Franklin I Aigbirhio

University of Cambridge, Cambridge, England, United Kingdom

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Publications (101)488.18 Total impact

  • Laurent Brichard, Franklin I. Aigbirhio
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    ABSTRACT: The standard method used to generate reactive [18F]fluoride for [18F]radiolabelling is to trap it on an anion-exchange cartridge then elute it with a basic aqueous solution, which is then subjected to azeotropic evaporation to remove water. We have now developed a method through the use of tetraethylammonium hydrogen carbonate in which we can obtain efficient recovery of [18F]fluoride (up to 99 %), remove the requirement for the time-consuming and inefficient azeotropic evaporation process and produce a reactive [18F]fluoride that can undergo a wide range of aliphatic and aromatic [18F]nucleophilic substitutions in up to 93 % radiochemical conversion at end-of-synthesis in the presence or without water.
    Annalen der Chemie und Pharmacie 08/2014; · 3.15 Impact Factor
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    ABSTRACT: Schizophrenia is associated with upregulation of dopamine (DA) release in the caudate nucleus. The caudate has dense connections with the orbitofrontal cortex (OFC) via the frontostriatal loops, and both areas exhibit pathophysiological change in schizophrenia. Despite evidence that abnormalities in dopaminergic neurotransmission and prefrontal cortex function co-occur in schizophrenia, the influence of OFC DA on caudate DA and reinforcement processing is poorly understood. To test the hypothesis that OFC dopaminergic dysfunction disrupts caudate dopamine function, we selectively depleted dopamine from the OFC of marmoset monkeys and measured striatal extracellular dopamine levels (using microdialysis) and dopamine D2/D3 receptor binding (using positron emission tomography), while modeling reinforcement-related behavior in a discrimination learning paradigm. OFC dopamine depletion caused an increase in tonic dopamine levels in the caudate nucleus and a corresponding reduction in D2/D3 receptor binding. Computational modeling of behavior showed that the lesion increased response exploration, reducing the tendency to persist with a recently chosen response side. This effect is akin to increased response switching previously seen in schizophrenia and was correlated with striatal but not OFC D2/D3 receptor binding. These results demonstrate that OFC dopamine depletion is sufficient to induce striatal hyperdopaminergia and changes in reinforcement learning relevant to schizophrenia.
    Journal of Neuroscience 05/2014; 34(22):7663-76. · 6.75 Impact Factor
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    ABSTRACT: By detecting β-amyloid (Aβ) in the wall of cortical arterioles, amyloid positron emission tomography (PET) imaging might help diagnose cerebral amyloid angiopathy (CAA) in patients with lobar intracerebral hemorrhage (l-ICH). No previous study has directly assessed the diagnostic value of (11)C-Pittsburgh compound B (PiB) PET in probable CAA-related l-ICH against healthy controls (HCs). (11)C-PiB-PET and magnetic resonance imaging (MRI) including T2* were obtained in 11 nondemented patients fulfilling the Boston criteria for probable CAA-related symptomatic l-ICH (sl-ICH) and 20 HCs without cognitive complaints or impairment. After optimal spatial normalization, cerebral spinal fluid (CSF)-corrected PiB distribution volume ratios (DVRs) were obtained. There was no significant difference in whole cortex or regional DVRs between CAA patients and age-matched HCs. The whole cortex DVR was above the 95% confidence limit in 4/9 HCs and 10/11 CAA patients (sensitivity=91%, specificity=55%). Region/frontal or occipital ratios did not have better discriminative value. Similar but less accurate results were found using visual analysis. In patients with sl-ICH, (11)C-PiB-PET has low specificity for CAA due to the frequent occurrence of high (11)C-PiB uptake in the healthy elderly reflecting incipient Alzheimer's disease (AD), which might also be present in suspected CAA. However, a negative PiB scan rules out CAA with excellent sensitivity, which has clinical implications for prognostication and selection of candidates for drug trials.Journal of Cerebral Blood Flow & Metabolism advance online publication, 12 March 2014; doi:10.1038/jcbfm.2014.43.
    Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 03/2014; · 5.46 Impact Factor
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    ABSTRACT: The 22nd annual symposium of the International Isotope Society's United Kingdom Group took place at the Møller Centre, Churchill College, Cambridge, UK, on Friday, 18 October 2013. The meeting was attended by 65 delegates from academia and industry; the life sciences; and chemical, radiochemical and scientific instrument suppliers. Delegates were welcomed by Dr Ken Lawrie (GlaxoSmithKline, UK, chair of the IIS UK group). The subsequent scientific programme consisted of oral and poster presentations on isotopic chemistry and applications of labelled compounds, or of chemistry with potential implications for isotopic synthesis. Both short-lived and long-lived isotopes were represented, as were stable isotopes. The symposium programme was divided into a morning session chaired by Dr Karl Cable (GlaxoSmithKline, UK) and afternoon sessions chaired by Mr Mike Chappelle (Quotient Biosciences, UK) and by Dr Nick Bushby (AstraZeneca, UK). The UK meeting concluded with remarks from Dr Ken Lawrie (GlaxoSmithKline, UK).
    Journal of Labelled Compounds 01/2014;
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    ABSTRACT: Changes in the magnitude of the mitochondrial membrane potential occur in a range of important pathologies. To assess changes in membrane potential in patients, we set out to develop an improved mitochondria-targeted positron emission tomography probe comprising a lipophilic triphenylphosphonium cation attached to a fluorine-18 radionuclide via an 11-carbon alkyl chain, which is well-established to effectively transport to and localise within mitochondria. Here, we describe the radiosynthesis of this probe, 11-[(18) F]fluoroundecyl-triphenylphosphonium (MitoF), from no-carrier-added [(18) F]fluoride and a fully automated synthetic protocol to prepare it in good radiochemical yields (2-3 GBq at end-of-synthesis) and radiochemical purity (97-99%). Copyright © 2013 John Wiley & Sons, Ltd.
    Journal of Labelled Compounds 12/2013; 56(14):717-21.
  • Circulation 11/2013; 128(A14673). · 14.95 Impact Factor
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    ABSTRACT: OBJECTIVES To image amyloid deposition in patients with traumatic brain injury (TBI) using carbon 11-labeled Pittsburgh Compound B ([11C]PiB) positron emission tomography (PET) and to validate these findings using tritium-labeled PiB ([3H]PiB) autoradiography and immunocytochemistry in autopsy-acquired tissue. DESIGN, SETTING, AND PARTICIPANTS In vivo PET at tertiary neuroscience referral center and ex vivo immunocytochemistry of autopsy-acquired brain tissue from a neuropathology archive. [11C]PiB PET was used to image amyloid deposition in 11 controls (median [range] age, 35 [24-60] years) and in 15 patients (median [range] age, 33 [21-50] years) between 1 and 361 days after a TBI. [3H]PiB autoradiography and immunocytochemistry for β-amyloid (Aβ) and β-amyloid precursor protein in brain tissue were obtained from separate cohorts of 16 patients (median [range] age, 46 [21-70] years) who died between 3 hours and 56 days after a TBI and 7 controls (median [range] age, 61 [29-71] years) who died of other causes. MAIN OUTCOMES AND MEASURES We quantified the [11C]PiB distribution volume ratio and standardized uptake value ratio in PET images. The distribution volume ratio and the standardized uptake value ratio were measured in cortical gray matter, white matter, and multiple cortical and white matter regions of interest, as well as in striatal and thalamic regions of interest. We examined [3H]PiB binding and Aβ and β-amyloid precursor protein immunocytochemistry in autopsy-acquired brain tissue. RESULTS Compared with the controls, the patients with TBI showed significantly increased [11C]PiB distribution volume ratios in cortical gray matter and the striatum (corrected P < .05 for both), but not in the thalamus or white matter. Increases in [11C]PiB distribution volume ratios in patients with TBI were seen across most cortical subregions, were replicated using comparisons of standardized uptake value ratios, and could not be accounted for by methodological confounders. Autoradiography revealed [3H]PiB binding in neocortical gray matter, in regions where amyloid deposition was demonstrated by immunocytochemistry; white matter showed Aβ and β-amyloid precursor protein by immunocytochemistry, but no [3H]PiB binding. No plaque-associated amyloid immunoreactivity or [3H]PiB binding was seen in cerebellar gray matter in autopsy-acquired tissue from either controls or patients with TBI, although 1 sample of cerebellar tissue from a patient with TBI showed amyloid angiopathy in meningeal vessels. CONCLUSIONS AND RELEVANCE [11C]PiB shows increased binding following TBI. The specificity of this binding is supported by neocortical [3H]PiB binding in regions of amyloid deposition in the postmortem tissue of patients with TBI. [11C]PiB PET could be valuable in imaging amyloid deposition following TBI.
