Neuroscience
This research study noted below been reported today in some media, in terms of potential implications for the diagnosis of Alzheimer disease. Here is the study's abstract, which is more technical in content and less speculative in nature:
Chattopadhyay S, Xue B, Collins D, Pichika R, Bagnera R, Leslie FM, Christian BT, Shi B, Narayanan TK, Potkin SG, Mukherjee J.
Synthesis and Evaluation of Nicotine {alpha}4{beta}2 Receptor Radioligand, 5-(3'-18F-Fluoropropyl)-3-(2-(S)-Pyrrolidinylmethoxy)Pyridine, in Rodents and PET in Nonhuman Primate. Journal of Nuclear Medicine. 2005 Jan; 46(1): 130-140.
Department of Psychiatry and Human Behavior. Brain Imaging Center, University of California, Irvine, California.
Nicotine alpha(4)beta(2) receptor subtypes are implicated in the study of Alzheimer's disease, schizophrenia, substance abuse, lung cancer, and other disorders. We report the development and evaluation of a putative antagonist, 5-(3'-fluoropropyl)-3-(2-(S)-pyrrolidinylmethoxy)pyridine (nifrolidine) as a PET agent for nicotine alpha(4)beta(2) receptors. METHODS: In vitro binding affinity of nifrolidine was measured in rat brain slices labeled with (125)I-iodoepibatidine or (125)I-bungaratoxin. Selectivity of binding was measured in the presence of cytisine. (18)F radiolabeling was performed by reacting the tosylate precursor with (18)F-fluoride followed by deprotection. In vitro autoradiographic studies in rat brain slices with 5-(3'-(18)F-fluoropropyl)-3-(2-(S)-pyrrolidinylmethoxy)pyridine ((18)F-nifrolidine) were read on a phosphor imager. Rats were injected with (18)F-nifrolidine (3.7 MBq each), and brain regions were counted at various times (2-120 min). Blocking studies were performed by subcutaneous injection of nicotine (10 mg/kg). A PET study of (18)F-nifrolidine (approximately 148 MBq) was performed on an anesthetized rhesus monkey using a high-resolution scanner. RESULTS: In vitro binding affinity of nifrolidine exhibited an inhibition constant of 2.89 nmol/L for the alpha(4)beta(2) sites. Radiosynthesis and high-performance liquid chromatography purifications yielded the product in approximately 20%-40% decay-corrected radiochemical yield to provide (18)F-nifrolidine specific activities of approximately 111-185 GBq/mumol. In vitro autoradiography in rat brain slices revealed selective binding of (18)F-nifrolidine to the anteroventral thalamic nucleus, ventral posteriomedial thalamus, dorsolateral geniculate, and, to a lesser extent, cortex and striata, which are known to contain alpha(4)beta(2) sites. This specific binding was completely abolished by 300 mumol/L nicotine. Ex vivo rat brain distribution studies indicated selective binding in the thalamus with a maximal thalamus-to-cerebellum ratio of approximately 3. The PET study revealed selective maximal uptake (0.01% injected dose/mL) in regions of the thalamus (anteroventral and anteromedial thalamus, ventrolateral thalamus) and extrathalamic regions such as cingulate gyrus, lateral geniculate, temporal cortex, and frontal cortex. CONCLUSION: Binding of (18)F-nifrolidine to alpha(4)beta(2) receptor-rich regions in rats and monkeys indicates promise as a PET agent. Additionally, the thalamus-to-cerebellum ratio approached a plateau of 1.7 in 120 min, indicating relatively faster kinetics compared with previously reported imaging agents.
PMID: 15632043 [PubMed - as supplied by publisher]
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de Jong LW, van der Hiele K, Veer IM, Houwing JJ, Westendorp RG, Bollen EL, de Bruin PW, Middelkoop HA, van Buchem MA, & van der Grond J. Strongly reduced volumes of putamen and thalamus in Alzheimer's disease: An MRI study. Brain. 2008 Nov 20. Department...
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Hubbard PS, Esiri MM, Reading M, McShane R, & Nagy Z. Alpha-synuclein pathology in the olfactory pathways of dementia patients. Journal of Anatomy. 2007 Jun 6; [Epub ahead of print] Division of Neuroscience, The Medical School, University of Birmingham,...
Neuroscience
In The News: Nifrolidine
This research study noted below been reported today in some media, in terms of potential implications for the diagnosis of Alzheimer disease. Here is the study's abstract, which is more technical in content and less speculative in nature:
Chattopadhyay S, Xue B, Collins D, Pichika R, Bagnera R, Leslie FM, Christian BT, Shi B, Narayanan TK, Potkin SG, Mukherjee J.
Synthesis and Evaluation of Nicotine {alpha}4{beta}2 Receptor Radioligand, 5-(3'-18F-Fluoropropyl)-3-(2-(S)-Pyrrolidinylmethoxy)Pyridine, in Rodents and PET in Nonhuman Primate. Journal of Nuclear Medicine. 2005 Jan; 46(1): 130-140.
