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Pimlott S.L.,West of Scotland Radionuclide Dispensary | Sutherland A.,University of Glasgow
Chemical Society Reviews | Year: 2011

The development of positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging continues to grow due to the ability of these techniques to allow the non-invasive in vivo visualisation of biological processes at the molecular and cellular levels. As well as finding application for the diagnosis of disease, these techniques have also been used in the drug discovery process. Crucial to the growth of these techniques is the continued development of molecular probes that can bind to the target biological receptor with high selectivity. This tutorial review describes the use of PET and SPECT for molecular imaging and highlights key strategies for the development of molecular probes for the imaging of both cancer and neurological diseases. © 2011 The Royal Society of Chemistry.

Colloby S.J.,Vitality | Firbank M.J.,Vitality | Pakrasi S.,Vitality | Perry E.K.,Vitality | And 5 more authors.
Neurobiology of Aging | Year: 2011

Objective: To investigate differences in distribution of α4β2 subtypes of nicotinic acetylcholine receptors (nAChRs) using the ligand 123I-5-Iodo-3-[2(S)-2-azetidinylmethoxy] pyridine (5IA-85380) and single photon emission computed tomography (SPECT) in subjects with vascular dementia and age-matched controls. 123I-5IA-85380 binding was compared to corresponding regional cerebral blood flow (rCBF) changes in the same subjects. Methods: Thirty subjects (14 vascular dementia and 16 controls) underwent 123I-5IA-85380 and rCBF (99mTc-exametazime) SPECT scanning. Image analysis was performed on voxel basis using statistical parametric mapping (SPM2). Results: Compared to controls, reductions in relative 123I-5IA-85380 uptake were identified in dorsal thalamus and right caudate in vascular dementia. Increase in scaled 123I-5IA-85380 uptake in cuneus was also demonstrated in vascular dementia relative to controls. Perfusion deficits in anterior cingulate were apparent in the patient group and did not appear to be associated with 123I-5IA-85380 changes. Conclusions: Reduced 123I-5IA-85380 uptake in vascular dementia was confined to sub-cortical regions, unlike the cortical reductions previously described in Alzheimer's disease. Elevation of normalised 123I-5IA-85380 uptake in cuneus in vascular dementia could be a compensatory response to reduced cholinergic activity in dorsal thalamus. © 2009 Elsevier Inc.

McCluskey A.G.,University of Strathclyde | Mairs R.J.,University of Glasgow | Tesson M.,University of Glasgow | Pimlott S.L.,West of Scotland Radionuclide Dispensary | And 4 more authors.
Journal of Nuclear Medicine | Year: 2012

Targeted radiotherapy using 131I-metaiodobenzylguanidine ( 131I-MIBG) has produced remissions in some neuroblastoma patients. We previously reported that combining 131I-MIBG with the topoisomerase I inhibitor topotecan induced long-term DNA damage and supraadditive toxicity to noradrenaline transporter (NAT)-expressing cells and xenografts. This combination treatment is undergoing clinical evaluation. This present study investigated the potential of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP-1) inhibition, in vitro and in vivo, to further enhance 131I-MIBG/topotecan efficacy. Methods: Combinations of topotecan and the PARP-1 inhibitor PJ34 were assessed for synergism in vitro by combination-index analysis in SK-N-BE(2c) (neuroblastoma) and UVW/NAT (NAT-transfected glioma) cells. Three treatment schedules were evaluated: topotecan administered 24 h before, 24 h after, or simultaneously with PJ34. Combinations of PJ34 and 131I-MIBG and of PJ34 and 131I-MIBG/topotecan were also assessed using similar scheduling. In vivo efficacy was measured by growth delay of tumor xenografts. We also assessed DNA damage by γH2A.X assay, cell cycle progression by fluorescence-activated cell sorting analysis, and PARP-1 activity in treated cells. Results: In vitro, only simultaneous administration of topotecan and PJ34 or PJ34 and 131I-MIBG induced supraadditive toxicity in both cell lines. All scheduled combinations of PJ34 and 131I-MIBG/topotecan induced supraadditive toxicity and increased DNA damage in SK-N-BE(2c) cells, but only simultaneous administration induced enhanced efficacy in UVW/NAT cells. The PJ34 and 131I-MIBG/ topotecan combination treatment induced G2 arrest in all cell lines, regardless of the schedule of delivery. In vivo, simultaneous administration of PJ34 and 131I-MIBG/topotecan significantly delayed the growth of SK-N-BE(2c) and UVW/NAT xenografts, compared with 131I-MIBG/topotecan therapy. Conclusion: The antitumor efficacy of topotecan, 131I-MIBG, and 131I-MIBG/topotecan combination treatment was increased by PARP-1 inhibition in vitro and in vivo. Copyright © 2012 by the Society of Nuclear Medicine, Inc.

Colloby S.J.,Vitality | Perry E.K.,Vitality | Pakrasi S.,Vitality | Pimlott S.L.,West of Scotland Radionuclide Dispensary | And 4 more authors.
American Journal of Geriatric Psychiatry | Year: 2010

OBJECTIVE: To investigate normalized I-5-Iodo-3-[2(S)-2-azetidinylmethoxy] pyridine (5IA-85380) single photon emission computed tomography (SPECT) imaging, a marker for the α4β2 nicotinic receptor, as a predictor of cognitive progression in Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). METHODS: Thirty-one patients with dementia (16 patients with AD and 15 patients with DLB) underwent I-5IA-85380 SPECT scanning. Image analysis was performed using statistical parametric mapping (SPM2), which involved spatial preprocessing of scans to standard Montreal Neurological Institute space and intensity normalization of each image to its mean global brain activity. RESULTS: Regression analysis revealed that reduced normalized I-5IA-85380 uptake in left superior, middle, and inferior frontal gyri and prepost central and anterior cingulate regions significantly correlated with decline in executive function in a pooled group comprising AD and DLB. CONCLUSION: The findings, although preliminary, suggest that the cholinergic system may be more involved in neurodegenerative processes affecting some cognitive processes more than others, as such, this procedure may be useful for increased understanding of the pathophysiological mechanisms responsible for neurodegeneration. © 2009 American Association for Geriatric Psychiatry.

Cant A.A.,University of Glasgow | Bhalla R.,Grove Center | Pimlott S.L.,West of Scotland Radionuclide Dispensary | Sutherland A.,University of Glasgow
Chemical Communications | Year: 2012

A fast and efficient nickel-catalysed iodination reaction of aryl and heteroaryl bromides has been developed. The transformation was found to be general for a wide range of substrates and was used for the synthesis of iodo-PK11195, an imaging agent of Alzheimer's disease and iniparib, a compound used in the treatment of breast cancer. © 2012 The Royal Society of Chemistry.

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