    JAMA neurology. 11/2013;
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    ABSTRACT: Through the combined use of (18)F-fallypride positron emission tomography and magnetic resonance imaging this study examined the neural mechanisms underlying the attentional deficits associated with attention deficit/hyperactivity disorder and their potential reversal with a single therapeutic dose of methylphenidate. Sixteen adult patients with attention deficit/hyperactivity disorder and 16 matched healthy control subjects were positron emission tomography and magnetic resonance imaging scanned and tested on a computerized sustained attention task after oral methylphenidate (0.5 mg/kg) and placebo administration in a within-subject, double-blind, cross-over design. Although patients with attention deficit/hyperactivity disorder as a group showed significant attentional deficits and reduced grey matter volume in fronto-striato-cerebellar and limbic networks, they had equivalent D2/D3 receptor availability and equivalent increases in endogenous dopamine after methylphenidate treatment to that observed in healthy control subjects. However, poor attentional performers drawn from both the attention deficit/hyperactivity disorder and the control groups had significantly reduced left caudate dopamine activity. Methylphenidate significantly increased dopamine levels in all nigro-striatal regions, thereby normalizing dopamine levels in the left caudate in low performers. Behaviourally, methylphenidate improved sustained attention in a baseline performance-dependent manner, irrespective of diagnosis. This finding was accompanied by an equally performance-dependent effect of the drug on dopamine release in the midbrain, whereby low performers showed reduced dopamine release in this region. Collectively, these findings support a dimensional model of attentional deficits and underlying nigro-striatal dopaminergic mechanisms of attention deficit/hyperactivity disorder that extends into the healthy population. Moreover, they confer midbrain dopamine autoreceptors a hitherto neglected role in the therapeutic effects of oral methylphenidate in attention deficit/hyperactivity disorder. The absence of significant case-control differences in D2/D3 receptor availability (despite the observed relationships between dopamine activity and attention) suggests that dopamine dysregulation per se is unlikely to be the primary cause underlying attention deficit/hyperactivity disorder pathology in adults. This conclusion is reinforced by evidence of neuroanatomical changes in the same set of patients with attention deficit/hyperactivity disorder.
    Brain 11/2013; 136(Pt 11):3252-70. · 10.23 Impact Factor
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    ABSTRACT: Mapping the ischaemic penumbra in acute stroke is of considerable clinical interest. For this purpose, mapping tissue hypoxia with (18)F-misonidazole (FMISO) PET is attractive, and is straightforward compared to (15)O PET. Given the current emphasis on penumbra imaging using diffusion/perfusion MR or CT perfusion, investigating the relationships between FMISO uptake and abnormalities with these modalities is important. According to a prospective design, three patients (age 54-81 years; admission NIH stroke scale scores 16-22) with an anterior circulation stroke and extensive penumbra on CT- or MR-based perfusion imaging successfully completed FMISO PET, diffusion-weighted imaging and MR angiography 6-26 h after stroke onset, and follow-up FLAIR to map the final infarction. All had persistent proximal occlusion and a poor outcome despite thrombolysis. Significant FMISO trapping was defined voxel-wise relative to ten age-matched controls and mapped onto coregistered maps of the penumbra and irreversibly damaged ischaemic core. FMISO trapping was present in all patients (volume range 18-119 ml) and overlapped mainly with the penumbra but also with the core in each patient. There was a significant (p ≤ 0.001) correlation in the expected direction between FMISO uptake and perfusion, with a sharp FMISO uptake bend around the expected penumbra threshold. FMISO uptake had the expected overlap with the penumbra and relationship with local perfusion. However, consistent with recent animal data, our study suggests FMISO trapping may not be specific to the penumbra. If confirmed in larger samples, this preliminary finding would have potential implications for the clinical application of FMISO PET in acute ischaemic stroke.
