Assess 123-I IMPY and SPECT Imaging as a Tool to Detect β-Amyloid in the Brain

Summary

This research is designed to obtain efficacy and safety information for 123-I IMPY as an imaging biomarker for Alzheimer's disease (AD). The distribution of this agent will be measured by obtaining single photon emission computed tomography (SPECT) images of the brain serially over time to determine the relative localization of the radiopharmaceutical in regions of the cortex relative to background regions and develop an optimal technique of radiotracer administration (bolus or bolus with constant infusion). The researchers will then evaluate the utility of 123-I IMPY and SPECT in AD patients as an early diagnostic tool and subsequently serial evaluations of AD patients will be performed to determine if this technique may be useful as a tool for evaluation of progressive brain β-amyloid deposition in AD.

Timeline

Start

2006-02

Primary completion

2008-02

Completion

2008-03

Publications

• Background Bacskai BJ, Kajdasz ST, Christie RH, Carter C, Games D, Seubert P, Schenk D, Hyman BT. Imaging of amyloid-beta deposits in brains of living mice permits direct observation of clearance of plaques with immunotherapy. Nat Med. 2001 Mar;7(3):369-72. doi: 10.1038/85525. No abstract available.
• Background Bard F, Barbour R, Cannon C, Carretto R, Fox M, Games D, Guido T, Hoenow K, Hu K, Johnson-Wood K, Khan K, Kholodenko D, Lee C, Lee M, Motter R, Nguyen M, Reed A, Schenk D, Tang P, Vasquez N, Seubert P, Yednock T. Epitope and isotype specificities of antibodies to beta -amyloid peptide for protection against Alzheimer's disease-like neuropathology. Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):2023-8. doi: 10.1073/pnas.0436286100. Epub 2003 Feb 3.
• Background Bard F, Cannon C, Barbour R, Burke RL, Games D, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Lieberburg I, Motter R, Nguyen M, Soriano F, Vasquez N, Weiss K, Welch B, Seubert P, Schenk D, Yednock T. Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med. 2000 Aug;6(8):916-9. doi: 10.1038/78682.
• Background Cai L, Chin FT, Pike VW, Toyama H, Liow JS, Zoghbi SS, Modell K, Briard E, Shetty HU, Sinclair K, Donohue S, Tipre D, Kung MP, Dagostin C, Widdowson DA, Green M, Gao W, Herman MM, Ichise M, Innis RB. Synthesis and evaluation of two 18F-labeled 6-iodo-2-(4'-N,N-dimethylamino)phenylimidazo[1,2-a]pyridine derivatives as prospective radioligands for beta-amyloid in Alzheimer's disease. J Med Chem. 2004 Apr 22;47(9):2208-18. doi: 10.1021/jm030477w.
• Background Cummings JL. Alzheimer's disease. N Engl J Med. 2004 Jul 1;351(1):56-67. doi: 10.1056/NEJMra040223. No abstract available.
• Background DeMattos RB, Bales KR, Cummins DJ, Dodart JC, Paul SM, Holtzman DM. Peripheral anti-A beta antibody alters CNS and plasma A beta clearance and decreases brain A beta burden in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2001 Jul 17;98(15):8850-5. doi: 10.1073/pnas.151261398. Epub 2001 Jul 3.
• Background DeMattos RB, Bales KR, Cummins DJ, Paul SM, Holtzman DM. Brain to plasma amyloid-beta efflux: a measure of brain amyloid burden in a mouse model of Alzheimer's disease. Science. 2002 Mar 22;295(5563):2264-7. doi: 10.1126/science.1067568.
• Background Dodart JC, Bales KR, Gannon KS, Greene SJ, DeMattos RB, Mathis C, DeLong CA, Wu S, Wu X, Holtzman DM, Paul SM. Immunization reverses memory deficits without reducing brain Abeta burden in Alzheimer's disease model. Nat Neurosci. 2002 May;5(5):452-7. doi: 10.1038/nn842.
• Background Ferrer I, Boada Rovira M, Sanchez Guerra ML, Rey MJ, Costa-Jussa F. Neuropathology and pathogenesis of encephalitis following amyloid-beta immunization in Alzheimer's disease. Brain Pathol. 2004 Jan;14(1):11-20. doi: 10.1111/j.1750-3639.2004.tb00493.x.
• Background Folstein MF, Folstein SE, McHugh PR.
• Background Foster DM. Developing and testing integrated multicompartment models to describe a single-input multiple-output study using the SAAM II software system. Adv Exp Med Biol. 1998;445:59-78. doi: 10.1007/978-1-4899-1959-5_4.
