Nicola K Jobson

Publications (7)17.91 Total impact

• Article: Iodine-123 labeled reboxetine analogues for imaging of noradrenaline transporter in brain using single photon emission computed tomography.

  Adriana Alexandre S Tavares, Nicola K Jobson, Deborah Dewar, Andrew Sutherland, Sally L Pimlott, Jeffery Batis, Olivier Barret, John Seibyl, Gilles Tamagnan
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  ABSTRACT: Preliminary investigation of the radioiodinated (S,S)-reboxetine analogue, (123) I-INER, in baboons showed this tracer to have promise for imaging the noradrenaline transporter (NAT) using single photon emission computed tomography (SPECT). More recently, the radioiodinated (R,S)-stereoisomer of (123) I-INER, (123) I-NKJ64, has been synthesized and preliminary evaluation in rats has been reported. This article reports the brain distribution and pharmacokinetic properties of (123) I-NKJ64 in baboons and compares results with (123) I-INER data in the same species. SPECT studies were conducted in two ovariectomized adult female baboons using two different protocols: (1) bolus of (123) I-INER or (123) I-NKJ64; and (2) bolus plus constant infusion of (123) I-NKJ64 with reboxetine (2.0 mg/kg) administration at equilibrium. Following bolus injection, both radiotracers rapidly and avidly entered the baboon brain. The regional brain accumulation of (123) I-NKJ64 did not match the known distribution of NAT in baboon brain, contrasting with previous results obtained in rats. Conversely, the regional distribution of (123) I-INER was consistent with known distribution of NAT in baboon brain. No displacement of (123) I-NKJ64 was observed following administration of reboxetine. This contrasts with previous data obtained for (123) I-INER, where 60% of specific binding was displaced by a lower dose of reboxetine. These data suggest that (123) I-NKJ64 may lack affinity and selectivity for NAT in baboon brain and (123) I-INER is the most promising iodinated reboxetine analogue developed to date for in vivo imaging of NAT in brain using SPECT. This study highlights the importance of species differences during radiotracer development and the stereochemical configuration of analogues of reboxetine in vivo. Synapse 66:923-930, 2012. © 2012 Wiley Periodicals, Inc.
  Synapse 07/2012; 66(11):923-30. · 2.94 Impact Factor
• Article: Development of the radiosynthesis of high-specific-activity 123I-NKJ64.

  Adriana Alexandre S Tavares, Nicola K Jobson, Deborah Dewar, Andrew Sutherland, Sally L Pimlott
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  ABSTRACT: (123)I-NKJ64, a reboxetine analogue, is currently under development as a potential novel single photon emission computed tomography radiotracer for imaging the noradrenaline transporter in brain. This study describes the development of the radiosynthesis of (123)I-NKJ64, highlighting the advantages and disadvantages, pitfalls and solutions encountered while developing the final radiolabelling methodology. The synthesis of (123)I-NKJ64 was evaluated using an electrophilic iododestannylation method, where a Boc-protected trimethylstannyl precursor was radioiodinated using peracetic acid as an oxidant and deprotection was investigated using either trifluoroacetic acid (TFA) or 2 M hydrochloric acid (HCl). Radioiodination of the Boc-protected trimethylstannyl precursor was achieved with an incorporation yield of 92±6%. Deprotection with 2 M HCl produced (123)I-NKJ64 with the highest radiochemical yield of 98.05±1.63% compared with 83.95±13.24% with TFA. However, the specific activity of the obtained (123)I-NKJ64 was lower when measured after using 2 M HCl (0.15±0.23 Ci/μmol) as the deprotecting agent in comparison to TFA (1.76±0.60 Ci/μmol). Further investigation of the 2 M HCl methodology found a by-product, identified as the deprotected proto-destannylated precursor, which co-eluted with (123)I-NKJ64 during the high-performance liquid chromatography (HPLC) purification. The radiosynthesis of (123)I-NKJ64 was achieved with good isolated radiochemical yield of 68% and a high specific activity of 1.8 Ci/μmol. TFA was found to be the most suitable deprotecting agent, since 2 M HCl generated a by-product that could not be fully separated from (123)I-NKJ64 using the HPLC methodology investigated. This study highlights the importance of HPLC purification and accurate measurement of specific activity while developing new radiosynthesis methodologies.
  Nuclear Medicine and Biology 05/2011; 38(4):493-500. · 3.02 Impact Factor
• Article: ¹²³I-NKJ64: a novel single photon emission computed tomography radiotracer for imaging the noradrenaline transporter in brain.

