This may be especially important in diseases or experimental states in which dopaminergic neurons are selectively reduced, and may allow for the study of nondopaminergic neuronal systems in vivo with this tracer.
Synapse 12/1999; 34(2):111-23. · 2.94 Impact Factor
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ABSTRACT: To evaluate the visible and quantitative anatomic distribution of fluorine-18-labeled L-DOPA in the healthy human brain, to thereby expand the understanding of extrastriatal sites of levodopa function, and to provide a broader foundation for clinical and research studies of fluoroDOPA accumulation in patients.
The authors performed dynamic three-dimensional fluoroDOPA PET imaging in 10 healthy volunteers and analyzed the images visually and quantitatively. Twenty-eight regions of interest were applied to parametric images of the uptake rate constant (using the multiple-time graphic plot method with cortical input function) and also were used to quantitate regional radioactivity at 80 to 90 minutes. The authors correlated the uptake constants with published human regional neurotransmitter and decarboxylation data.
PET imaging with fluoroDOPA demonstrates trapping of labeled dopamine or its metabolites in substantial quantities in many areas of the brain other than the mesostriatal pathways, including considerable uptake in the serotonergic and noradrenergic areas of the hypothalamus and brainstem as well as in extrastriatal cerebral sites. Total fluoroDOPA uptake correlates best with the sum of catecholamine and indolamine concentrations in the brain and moderately well with regional activity of aromatic L-amino acid decarboxylase, but correlates poorly with extrastriatal dopamine concentration.
Neither L-DOPA nor its radiolabeled analog fluoroDOPA is metabolized or accumulates specifically in dopaminergic or even catecholaminergic neurons. Substantial dopamine production within serotonin and norepinephrine neurons may play a role in either therapeutic effects or adverse effects of therapy with L-DOPA.
Neurology 11/1999; 53(6):1212-8. · 8.31 Impact Factor
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ABSTRACT: The effectiveness of 6-[18F]fluoro-L-m-tyrosine (6FMT) to evaluate dopamine presynaptic integrity was compared to that of 6-[18F]fluoro-L-dopa (6FDOPA) in vivo by positron emission tomography (PET). Six normal and six 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys received 6FDOPA and 6FMT PET scans on separate occasions with identical scanning protocols. Four measures, the rate of uptake of tracer into striatum using either the arterial input function (Ki) or the activity in the occipital cortex as the input function (Kc), the rate of loss of striatal radioactivity (k(loss)), and an index of "effective turnover" of dopamine (k(loss)/Ki), were obtained for both tracers during extended PET studies. 6-[18F]Fluoro-L-m-tyrosine was as effective as 6FDOPA in separating normals from MPTP-lesioned subjects on the basis of the uptake rate constants Ki and Kc. However, in contrast to 6FDOPA, it was not possible to differentiate the normal from the lesioned animal using k(loss) or k(loss)/Ki for 6FMT. Thus, FMT appears to be a reasonable, highly specific tracer for studying the activity of aromatic dopa decarboxylase enzyme as an index of presynaptic integrity. However, if one is interested in investigating further the metabolic pathway and obtaining an in vivo estimate of the effective turnover of dopamine (after pharmacologic manipulation, for example), 6FDOPA remains the tracer of choice.
Journal of Cerebral Blood Flow & Metabolism 04/1999; 19(3):278-87. · 5.01 Impact Factor
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ABSTRACT: We have prepared 4'-epi-iodo-4'-deoxy-daunorubicin (IDDNR)(1), a doxorubicin analog, via a 5-step synthesis involving a protected daunorubicin triflate derivative (4). This triflate derivative will allow the facile and regiospecific nucleophilic preparation of I-125 or Br-80 m labelled analogs of IDDNR. Auger electron-emitting I-125- or Br-80 m-labelled analogs of IDDNR may have potential as cancer radiotherapeutic agents.
Bioorganic & Medicinal Chemistry Letters 01/1999; 8(23):3419-22. · 2.55 Impact Factor
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ABSTRACT: This article presents dosimetry based on the measurement of fluoro-DOPA activity in major tissues and in the bladder contents in humans after oral pretreatment with 100 mg carbidopa.
Bladder activity was measured continuously by external probe and calibrated using complete urine collections. Quantitative dynamic PET scans provided time-activity curves for the major organs. Bladder wall dosimetry was calculated using the methods of MIRD Pamphlet No. 14. Effective dose was calculated as described in ICRP Publication 60.
