PET Imaging of the dopamine transporter with 18F-FECNT: A polar radiometabolite confounds brain radioligand measurements

Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-0135, USA.
Journal of Nuclear Medicine (Impact Factor: 6.16). 04/2006; 47(3):520-7.
Source: PubMed


18F-2beta-Carbomethoxy-3beta-(4-chlorophenyl)-8-(2-fluoroethyl)nortropane (18F-FECNT), a PET radioligand for the dopamine transporter (DAT), generates a radiometabolite that enters the rat brain. The aims of this study were to characterize this radiometabolite and to determine whether a similar phenomenon occurs in human and nonhuman primate brains by examining the stability of the apparent distribution volume in DAT-rich (striatum) and DAT-poor (cerebellum) regions of the brain.
Two rats were infused with 18F-FECNT and sacrificed at 60 min. Extracts of brain and plasma were analyzed by high-performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometric (LC-MS) techniques. Two human participants and 3 rhesus monkeys were injected with 18F-FECNT and scanned kinetically, with serial arterial blood analysis.
At 60 min after the injection of rats, 18F-FECNT accumulated to levels about 7 times higher in the striatum than in the cortex and cerebellum. The radiometabolite was distributed at equal concentrations in all brain regions. The LC-MS techniques identified N-dealkylated FECNT as a major metabolite in the rat brain, and reverse-phase HPLC detected an equivalent amount of radiometabolite eluting with the void volume. The radiometabolite likely was 18F-fluoroacetaldehyde, the product expected from the N-dealkylation of 18F-FECNT, or its oxidation product, 18F-fluoroacetic acid. The distribution volume in the cerebellum increased up to 1.7-fold in humans between 60 and 300 min after injection and 2.0 +/- 0.1-fold (mean +/- SD; n = 3) in nonhuman primates between 60 and 240 min after injection.
An 18F-fluoroalkyl metabolite of 18F-FECNT originating in the periphery confounded the measurements of DAT in the rat brain with a reference tissue model. Its uniform distribution across brain regions suggests that it has negligible affinity for DAT (i.e., it is an inactive radiometabolite). Consistent with the rodent data, the apparent distribution volume in the cerebellum of both humans and nonhuman primates showed a continual increase at late times after injection, a result that may be attributed to entry of the radiometabolite into the brain. Thus, reference tissue modeling of 18F-FECNT will be prone to more errors than analysis with a measured arterial input function.

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Available from: Sami S Zoghbi
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    • "CYP mediated O-deethylation has been described before for other tracer containing a [ 18 F]fluoroethyl group like [ 18 F]DPA-714 and [ 18 F]PBR102 [27]. This dealkylation will result in the formation of radiometabolites [ 18 F]fluoroethanol, [ 18 F]fluoroacetaldehyde and [ 18 F]fluoroacetic acid which are expected to be metabolically interchangeable in vivo and to be able to cross the blood-brain-barrier [28]. In rodents, in vivo defluorination of [ 18 F] fluoroacetic acid has been described, resulting in accumulation of radioactivity in skeletal structures [29]. "
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    ABSTRACT: Introduction The tetrazine-trans-cylooctene cycloaddition using radiolabeled tetrazine or radiolabeled trans-cyclooctene (TCO) has been reported to be a very fast, selective and bioorthogonal reaction that could be useful for in vivo radiolabeling of molecules. We wanted to evaluate the in vivo biodistribution profile and brain uptake of 18F-labeled TCO ([18F]TCO) to assess its potential for pre-targeted imaging in the brain. Methods We evaluated the in vivo behavior of [18F]TCO via an ex vivo biodistribution study complemented by in vivo μPET imaging at 5, 30, 60, 90, 120 and 240 min post tracer injection. An in vivo metabolite study was performed at 5 min, 30 min and 120 min post [18F]TCO injection by RP-HPLC analysis of plasma and brain extracts. Incubation with human liver microsomes was performed to further evaluate the metabolite profile of the tracer. Results μPET imaging and ex-vivo biodistribution revealed an high initial brain uptake of [18F]TCO (3.8 %ID/g at 5 min pi) followed by a washout to 3.0 %ID/g at 30 min pi. Subsequently the brain uptake increased again to 3.7 %ID/g at 120 min pi followed by a slow washout until 240 min pi (2.9 %ID/g). Autoradiography confirmed homogenous brain uptake. On the μPET images bone uptake became gradually visible after 120 min pi and was clearly visible at 240 min pi. The metabolite study revealed a fast metabolization of [18F]TCO in plasma and brain into three main polar radiometabolites. Conclusions Although [18F]TCO has previously been described to be a useful tracer for radiolabeling of tetrazine modified targeting molecules, our study indicates that its utility for in vivo chemistry and pre-targeted imaging will be limited. Although [18F]TCO clearly enters the brain, it is quickly metabolized with a non-specific accumulation of radioactivity in the brain and bone.
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    • "[ 18 F]FECNT PET imaging in humans can distinguish DAT deficits between Parkinson's patients and normal controls using uptake ratios [20]. Later work by Zoghbi and colleagues showed that metabolism of [ 18 F]FECNT yields a 18 F-labeled metabolite that crosses the blood– brain-barrier in rat and monkey brain [26]. These findings suggest the hypothesis that quantification with compartment modeling could be confounded in humans by the presence of a radiolabeled metabolite. "
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    ABSTRACT: Fluorine-18 labeled 2β-carbomethoxy-3β-(4-chlorophenyl)-8-(2-fluoroethyl)nortropane ([(18)F]FECNT) binds reversibly to the dopamine transporter (DAT) with high selectivity. [(18)F]FECNT has been used extensively in the quantification of DAT occupancy in non-human primate brain and can distinguish between Parkinson's and healthy controls in humans. The purpose of this work was to develop a compartment model to characterize the kinetics of [(18)F]FECNT for quantification of DAT density in healthy human brain. Twelve healthy volunteers underwent 180min dynamic [(18)F]FECNT PET imaging including sampling of arterial blood. Regional time-activity curves were extracted from the caudate, putamen and midbrain including a reference region placed in the cerebellum. Binding potential, BPND, was calculated for all regions using kinetic parameters estimated from compartmental and Logan graphical model fits to the time-activity data. Simulations were performed to determine whether the compartment model could reliably fit time-activity data over a range of BPND values. The kinetics of [(18)F]FECNT were well-described by the reversible 2-tissue arterial input and full reference tissue compartment models. Calculated binding potentials in the caudate, putamen and midbrain were in good agreement between the arterial input model, reference tissue model and the Logan graphical model. The distribution volume in the cerebellum did not reach a plateau over the duration of the study, which may be a result of non-specific binding in the cerebellum. Simulations that included non-specific binding show that the reference and arterial input models are able to estimate BPND for DAT densities well below that observed in normal volunteers. The kinetics of [(18)F]FECNT in human brain are well-described by arterial input and reference tissue compartment models. Measured and simulated data show that BPND calculated with reference tissue model is proportional to BPND calculated from the arterial input model.
    Full-text · Article · Mar 2014 · Nuclear Medicine and Biology
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    • "Radioactivity in plasma was quantified by a gamma-counter and analysed by reverse-phase chromatography to separate parent radioligand from radiometabolites (Zoghbi et al., 2006). Free fraction of 11 C-PBR28 in plasma (f P ) was measured by ultrafiltration and normalized using a standard derived from pooled donor plasma (Abi-Dargham et al., 1995). "

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