    European Journal of Nuclear Medicine 10/2013; · 4.53 Impact Factor
  • Franklin I Aigbirhio
    Journal of Labelled Compounds 05/2013; 56(6):338-339.
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    ABSTRACT: After stroke, penumbral salvage determines clinical recovery. However, the rescued penumbra may be affected by selective neuronal loss, as documented both histopathologically in animals and using the validated in vivo positron emission tomography marker (11)C-flumazenil in humans. However, whether the non-infarcted penumbra is capable of neuronal activation, and how selective neuronal loss may interfere, is unknown. Here we prospectively mapped the topographical relationships between functional magnetic resonance imaging responses and non-infarcted penumbra, and tested the hypothesis that the former do take place in the latter, but only in its subsets spared selective neuronal loss. Seven patients (mean age 74 years; three thrombolysed) with first-ever acute anterior circulation stroke, presence of penumbra on computed tomography perfusion performed within 6 h of onset, and substantial deficit on admission but good outcome at 1-3 months (National Institute of Health Stroke Score range 6-13 and 0-1, respectively, P = 0.001), were studied. At follow-up, patients underwent structural magnetic resonance imaging to map the infarct, functional magnetic resonance imaging (three tasks selected to probe the right or left hemisphere), and (11)C-flumazenil positron emission tomography generating binding potential maps. Patients with significant carotid or middle-cerebral artery disease or impaired vasoreactivity were excluded. Following image coregistration, the non-infarcted penumbra comprised all acutely ischaemic voxels (identified on acute computed tomography perfusion using previously validated thresholds) not part of the final infarct. To test our hypotheses, the overlap between functional magnetic resonance imaging activation clusters and non-infarcted penumbra was mapped, and binding potential values then computed both within and outside this overlap. In addition, the overlap between functional magnetic resonance imaging activation clusters and areas of significantly reduced binding potential (determined using Statistical Parametric Mapping against 16 age-matched control subjects) was assessed in each patient. An overlap between non-infarcted penumbra and functional magnetic resonance imaging clusters was present in seven of seven patients, substantial in four. Binding potential was significantly reduced in the whole non-infarcted penumbra (P < 0.01) but not within the functional magnetic resonance imaging overlap. Clusters with significantly reduced binding potential showed virtually no overlap with functional magnetic resonance imaging activation compared with 12 age-matched controls (P = 0.04).The results from this proof of principle study suggest that 1-3 months after stroke the non-infarcted penumbra is capable of neuronal activation, consistent with its established role in recovery of neurological functions. However, although the non-infarcted penumbra as a whole was affected by selective neuronal loss, activations tended to occur within portions spared selective neuronal loss, suggesting the latter impedes neuronal activation. Although its clinical correlates are still elusive, selective neuronal loss may represent a novel therapeutic target in the aftermath of ischaemic stroke.
    Brain 05/2013; · 10.23 Impact Factor
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    ABSTRACT: Addiction is a chronically relapsing brain disorder that insidiously affects the motivational and cognitive control systems of susceptible individuals. Clinical research over the last two decades has profited from the technique of positron emission tomography (PET), a non-invasive imaging technique that allows the longitudinal assessment of addiction-relevant biomarkers in current and former drug users. The vast majority of this research has unsurprisingly focused on the brain dopamine (DA) systems given their pivotal role in primary drug reinforcement and the rich abundance of dopaminergic PET tracers. However, the provocative failure of dopaminergic medications in addiction has fuelled the search for alternative treatments. This article considers current controversies in this field as well as prospects for elucidating neurotransmitter mechanisms in addiction beyond DA.
    Current opinion in neurobiology 05/2013; · 7.21 Impact Factor
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    ABSTRACT: Formation of neurofibrillary tangles, comprising of microtubule-associated tau protein, is a hallmark of a group of neurodegenerative diseases, including Alzheimer's disease. In consequence, in vivo imaging of neurofibrillary tangles is a current focus of positron emission tomography research. Herein, development of an in vitro radioligand binding assay which uses synthetic aggregates as a model of neurofibrillary tangles is reported, together with evaluation of novel derivatives of the tau protein ligand astemizole.