  Adriana Alexandre S Tavares, Nicola K Jobson, Deborah Dewar, Andrew Sutherland, Sally L Pimlott
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  ABSTRACT: Dysregulation of noradrenergic function has been implicated in a variety of psychiatric and neurodegenerative disorders, including depression and Alzheimer's disease. The noradrenaline transporter (NAT) is a major target for antidepressant drugs, including reboxetine, a selective noradrenaline reuptake inhibitor. Therefore, the development of a radiotracer for imaging of the NAT is desirable. In this study, NKJ64, a novel iodinated analog of reboxetine, was radiolabeled and evaluated as a potential single photon emission computerized tomography (SPECT) radiotracer for imaging the NAT in brain. Biological evaluation of the novel radiotracer, ¹²³/¹²⁵I-NKJ64, was carried out in rats using: in vitro ligand binding assays; in vitro and ex vivo autoradiography; in vivo biodistribution studies and ex vivo pharmacological blocking studies. ¹²⁵I-NKJ64 displayed saturable binding with high affinity for NAT in cortical homogenates (K(D) = 4.82 ± 0.87 nM, mean ± SEM, n = 3). In vitro and ex vivo autoradiography showed the regional distribution of ¹²³I-NKJ64 binding to be consistent with the known density of NAT in brain. Following i.v. injection there was rapid uptake of ¹²³I-NKJ64 in brain, with maximum uptake of 2.93% ± 0.14% (mean ± SEM, n = 3) of the injected dose. The specific to nonspecific ratio (locus coeruleus:caudate putamen) of ¹²³I-NKJ64 uptake measured by ex vivo autoradiography was 2.8 at 30 min post i.v. injection. The prior administration of reboxetine significantly reduced the accumulation of ¹²³I-NKJ64 in the locus coeruleus (>50% blocking). The data indicate that further evaluation of ¹²³I-NKJ64 in nonhuman primates is warranted in order to determine its utility as a SPECT radiotracer for imaging of NAT in brain.
  Synapse 12/2010; 65(7):658-67. · 2.94 Impact Factor
• Article: Design and synthesis of (2R,3S)-iodoreboxetine analogues for SPECT imaging of the noradrenaline transporter.

  Nicola K Jobson, Andrew R Crawford, Deborah Dewar, Sally L Pimlott, Andrew Sutherland
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  ABSTRACT: A stereoselective 10-step synthesis of iodophenoxy analogues of (2R,3S)-reboxetine has been developed with the aim of generating a new SPECT imaging agent for the noradrenaline transporter (NAT). In vitro testing of these compounds against various mono-amine transporters showed an ortho-iodophenoxy analogue to have excellent affinity (K(i) 8.4 nM) and good selectivity for NAT.
  Bioorganic & medicinal chemistry letters 08/2009; 19(17):4996-8. · 2.65 Impact Factor
• Article: New iodoreboxetine analogues for SPECT imaging of the noradrenaline transporter.

  Nicola K Jobson, Andrew R Crawford, Deborah Dewar, Sally L Pimlott, Andrew Sutherland
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  ABSTRACT: A new route for the stereoselective synthesis of iodinated reboxetine analogues has been developed for the generation of SPECT imaging agents for the noradrenaline transporter (NAT). (2S,3S)- and (2R,3R)-iodoreboxetine were prepared and biological testing against various mono-amine transporters showed these compounds to be potent and selective for NAT.
  Bioorganic & medicinal chemistry letters 09/2008; 18(18):4940-3. · 2.65 Impact Factor
• Article: Stereoselective synthesis of (2S,3R)- and (2R,3S)-iodoreboxetine; potential SPECT imaging agents for the noradrenaline transporter.

  Nicola K Jobson, Rosemary Spike, Andrew R Crawford, Deborah Dewar, Sally L Pimlott, Andrew Sutherland
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  ABSTRACT: With the aim of developing a new SPECT imaging agent for the noradrenaline transporter, a twelve-step stereoselective synthesis of iodinated analogues of (2S,3R)- and (2R,3S)-reboxetine has been achieved from 4-bromobenzaldehyde. The key steps involve a Sharpless asymmetric epoxidation to establish the stereogenic centres and a copper catalysed aromatic halogen exchange reaction to introduce the key iodine atom. In vitro testing of these compounds using a [(3)H]nisoxetine displacement assay with homogenised rat brain shows both compounds to have significant affinity, with K(i) values of 320.8 nM and 58.2 nM for (2S,3R)- and (2R,3S)-iodoreboxetine respectively.
  Organic & Biomolecular Chemistry 08/2008; 6(13):2369-76. · 3.70 Impact Factor
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  Available from: gla.ac.uk

  Article: The stereoselective synthesis of iodinated analogues of reboxetine: new imaging agents for the noradrenaline transporter

  Nicola K. Jobson
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  ABSTRACT: The noradrenaline reuptake transporter is located on the pre-synaptic membrane of noradrenic neurons. Its main function is to terminate the action of the neurotransmitter noradrenaline by reuptake back into the nerve terminal. Changes in the function and density of the noradrenaline reuptake transporter have been implicated in neurological disorders such as clinical depression and Alzheimer’s disease. In vivo imaging of the noradrenaline transporter using single photon emission computed tomography has been hampered by the lack of a suitable imaging agent. The information from imaging studies could lead to a better understanding of transporter function and the development of more efficient and faster acting drugs to treat the diseases associated it. For the first time, all four stereoisomers of an iodinated analogue of reboxetine were stereoselectively synthesised and biologically evaluated in an effort to understand the relationship between stereochemistry and potency. All four compounds were found to have nanomolar affinity for the noradrenaline transporter. Of most interest was the (2R,3S)-stereoisomer, which was identified as being as potent as the more studied (2S,3S)-stereoisomer. Therefore, a new series of iodoanalogues based on the (2R,3S)-stereochemical scaffold were synthesised and tested for their affinity with the noradrenaline transporter. This study revealed the derivative with ortho substitution on the phenoxy ring to be a potential lead for the development of a novel imaging agent for the noradrenaline transporter.