Department of Psychiatry and Human Behavior. Brain Imaging Center, University of California, Irvine, California.
Nicotine alpha(4)beta(2) receptor subtypes are implicated in the study of Alzheimer's disease, schizophrenia, substance abuse, lung cancer, and other disorders. We report the development and evaluation of a putative antagonist, 5-(3'-fluoropropyl)-3-(2-(S)-pyrrolidinylmethoxy)pyridine (nifrolidine) as a PET agent for nicotine alpha(4)beta(2) receptors. METHODS: In vitro binding affinity of nifrolidine was measured in rat brain slices labeled with (125)I-iodoepibatidine or (125)I-bungaratoxin. Selectivity of binding was measured in the presence of cytisine. (18)F radiolabeling was performed by reacting the tosylate precursor with (18)F-fluoride followed by deprotection. In vitro autoradiographic studies in rat brain slices with 5-(3'-(18)F-fluoropropyl)-3-(2-(S)-pyrrolidinylmethoxy)pyridine ((18)F-nifrolidine) were read on a phosphor imager. Rats were injected with (18)F-nifrolidine (3.7 MBq each), and brain regions were counted at various times (2-120 min). Blocking studies were performed by subcutaneous injection of nicotine (10 mg/kg). A PET study of (18)F-nifrolidine (approximately 148 MBq) was performed on an anesthetized rhesus monkey using a high-resolution scanner. RESULTS: In vitro binding affinity of nifrolidine exhibited an inhibition constant of 2.89 nmol/L for the alpha(4)beta(2) sites. Radiosynthesis and high-performance liquid chromatography purifications yielded the product in approximately 20%-40% decay-corrected radiochemical yield to provide (18)F-nifrolidine specific activities of approximately 111-185 GBq/mumol. In vitro autoradiography in rat brain slices revealed selective binding of (18)F-nifrolidine to the anteroventral thalamic nucleus, ventral posteriomedial thalamus, dorsolateral geniculate, and, to a lesser extent, cortex and striata, which are known to contain alpha(4)beta(2) sites. This specific binding was completely abolished by 300 mumol/L nicotine. Ex vivo rat brain distribution studies indicated selective binding in the thalamus with a maximal thalamus-to-cerebellum ratio of approximately 3. The PET study revealed selective maximal uptake (0.01% injected dose/mL) in regions of the thalamus (anteroventral and anteromedial thalamus, ventrolateral thalamus) and extrathalamic regions such as cingulate gyrus, lateral geniculate, temporal cortex, and frontal cortex. CONCLUSION: Binding of (18)F-nifrolidine to alpha(4)beta(2) receptor-rich regions in rats and monkeys indicates promise as a PET agent. Additionally, the thalamus-to-cerebellum ratio approached a plateau of 1.7 in 120 min, indicating relatively faster kinetics compared with previously reported imaging agents.
PMID: 15632043 [PubMed - as supplied by publisher]
- Fda: Approval Of Alzheimer's Neuroimaging Diagnostic Drug, Vizamyl (flutemetamol F 18 Injection)
From the FDA on the 25th of October, quoting the press release: FDA approves second brain imaging drug to help evaluate patients for Alzheimer’s disease, dementia The U.S. Food and Drug Administration today approved Vizamyl (flutemetamol F 18 injection),...
- Alzheimer's: Impaired Beta-amyloid Clearance
From the NIH: Impaired clearance, not overproduction of toxic proteins, may underlie Alzheimer’s disease 09 December 2010 In Alzheimer's disease, a protein fragment called beta-amyloid accumulates at abnormally high levels in the brain. Now researchers...
- Neuropsychology Abstract Of The Day: Neurodegeneration In Alzheimer Disease
de Jong LW, van der Hiele K, Veer IM, Houwing JJ, Westendorp RG, Bollen EL, de Bruin PW, Middelkoop HA, van Buchem MA, & van der Grond J. Strongly reduced volumes of putamen and thalamus in Alzheimer's disease: An MRI study. Brain. 2008 Nov 20. Department...
- Neuropsychology Abstract Of The Day: Parkinson's Disease
Bohnen NI, Kuwabara H, Constantine GM, Mathis CA, & Moore RY. Grooved pegboard test as a biomarker of nigrostriatal denervation in Parkinson's disease. Neuroscience Letters. 2007 September 13; 424(3): 185-189. Department of Radiology, University of...
- Neuropsychology Abstract Of The Day: Olfaction And Dementia
Hubbard PS, Esiri MM, Reading M, McShane R, & Nagy Z. Alpha-synuclein pathology in the olfactory pathways of dementia patients. Journal of Anatomy. 2007 Jun 6; [Epub ahead of print] Division of Neuroscience, The Medical School, University of Birmingham,...