    Medicinal Chemistry Communication 04/2013; 4(5):852-855. · 2.63 Impact Factor
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    ABSTRACT: BACKGROUND: Mitochondrial dysfunction contributes to degenerative neurological disorders, consequently there is a need for mitochondria-targeted therapies that are effective within the brain. One approach to deliver pharmacophores is by conjugation to the lipophilic triphenylphosphonium (TPP) cation that accumulates in mitochondria driven by the membrane potential. While this approach has delivered TPP-conjugated compounds to the brain, the amounts taken up are lower than by other organs. METHODS: To discover why uptake of hydrophobic TPP compounds by the brain is relatively poor, we assessed the role of the P-glycoprotein (Mdr1a/b) and breast cancer resistance (Brcp) ATP Binding Cassette (ABC) transporters, which drive the efflux of lipophilic compounds from the brain thereby restricting the uptake of lipophilic drugs. We used a triple transgenic mouse model lacking two isoforms of P-glycoprotein (Mdr1a/b) and the Bcrp protein. RESULTS: There was a significant increase in the uptake into the brain of two hydrophobic TPP compounds, MitoQ and MitoF, in the triple transgenics following intra venous (iv) administration compared to control mice. Greater amounts of the hydrophobic TPP compounds were also retained in the liver of transgenic mice compared to controls. The uptake into the heart, white fat, muscle and kidneys was comparable between the transgenic mice and controls. CONCLUSION: Efflux of hydrophobic TPP compounds by ABC transporters contributes to their lowered uptake into the brain and liver. GENERAL SIGNIFICANCE: These findings suggest that strategies to bypass ABC transporters in the BBB will enhance delivery of mitochondria-targeted antioxidants, probes and pharmacophores to the brain.
    Biochimica et Biophysica Acta 02/2013; · 4.66 Impact Factor
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    ABSTRACT: We have previously shown that impulsivity in rats predicts the emergence of compulsive cocaine seeking and taking, and is coupled to decreased D(2/3) receptor availability in the ventral striatum. Since withdrawal from cocaine normalises high impulsivity in rats, we investigated, using positron emission tomography (PET), the effects of response-contingent cocaine administration on D(2/3) receptor availability in the striatum. Rats were screened for impulsive behavior on the 5-choice serial reaction time task. After a baseline PET scan with the D(2/3) ligand [(18)F]fallypride, rats were trained to self-administer cocaine for 15 days under a long-access schedule. As a follow up, rats were assessed for impulsivity and underwent a second [(18)F]fallypride PET scan. At baseline, we found that D(2/3) receptor availability was significantly lower in the left, but not right, ventral striatum of high-impulsive rats compared with low-impulsive rats. While the number of self-administered cocaine infusions was not different between the two impulsivity groups, impulsivity selectively decreased in high-impulsive rats withdrawn from cocaine. This effect was accompanied by a significant increase in D(2/3) receptor availability in the left, but not right, ventral striatum. We further report that D(2/3) receptor availability was inversely related to baseline D(2/3) receptor availability in the ventral striatum of high-impulsive rats, as well as to the left and right dorsal striatum of both low-impulsive and high-impulsive rats. These findings indicate that the reduction in impulsivity in high-impulsive rats by prior cocaine exposure may be mediated by a selective correction of deficient D(2/3) receptor availability in the ventral striatum. A similar baseline-dependent mechanism may account for the therapeutic effects of stimulant drugs in clinical disorders such as ADHD.Neuropsychopharmacology accepted article preview online, 11 February 2013; doi:10.1038/npp.2013.44.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 02/2013; · 8.68 Impact Factor