• Background Fox NC, Black RS, Gilman S, Rossor MN, Griffith SG, Jenkins L, Koller M; AN1792(QS-21)-201 Study. Effects of Abeta immunization (AN1792) on MRI measures of cerebral volume in Alzheimer disease. Neurology. 2005 May 10;64(9):1563-72. doi: 10.1212/01.WNL.0000159743.08996.99.
• Background Frank RA, Galasko D, Hampel H, Hardy J, de Leon MJ, Mehta PD, Rogers J, Siemers E, Trojanowski JQ; National Institute on Aging Biological Markers Working Group. Biological markers for therapeutic trials in Alzheimer's disease. Proceedings of the biological markers working group; NIA initiative on neuroimaging in Alzheimer's disease. Neurobiol Aging. 2003 Jul-Aug;24(4):521-36. doi: 10.1016/s0197-4580(03)00002-2. No abstract available.
• Background Gilman S, Koller M, Black RS, Jenkins L, Griffith SG, Fox NC, Eisner L, Kirby L, Rovira MB, Forette F, Orgogozo JM; AN1792(QS-21)-201 Study Team. Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology. 2005 May 10;64(9):1553-62. doi: 10.1212/01.WNL.0000159740.16984.3C.
• Background Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science. 2002 Jul 19;297(5580):353-6. doi: 10.1126/science.1072994.
• Background Hock C, Konietzko U, Papassotiropoulos A, Wollmer A, Streffer J, von Rotz RC, Davey G, Moritz E, Nitsch RM. Generation of antibodies specific for beta-amyloid by vaccination of patients with Alzheimer disease. Nat Med. 2002 Nov;8(11):1270-5. doi: 10.1038/nm783. Epub 2002 Oct 15.
• Background Hock C, Konietzko U, Streffer JR, Tracy J, Signorell A, Muller-Tillmanns B, Lemke U, Henke K, Moritz E, Garcia E, Wollmer MA, Umbricht D, de Quervain DJ, Hofmann M, Maddalena A, Papassotiropoulos A, Nitsch RM. Antibodies against beta-amyloid slow cognitive decline in Alzheimer's disease. Neuron. 2003 May 22;38(4):547-54. doi: 10.1016/s0896-6273(03)00294-0.
• Background Holtzman DM. Role of apoe/Abeta interactions in the pathogenesis of Alzheimer's disease and cerebral amyloid angiopathy. J Mol Neurosci. 2001 Oct;17(2):147-55. doi: 10.1385/JMN:17:2:147.
• Background Jost BC, Grossberg GT. The natural history of Alzheimer's disease: a brain bank study. J Am Geriatr Soc. 1995 Nov;43(11):1248-55. doi: 10.1111/j.1532-5415.1995.tb07401.x.
• Background Kung HF, Kung MP, Zhuang ZP, Hou C, Lee CW, Plossl K, Zhuang B, Skovronsky DM, Lee VM, Trojanowski JQ. Iodinated tracers for imaging amyloid plaques in the brain. Mol Imaging Biol. 2003 Nov-Dec;5(6):418-26. doi: 10.1016/j.mibio.2003.09.003.
• Background Kung MP, Hou C, Zhuang ZP, Cross AJ, Maier DL, Kung HF. Characterization of IMPY as a potential imaging agent for beta-amyloid plaques in double transgenic PSAPP mice. Eur J Nucl Med Mol Imaging. 2004 Aug;31(8):1136-45. doi: 10.1007/s00259-004-1487-z. Epub 2004 Mar 9.
• Background Kung MP, Hou C, Zhuang ZP, Zhang B, Skovronsky D, Trojanowski JQ, Lee VM, Kung HF. IMPY: an improved thioflavin-T derivative for in vivo labeling of beta-amyloid plaques. Brain Res. 2002 Nov 29;956(2):202-10. doi: 10.1016/s0006-8993(02)03436-4.
• Background Kung MP, Hou C, Zhuang ZP, Skovronsky D, Kung HF. Binding of two potential imaging agents targeting amyloid plaques in postmortem brain tissues of patients with Alzheimer's disease. Brain Res. 2004 Oct 29;1025(1-2):98-105. doi: 10.1016/j.brainres.2004.08.004.
• Background Kung MP, Zhuang ZP, Hou C, Kung HF. Development and evaluation of iodinated tracers targeting amyloid plaques for SPECT imaging. J Mol Neurosci. 2004;24(1):49-53. doi: 10.1385/JMN:24:1:049.
• Background Kung MP, Zhuang ZP, Hou C, Jin LW, Kung HF. Characterization of radioiodinated ligand binding to amyloid beta plaques. J Mol Neurosci. 2003;20(3):249-54. doi: 10.1385/JMN:20:3:249.
• Background Loevinger R, Budinger T, Watson E: MIRD Primer for Absorbed Dose Calculations, Society of Nuclear Medicine, 1988.
• Background Masliah E, Hansen L, Adame A, Crews L, Bard F, Lee C, Seubert P, Games D, Kirby L, Schenk D. Abeta vaccination effects on plaque pathology in the absence of encephalitis in Alzheimer disease. Neurology. 2005 Jan 11;64(1):129-31. doi: 10.1212/01.WNL.0000148590.39911.DF.