Mean absorbed dose to the bladder wall surface per unit administered activity was 0.150 mGy/MBq (0.556 rad/mCi) with the realistic void schedule used in our studies. The dose was 0.027 mGy/MBq (0.101 rad/mCi) to the kidneys, 0.0197 mGy/MBq (0.0728 rad/mCi) to the pancreas, and 0.0186 mGy/MBq (0.0688 rad/mCi) to the uterus. Absorbed doses to other organs were an order of magnitude or more lower than the bladder, 0.009-0.015 mGy/MBq. The effective dose per unit administered activity was 0.0199 mSv/MBq (0.0735 rem/mCi.)
Urinary excretion of fluoro-DOPA was altered significantly by pretreatment with carbidopa. In general, any manipulation of tracer metabolism in the body should be expected to produce changes in biodistribution and dosimetry. The largest radiation dose was to the bladder wall, for which our estimate was one-fifth of that from the original report. The methods used reflect realistic urinary physiology and typical use of this tracer. The principles of MIRD Pamphlet No. 14 should be used in planning studies using tracers excreted in the urine to minimize the absorbed dose.
Journal of Nuclear Medicine 12/1998; 39(11):1884-91. · 6.38 Impact Factor
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ABSTRACT: Fluorinated m-tyrosine analogs were evaluated as PET imaging agents and compared with 6-fluoroDOPA in the visualization of dopamine nerve terminals.
The three m-tyrosine analogs, 6-[18F]fluoro-L-m-tyrosine (6-FMT), 2-[18F]fluoro-L-m-tyrosine (2-FMT) and 6-[18F]fluoro-fluoromethylene-DL-m-tyrosine (6-F-FMMT), were prepared via electrophilic radiofluorination using [18F]acetylhypofluorite. These three analogs, as well as 6-[18F]fluoro-L-DOPA (6-FD), were injected into sets of rhesus monkeys, and serial PET images were acquired. Plasma samples were collected at different times after tracer administration, and metabolite analyses were done using high-performance liquid chromatography (HPLC).
Visual inspection of the PET images obtained using these four tracers showed that the best image contrast was obtained with 6-FMT. Patlak analysis with a reference tissue input function yielded a mean uptake rate constant for 6-FMT of 0.019 min-1, a value twice those for the other tracers including 6-FD.
These results demonstrate the superiority of 6-[18F]FMT in visualizing dopamine terminals in the rhesus monkey brain and suggest that 6-[18F]FMT is the tracer of choice in the assessment of dopamine metabolism in the living human brain.
Journal of Nuclear Medicine 05/1997; 38(4):630-6. · 6.38 Impact Factor
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ABSTRACT: Affinities of dopamine (DA) analogs to both granular and plasma membrane uptake transporters were measured in vitro by inhibition of [3H]DA uptake in bovine chromaffin granule ghosts and C6 glial cells transfected with cDNA for the rat presynaptic dopamine transporter, respectively. Five amines were studied: DA, 6-fluorodopamine (6FDA), m-tyramine (MTA), 6-fluoro-m-tyramine (6FMTA), and beta-fluoromethylene-m-tyramine (FMMTA). Direct uptake of 18F labeled 6FDA and 6FMTA was also measured in the chromaffin granule system and compared with [3H]DA uptake. Results show that the transporter affinities of 6FDA and MTA were similar to that of DA in both transport systems while affinities of 6FMTA and FMMTA were lower. Furthermore while the direct uptake of DA and FDA in chromaffin granules were essentially identical and significantly reserpine-inhibitable, the direct uptake of 6FMTA was about 15-fold less and only minimally sensitive to reserpine pretreatment. Thus, although vesicular protection and reuptake may influence the turnover of FDA in 6-fluoroDOPA studies, they are unlikely to be important determinants of the kinetics of the slowly clearing components in studies with either 6-fluoro-m-tyrosine (6FMT) or 6-fluoro-beta-fluoro-methylene-m-tyrosine (6FFMMT), the bioprecursors of 6FMTA and 6-fluoro-FMMTA, respectively. These results are consistent with the finding that the longterm component in 6FMT PET studies is 6-fluoro-hydroxyphenylacetic acid (6FHPAC), which can be explained by the lack of vesicular protection of 6FMTA from MAO oxidation.