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    ABSTRACT: We have investigated the opioid receptor (OR) agonist (20R)-4,5-α-epoxy-6-(2-(18)F-fluoroethoxy)-3-hydroxy-α,17-dimethyl-α-(2-phenyleth-1-yl)-6,14-ethenomorphinan-7-methanol ((18)F-FE-PEO) as a candidate OR PET ligand. This tracer is attractive because it combines (18)F labeling, is suited to the slow kinetics of high-affinity ligands, and has agonist binding, which has been shown to be more sensitive to changes in OR occupation than is antagonist binding. METHODS: Agonist potency and off-target binding were investigated in vitro, and autoradiographic studies on rat brain sections were used to assess binding patterns. Quantification of the tracer in vivo was investigated using small-animal PET in rats with blood sampling. RESULTS: (18)F-FE-PEO was obtained by direct nucleophilic radiofluorination and subsequent deprotection with a yield of 28% ± 15%, a specific activity of 52-224 MBq/nmol, and a radiochemical purity of more than 97% (90 min from end of bombardment). In vitro studies showed it to be a full agonist ligand, which selectively binds to OR with high affinity, although it is not selective to a single OR subtype (inhibition constant, 0.4-1.6 nM across OR subtypes). Autoradiography binding patterns were consistent with the known distribution of OR, although nondisplaceable signal typically constituted one third of the signal in OR-dense regions. Although metabolites were present in blood (∼40% of plasma radioactivity was nonparent 3 h after injection), no significant metabolite fraction was found in brain tissue, aiding PET quantification. A plasma input 2-tissue-compartment model provided good fits to the PET data, and regional distribution volumes from the latter correlated well with those from Logan plot analysis (r(2) = 0.98). The cerebellum had the lowest distribution volume, but the time-activity curve data could not be adequately fitted with a 1-tissue-compartment model. Reference tissue models using the cerebellum as the reference region did not provide good fits to the data, so blood-based kinetic analysis is recommended. CONCLUSION: As the first (18)F-labeled OR agonist ligand, (18)F-FE-PEO is a useful addition to the existing OR ligand portfolio.
    Journal of Nuclear Medicine 01/2013; · 5.56 Impact Factor
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    ABSTRACT: INTRODUCTION: Severe brain hypoxia in the territory of the occluded artery is a key feature of ischemic stroke. This region can be imaged using positron emission tomography (PET) and the standard hypoxia radiotracer (18)F-fluoromisonidazole ((18)F-FMISO). However, the utility of (18)F-FMISO is limited by its slow accumulation in the lesion. Therefore, this study investigated three hypoxia-sensitive radiotracers, namely the nitroimidazole (18)F-fluoroazomycin arabinoside ((18)F-FAZA) and two (64)Cu bis(thiosemicarbazone) complexes ((64)Cu-ATSM and (64)Cu-ATSE), expected to have improved pharmacokinetic profiles relative to (18)F-FMISO, in a rodent model of ischemic stroke. METHODS: In anaesthetised Wistar rats, the distal middle cerebral artery was permanently occluded by electrocoagulation, the radiotracers administered intravenously and animals PET scanned for up to 3hours, followed by T2-weighted magnetic resonance imaging to map the infarct. RESULTS: As expected, late and prominent (18)F-FMISO retention was observed despite lower tracer delivery into the affected region. Time-activity curves revealed that both (64)Cu-ATSM and (64)Cu-ATSE showed rapid entry and efflux from the brain, but did not show significant accumulation in the lesion. (18)F-FAZA showed limited brain penetration, and accumulation in the lesion was inconsistent, low and as slow as (18)F-FMISO. CONCLUSIONS: This study suggests further development of these radiotracers as hypoxia markers for ischemic stroke may not be warranted.
