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Daniele Caprioli,
Young T Hong,
Stephen J Sawiak, Valentina Ferrari,
David J Williamson,
Bianca Jupp,
T Adrian Carpenter,
Franklin I Aigbirhio,
Barry J Everitt,
Trevor W Robbins,
Tim D Fryer,
Jeffrey W Dalley
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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was not different between the two impulsivity groups, impulsivity selectively decreased in high-impulsive rats withdrawn from cocaine.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; · 6.99 Impact Factor
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Patrick J Riss,
Young T Hong,
János Marton,
Daniele Caprioli,
David J Williamson, Valentina Ferrari,
Neil Saigal,
Bryan L Roth,
Gjermund Henriksen,
Tim D Fryer,
Jeffrey W Dalley,
Franklin I Aigbirhio
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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; · 6.38 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. · 3.70 Impact Factor
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Patrick J Riss,
Jacob M Hooker,
Colleen Shea,
Youwen Xu,
Pauline Carter,
Donald Warner, Valentina Ferrari,
Sung-Won Kim,
Franklin I Aigbirhio,
Joanna S Fowler,
Frank Roesch
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ABSTRACT: N-(4-fluorobut-2-yn-1-yl)-2β-carbomethoxy-3β-(4'-tolyl)nortropane (PR04.MZ, 1) is a PET radioligand for the non-invasive exploration of the function of the cerebral dopamine transporter (DAT). A reliable automated process for routine production of the carbon-11 labelled analogue [(11)C]PR04.MZ ([(11)C]-1) has been developed using GMP compliant equipment. An adult female Papio anubis baboon was studied using a test-retest protocol with [(11)C]-1 in order to assess test-retest reliability, metabolism and CNS distribution profile of the tracer in non-human primates. Blood sampling was performed throughout the studies for determination of the free fraction in plasma (f(P)), plasma input functions and metabolic degradation of the radiotracer [(11)C]-1. Time-activity curves were derived for the putamen, the caudate nucleus, the ventral striatum, the midbrain and the cerebellum. Distribution volumes (V(T)) and non-displaceable binding potentials (BP(ND)) for various brain regions and the blood were obtained from kinetic modelling. [(11)C]-1 shows promising results as a selective marker of the presynaptic dopamine transporter. With the reliable visualisation of the extra-striatal dopaminergic neurons and no indication on labelled metabolites, the tracer provides excellent potential for translation into man.
Bioorganic & medicinal chemistry letters 10/2011; 22(1):679-82. · 2.65 Impact Factor
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Patrick J Riss,
Young T Hong,
David Williamson,
Daniele Caprioli,
Sergey Sitnikov, Valentina Ferrari,
Steve J Sawiak,
Jean-Claude Baron,
Jeffrey W Dalley,
Tim D Fryer,
Franklin I Aigbirhio
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ABSTRACT: The 5-hydroxytryptamine type 2a (5-HT(2A)) selective radiotracer [(18)F]altanserin has been subjected to a quantitative micro-positron emission tomography study in Lister Hooded rats. Metabolite-corrected plasma input modeling was compared with reference tissue modeling using the cerebellum as reference tissue. [(18)F]altanserin showed sufficient brain uptake in a distribution pattern consistent with the known distribution of 5-HT(2A) receptors. Full binding saturation and displacement was documented, and no significant uptake of radioactive metabolites was detected in the brain. Blood input as well as reference tissue models were equally appropriate to describe the radiotracer kinetics. [(18)F]altanserin is suitable for quantification of 5-HT(2A) receptor availability in rats.
Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 07/2011; 31(12):2334-42. · 5.46 Impact Factor
