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: 5.56). 04/2006; 47(3):520-7.
Source: PubMed

ABSTRACT 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.

  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    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.
    Nuclear Medicine and Biology 07/2014; 41(6). DOI:10.1016/j.nucmedbio.2014.03.023 · 2.41 Impact Factor
  • Source
    • "Arterial blood was manually sampled at 15-s intervals for the first 2 min 30 s, then at 3, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 min. 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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Neuroinflammation is a pathological hallmark of Alzheimer's disease, but its role in cognitive impairment and its course of development during the disease are largely unknown. To address these unknowns, we used positron emission tomography with (11)C-PBR28 to measure translocator protein 18 kDa (TSPO), a putative biomarker for inflammation. Patients with Alzheimer's disease, patients with mild cognitive impairment and older control subjects were also scanned with (11)C-Pittsburgh Compound B to measure amyloid burden. Twenty-nine amyloid-positive patients (19 Alzheimer's, 10 mild cognitive impairment) and 13 amyloid-negative control subjects were studied. The primary goal of this study was to determine whether TSPO binding is elevated in patients with Alzheimer's disease, and the secondary goal was to determine whether TSPO binding correlates with neuropsychological measures, grey matter volume, (11)C-Pittsburgh Compound B binding, or age of onset. Patients with Alzheimer's disease, but not those with mild cognitive impairment, had greater (11)C-PBR28 binding in cortical brain regions than controls. The largest differences were seen in the parietal and temporal cortices, with no difference in subcortical regions or cerebellum. (11)C-PBR28 binding inversely correlated with performance on Folstein Mini-Mental State Examination, Clinical Dementia Rating Scale Sum of Boxes, Logical Memory Immediate (Wechsler Memory Scale Third Edition), Trail Making part B and Block Design (Wechsler Adult Intelligence Scale Third Edition) tasks, with the largest correlations observed in the inferior parietal lobule. (11)C-PBR28 binding also inversely correlated with grey matter volume. Early-onset (<65 years) patients had greater (11)C-PBR28 binding than late-onset patients, and in parietal cortex and striatum (11)C-PBR28 binding correlated with lower age of onset. Partial volume corrected and uncorrected results were generally in agreement; however, the correlation between (11)C-PBR28 and (11)C-Pittsburgh Compound B binding was seen only after partial volume correction. The results suggest that neuroinflammation, indicated by increased (11)C-PBR28 binding to TSPO, occurs after conversion of mild cognitive impairment to Alzheimer's disease and worsens with disease progression. Greater inflammation may contribute to the precipitous disease course typically seen in early-onset patients. (11)C-PBR28 may be useful in longitudinal studies to mark the conversion from mild cognitive impairment or to assess response to experimental treatments of Alzheimer's disease.
    Brain 06/2013; 136(7). DOI:10.1093/brain/awt145 · 10.23 Impact Factor
  • Source
    • "The third and most likely explanation for the increase is the production of radioactive metabolite that passed through the blood brain barrier (BBB). Zoghbi et al. (2006) reported that the major radioactive metabolite of [ 18 F]FECNT was [ 18 F]fluoroacetaldehyde or [ 18 F]fluoroacetic acid, both of which could penetrate the BBB to enter the brain. They were produced by peripheral metabolism with P-450-catalyzed N-dealkylation. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The competitive inhibition of dopamine transporters (DAT) with cocaine, a specific DAT inhibitor, was evaluated with a feedback-controlled bolus plus infusion (FC-B/I) method using animal positron emission tomography (PET) in the living brain of conscious monkey. 2β-Carbomethoxy-3β-(4-fluorophenyl)-8-(2-[(18) F]fluoroethyl) nortropane ([(18) F]β-CFT-FE; Harada et al., 2004) was used for this study because it provided specific, fast and reversible kinetic properties to DAT in the striatum. In FC-B/I method, the real-time image reconstruction was started just after intravenous bolus injection of [(18) F]β-CFT-FE to generate a time-activity curve (TAC) in the striatum, and the infusion rate was adjusted to achieve an equilibrium state of the striatal radioactivity concentrations by means of a feedback-control algorithm. The first equilibrium state in the brain was reached within 20 min after the infusion start. Intravenous administration of cocaine at the doses of 0.02, 0.1 and 0.5 mg/kg shifted the equilibrium radioactivity level to the second equilibrium state in a dose-dependent manner, while no significant alterations was observed in the cerebellum. The present results demonstrated that the combined use of FC-B/I method and PET probe with fast kinetics like [(18) F]β-CFT-FE could be useful to assess the occupancy of drugs in the living brain with PET. Synapse, 2012. © 2012 Wiley Periodicals, Inc.
    Synapse 01/2013; 67(1). DOI:10.1002/syn.21614 · 2.43 Impact Factor
Show more