Life Sciences 02/1997; 60(26):2399-406. · 2.53 Impact Factor
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ABSTRACT: 3-[18F]Fluoro-alpha-fluoromethyl-p-tyrosine (3-F-FMPT) was evaluated as a tracer for CNS tyrosine hydroxylase (TH) activity in rodents and in a rhesus monkey. Results of in vitro experiments using rat striatal homogenates showed that the introduction of fluorine into the 3-phenyl position did not significantly alter the ability of FMPT to act as a TH-activated L-aromatic amino acid decarboxylase (L-AAAD) inhibitor. These studies further showed that 3-F-FMPT-induced L-AAAD inhibition was dose-dependent. Furthermore, striatal homogenates prepared from rats pretreated with the potent TH inhibitor alpha-methyl-p-tyrosine was found to have diminished 3-F-FMPT-induced L-AAAD inhibition. However, despite these promising in vitro results, the biodistribution of this compound in mice showed low brain uptake and fast clearance through the kidneys. A PET study using a Rhesus monkey injected with 3-[18F]F-FMPT confirmed the results obtained in mice, i.e. negligible brain uptake but high localization in the bladder. We conclude that 3-[18F]F-FMPT would not be useful as a tracer for cerebral TH activity.
Nuclear Medicine and Biology 06/1994; 21(4):663-7. · 3.02 Impact Factor
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ABSTRACT: [18F]-6-Fluoro-beta-fluoromethylene-m-tyrosine ([18F]FFMMT) was evaluated as a potential imaging agent for dopamine nerve terminals using positron emission tomography (PET). Biodistribution and time course of this tracer in mice after i.p. injection was consistent with the distribution of dopamine. PET imaging studies involving rhesus macaques showed specific uptake in the dopamine-rich caudate-putamen region. This specific localization was blocked by inhibiting the enzyme L-aromatic amino acid decarboxylase and the transport of the tracer into brain was shown to be stereospecific. These results show the promise of L-[18F]FFMMT as a PET tracer in monitoring degeneration of the CNS dopamine system.
Brain Research 12/1992; 597(1):151-4. · 2.73 Impact Factor
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ABSTRACT: 18F-labeled (E)-beta-fluoromethylene-DL-m-tyrosine (FMMT) was prepared by the direct reaction of FMMT with [18F]acetylhypofluorite (AcOF) resulting into three product isomers. Extensive 1H, 13C and 19F-NMR spectroscopic analysis identify these products to be 2-fluoro, 6-fluoro-FMMT and 2,6-difluoro-FMMT. The HPLC isolated radiochemical EOB yields of these products were 22, 25 and 14%, respectively, based on starting [18F]AcOF. The specific activity at the end of a synthesis time of an hour was ca 200 mCi/mmol. With the possible advantage of "metabolic trapping" in dopamine nerve terminals via covalent binding to MAO and reduced metabolite formation, [18F]F-FMMT may potentially be the optimal PET tracer for CNS dopamine nerve terminals.
International Journal of Radiation Applications and Instrumentation Part A Applied Radiation and Isotopes 09/1992; 43(8):969-77.
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ABSTRACT: 80mBr (half-life = 4.43 h) is an Auger electron emitting nuclide with convenient properties for investigating Auger electron cytotoxicity and with potential for labeling in vivo radiotherapeutic agents. We have investigated three cyclotron target systems capable of generating 80mBr of sufficiently high specific radioactivity (no carrier added) for biomedical experiments. A 83Kr gas target irradiated with 21.5 MeV deuterons made 80mBr at a production yield of 1.6 +/- 0.2 mCi/muAh at saturation. A five-fold increase in 80mBr yield was obtained from 15 MeV proton irradiation of thin elemental Se enriched in 80Se targets although technical improvements are expected to further raise this production yield. This route is therefore superior for current medical cyclotrons. Irradiation of a reusable 80Se copper selenide target also yielded multi-millicurie amounts of 80mBr, and recovery of radiobromine by dry distillation is faster and more convenient than in the elemental Se target, but an optimum copper selenide target for 80mBr production has not yet been built.
International Journal of Radiation Applications and Instrumentation Part A Applied Radiation and Isotopes 02/1991; 42(1):57-61.
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Journal of Nuclear Medicine 01/1991; 31(12):2076-7. · 6.38 Impact Factor
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ABSTRACT: The direct electrophilic radiofluorination of m-tyrosine using [18F]acetylhypofluorite was investigated. Results showed that this reaction was both rapid and efficient with recovered decay corrected yield of 71% radiofluorinated m-tyrosines based on starting [18F]acetylhypofluorite. Specific activity of the product obtained in this study was 100-200 mCi/mmol although 1-5 Ci/mmol are easily achievable with our improved production of [18F]AcOF. Three positional isomers were found and identified by 19F-NMR to be 2-, 4-, 6-fluoro-m-tyrosine with a distribution of 36:11:52, respectively. This measured distribution allowed the assignment of the radio-HPLC peaks. Biological studies are currently underway in our laboratory using these fluoro-m-tyrosines to determine which isomer would be most suited for the evaluation of the dopamine system by positron tomography.
International Journal of Radiation Applications and Instrumentation Part A Applied Radiation and Isotopes 02/1990; 41(5):433-7.