• Background McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology. 1984 Jul;34(7):939-44. doi: 10.1212/wnl.34.7.939.
• Background Mohs RC, Knopman D, Petersen RC, Ferris SH, Ernesto C, Grundman M, Sano M, Bieliauskas L, Geldmacher D, Clark C, Thal LJ. Development of cognitive instruments for use in clinical trials of antidementia drugs: additions to the Alzheimer's Disease Assessment Scale that broaden its scope. The Alzheimer's Disease Cooperative Study. Alzheimer Dis Assoc Disord. 1997;11 Suppl 2:S13-21.
• Background Nicoll JA, Wilkinson D, Holmes C, Steart P, Markham H, Weller RO. Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat Med. 2003 Apr;9(4):448-52. doi: 10.1038/nm840. Epub 2003 Mar 17.
• Background Okamura N. [In vivo imaging of amyloid plaques in the brain]. Nihon Ronen Igakkai Zasshi. 2004 Mar;41(2):175-8. doi: 10.3143/geriatrics.41.175. Japanese.
• Background Orgogozo JM, Gilman S, Dartigues JF, Laurent B, Puel M, Kirby LC, Jouanny P, Dubois B, Eisner L, Flitman S, Michel BF, Boada M, Frank A, Hock C. Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology. 2003 Jul 8;61(1):46-54. doi: 10.1212/01.wnl.0000073623.84147.a8.
• Background Pfeifer M, Boncristiano S, Bondolfi L, Stalder A, Deller T, Staufenbiel M, Mathews PM, Jucker M. Cerebral hemorrhage after passive anti-Abeta immunotherapy. Science. 2002 Nov 15;298(5597):1379. doi: 10.1126/science.1078259. No abstract available.
• Background Pocock SJ, Simon R. Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial. Biometrics. 1975 Mar;31(1):103-15.
• Background Price DL, Sisodia SS, Borchelt DR. Alzheimer disease--when and why? Nat Genet. 1998 Aug;19(4):314-6. doi: 10.1038/1196. No abstract available.
• Background Racke MM, Boone LI, Hepburn DL, Parsadainian M, Bryan MT, Ness DK, Piroozi KS, Jordan WH, Brown DD, Hoffman WP, Holtzman DM, Bales KR, Gitter BD, May PC, Paul SM, DeMattos RB. Exacerbation of cerebral amyloid angiopathy-associated microhemorrhage in amyloid precursor protein transgenic mice by immunotherapy is dependent on antibody recognition of deposited forms of amyloid beta. J Neurosci. 2005 Jan 19;25(3):629-36. doi: 10.1523/JNEUROSCI.4337-04.2005.
• Background Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer's disease. Am J Psychiatry. 1984 Nov;141(11):1356-64. doi: 10.1176/ajp.141.11.1356.
• Background Rosen WG, Terry RD, Fuld PA, Katzman R, Peck A. Pathological verification of ischemic score in differentiation of dementias. Ann Neurol. 1980 May;7(5):486-8. doi: 10.1002/ana.410070516.
• Background Schenk DB, Rydel RE, May P, Little S, Panetta J, Lieberburg I, Sinha S. Therapeutic approaches related to amyloid-beta peptide and Alzheimer's disease. J Med Chem. 1995 Oct 13;38(21):4141-54. doi: 10.1021/jm00021a001. No abstract available.
• Background Schenk DB, Seubert P, Lieberburg I, Wallace J. beta-peptide immunization: a possible new treatment for Alzheimer disease. Arch Neurol. 2000 Jul;57(7):934-6. doi: 10.1001/archneur.57.7.934. No abstract available.
• Background Seibyl JP, Zea-Ponce Y, Brenner L, Baldwin RM, Krystal JH, Offord SJ, Mochoviak S, Charney DS, Hoffer PB, Innis RB. Continuous intravenous infusion of iodine-123-IBZM for SPECT determination of human brain dopamine receptor occupancy by antipsychotic agent RWJ-37796. J Nucl Med. 1996 Jan;37(1):11-5.
• Background Seibyl JP, Woods SW, Zoghbi SS, Baldwin RM, Dey HM, Goddard AW, Zea-Ponce Y, Zubal G, Germine M, Smith EO, et al. Dynamic SPECT imaging of dopamine D2 receptors in human subjects with iodine-123-IBZM. J Nucl Med. 1992 Nov;33(11):1964-71.
• Background Stabin MG, Sparks RB, Crowe E. OLINDA/EXM: the second-generation personal computer software for internal dose assessment in nuclear medicine. J Nucl Med. 2005 Jun;46(6):1023-7.
• Background Zhuang ZP, Kung MP, Wilson A, Lee CW, Plossl K, Hou C, Holtzman DM, Kung HF. Structure-activity relationship of imidazo[1,2-a]pyridines as ligands for detecting beta-amyloid plaques in the brain. J Med Chem. 2003 Jan 16;46(2):237-43. doi: 10.1021/jm020351j.

Drugs

Indications