    Nuclear Medicine and Biology 01/2013; · 2.41 Impact Factor
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    ABSTRACT: BACKGROUND AND PURPOSE: Current models dictate that, depending on occurrence of early reperfusion, the ischemic penumbra either undergoes or escapes infarction (i.e., "pan-necrosis"). However, tissue outcome following temporary middle-cerebral artery occlusion (tMCAo) in rodents can also include selective neuronal loss (SNL), which even if subtle may impede functional recovery. In order to explore the pathophysiology of ischemic stroke, determine potential therapeutic targets and monitor effects of therapy, in vivo imaging surrogates of these varied histopathological outcomes applicable in the clinical setting would be useful. Although hyperintense signal on T(2)-weighted MRI in the chronic post-stroke stage is considered a reliable surrogate of tissue infarction, SNL is not associated with T(2)W abnormal signal. In the clinical setting, the neuron-specific PET ligand (11)C-flumazenil (FMZ) has been used to identify both pan-necrosis and peri-infarct SNL, but this inference has not been histopathological confirmed so far. Here we investigated the late tissue sequelae of tMCAo in the rodent using in vivo T(2)W MRI and FMZ-PET against post mortem immunohistochemistry as gold standard. METHODS: Adult spontaneously hypertensive rats (SHRs) underwent 45min distal-clip middle-cerebral artery occlusion and, 28days later, FMZ-PET and T(2)W-MRI, immediately followed by immunohistochemistry for neuronal loss (NeuN), activated microglia and astrocytosis. Based on standard histopathological definitions, ischemic lesions were classified into pan-necrosis, partial infarction or SNL. NeuN changes and FMZ binding across the whole hemisphere were quantified in the same set of 44 regions-of-interest according to previously validated protocols; linear regressions between these two measures were carried out both within and across subjects. RESULTS: Both cortical pan-necrosis/partial infarction and SNL were present in all rats except one, where SNL was isolated and extensive. Infarction/partial infarction, but not SNL, was associated with T(2)W hyperintense signals and cortical atrophy. In contrast, FMZ binding was decreased in all types of lesions including SNL, in proportion with NeuN staining intensity both within (p<0.05 to <0.001) and across (p<0.001) subjects, including the subject that showed pure SNL (p=0.01). CONCLUSION: This novel study revealed three main facts: i) long-term histopathological cortical changes following 45min tMCAo in SHRs included all three of SNL, partial infarction and frank infarction; ii) T2W MRI showed conspicuous high signal lesions for complete or partial infarction, but no changes for SNL; and iii) FMZ-PET was sensitive to all three types of tMCAo-induced histopathological changes, including isolated SNL, suggesting it is a valid surrogate for the histological sequelae of focal cerebral ischemia. In addition, the finding of almost universal completed cortical infarction at 28days differed from our previous findings at 14-day survival using exactly the same experimental protocol and rat strain, where SNL was the almost exclusive outcome, suggesting a phenomenon of delayed cortical infarct maturation whereby the extensive neuronal loss present at two weeks matures into infarction at four. Prospective studies are needed to investigate this intriguing observation.
    Neurobiology of Disease 11/2012; · 5.62 Impact Factor
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    ABSTRACT: We have synthesized two potential positron emission tomography (PET) radioligands for the endothelin (ET) receptor. '11C'-PD156707 was produced by O-methylation of PD169390 using '11C'iodomethane. Radiochemical conversions of the order of 74+/- 3.2% (n=8) were obtained. The radiochemical purity of the isolated [11C]-PD156707 was 99% and the specific activity was 538mCi/[mu]mol.[18F]-BQ3020 was produced from [18]fluoride in a total radiochemical yield of 2.7 +/- 0.4% (n=10) in 238 +/- 5 min. The radiochemical purity was 95% and specific activities of the order of 670-930 mCi/[mu]mol were obtained. (C) 2000 Lippincott Williams & Wilkins, Inc.
    Journal of Cardiovascular Pharmacology 08/2012; 36(5). · 2.11 Impact Factor
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    ABSTRACT: A rapid and efficient protocol to afford the title compound 2-[(18)F]-fluoro-2,2-difluoroethyl tosylate ([(18)F]7b) is described. Starting from [(18)F]fluoride ion, labelling reagent 7b was obtained in good yields and a high specific radioactivity. Compound ([(18)F]7b) was then used to synthesise a prospective radiotracer for PET-imaging in dementia.
    Organic & Biomolecular Chemistry 07/2012; 10(34):6980-6. · 3.49 Impact Factor

Publication Stats

2k Citations
488.18 Total Impact Points


  • 2000–2014
    • University of Cambridge
      • • Behavioural and Clinical Neurosciences Institute (BCNI)
      • • Department of Clinical Neurosciences
      • • Wolfson Brain Imaging Centre
      • • Division of Clinical Pharmacology
      Cambridge, England, United Kingdom
  • 2008
    • University of Bath
      • Department of Chemistry
      Bath, ENG, United Kingdom
  • 2007
    • Johnson & Johnson
      New Brunswick, New Jersey, United States
    • University of Oxford
      • Department of Chemistry
      Oxford, ENG, United Kingdom
  • 2004
    • Karolinska Institutet
      • Institutionen för klinisk neurovetenskap
      Solna, Stockholm, Sweden