Brain and whole-body imaging in nonhuman primates with [11C]MeS-IMPY, a candidate radioligand for beta-amyloid plaques.

[(11)C]MeS-IMPY ([S-methyl-(11)C]N,N-dimethyl-4-(6-(methylthio)imidazo[1,2-a]pyridine-2-yl)aniline) is a potential radioligand for imaging beta-amyloid plaques with positron emission tomography (PET). The aims of this study were to evaluate [(11)C]MeS-IMPY uptake in nonhuman primate brain and to estimate radiation exposure from serial whole-body images. Eight PET studies were performed in rhesus monkeys to measure the brain uptake and washout of [(11)C]MeS-IMPY. Time-activity data were analyzed with one-tissue and two-tissue compartmental models using radiometabolite-corrected plasma input function. In addition, two whole-body PET scans were acquired for 120 min to determine the biodistribution of [(11)C]MeS-IMPY. Tomographic PET images were compressed into a single planar image to identify organs with the highest radiation exposures. Estimates of the absorbed dose of radiation were calculated using OLINDA 1.0. Injection of [(11)C]MeS-IMPY caused little change in pulse rate, blood pressure, respiratory rate and temperature. [(11)C]MeS-IMPY showed high standardized brain uptake values of approximately 500% and 600% between 2 and 3 min in cortical regions and the cerebellum, respectively. The brain uptake of [(11)C]MeS-IMPY was widespread and quite uniform across all cortical regions. Activity rapidly washed out of the brain, with 20% of peak activity remaining at 40 min. Thus, all brain regions showed minimal retention of radioactivity, consistent with these healthy young animals having negligible amyloid plaques. Regional brain activity fitted well into a one-tissue compartment model. The average volume of distribution in all brain regions was 7.66+/-2.14 ml/cm(3) (n=4). The organs with the highest radiation exposure (muSv/MBq) were the gallbladder wall (33.4), urinary bladder (17) and lungs (12.9), with a resulting effective dose of 4.9 microSv/MBq (18 mrem/mCi). The high brain uptake, rapid washout and quantifiable volume of distribution in nonhuman primate brain further support the evaluation of [(11)C]MeS-IMPY. Calculated dosimetry results are comparable with those for other (11)C-labeled brain imaging radioligands.

[1]  V. Kepe,et al.  In vitro detection of (S)-naproxen and ibuprofen binding to plaques in the Alzheimer’s brain using the positron emission tomography molecular imaging probe 2-(1-{6-[(2-[18F]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile , 2003, Neuroscience.

[2]  J. Liow,et al.  Human biodistribution and radiation dosimetry of the tachykinin NK1 antagonist radioligand [18F]SPA-RQ: comparison of thin-slice, bisected, and 2-dimensional planar image analysis. , 2007, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[3]  S. DeKosky,et al.  Kinetic Modeling of Amyloid Binding in Humans using PET Imaging and Pittsburgh Compound-B , 2005, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[4]  R. V. Van Heertum,et al.  Amyloid plaque imaging agent [C-11]-6-OH-BTA-1: biodistribution and radiation dosimetry in baboon , 2005, Nuclear medicine communications.

[5]  Sung-Cheng Huang,et al.  Visualizing pathology deposits in the living brain of patients with Alzheimer's disease. , 2006, Methods in enzymology.

[6]  Gina N. LaRossa,et al.  [11C]PIB in a nondemented population , 2006, Neurology.

[7]  H. Akaike.  A new look at the statistical model identification , 1974 .

[8]  Synthesis and 11C‐radiolabelling of a tropane derivative lacking the 2β ester group: a potential PET‐tracer for the dopamine transporter , 1999 .

[9]  Brian J Bacskai,et al.  Four-dimensional multiphoton imaging of brain entry, amyloid binding, and clearance of an amyloid-β ligand in transgenic mice , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[10]  Jeih-San Liow,et al.  PET imaging of the dopamine transporter with 18F-FECNT: a polar radiometabolite confounds brain radioligand measurements. , 2006, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[11]  R. P. Maguire,et al.  Consensus Nomenclature for in vivo Imaging of Reversibly Binding Radioligands , 2007, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[12]  V. Pike,et al.  Radioligand Development for PET Imaging of β-Amyloid (Aβ)-Current Status , 2007 .

[13]  P. Thompson,et al.  PET of brain amyloid and tau in mild cognitive impairment. , 2006, The New England journal of medicine.

[14]  D. Mann,et al.  The topographic distribution of brain atrophy in Alzheimer's disease , 2004, Acta Neuropathologica.

[15]  W. Klunk,et al.  Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound‐B , 2004, Annals of neurology.

[16]  C. Geula,et al.  Distribution, progression and chemical composition of cortical amyloid-β deposits in aged rhesus monkeys: similarities to the human , 2003, Acta Neuropathologica.

[17]  S. Zoghbi,et al.  Evaluation of ultrafiltration for the free-fraction determination of single photon emission computed tomography (SPECT) radiotracers: beta-CIT, IBF, and iomazenil. , 1994, Journal of pharmaceutical sciences.

[18]  Magnus Dahlbom,et al.  Radiation dose estimates in humans for (11)C-acetate whole-body PET. , 2004, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[19]  Alan A. Wilson,et al.  In-vivo imaging of Alzheimer disease beta-amyloid with [11C]SB-13 PET. , 2004, The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry.

[20]  W. Klunk,et al.  Synthesis and evaluation of 11C-labeled 6-substituted 2-arylbenzothiazoles as amyloid imaging agents. , 2003, Journal of medicinal chemistry.

[21]  S. DeKosky,et al.  Simplified quantification of Pittsburgh Compound B amyloid imaging PET studies: a comparative analysis. , 2005, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[22]  P. R. Bevington,et al.  Data Reduction and Error Analysis for the Physical Sciences , 1969 .

[23]  J. Cummings,et al.  Progression of clinical deterioration and pathological changes in patients with Alzheimer disease evaluated at biopsy and autopsy. , 1999, Archives of neurology.

[24]  S. DeKosky,et al.  Binding of the Positron Emission Tomography Tracer Pittsburgh Compound-B Reflects the Amount of Amyloid-β in Alzheimer's Disease Brain But Not in Transgenic Mouse Brain , 2005, The Journal of Neuroscience.

[25]  M. Phelps,et al.  Effects of Temporal Sampling, Glucose Metabolic Rates, and Disruptions of the Blood—Brain Barrier on the FDG Model with and without a Vascular Compartment: Studies in Human Brain Tumors with PET , 1986, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[26]  Michael G Stabin,et al.  OLINDA/EXM: the second-generation personal computer software for internal dose assessment in nuclear medicine. , 2005, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[27]  A. Toga,et al.  The Rhesus Monkey Brain in Stereotaxic Coordinates , 1999 .

[28]  A. Lockhart.  Imaging Alzheimer's disease pathology: one target, many ligands. , 2006, Drug discovery today.

[29]  D. Skovronsky,et al.  Safety, biodistribution, and dosimetry of 123I-IMPY: a novel amyloid plaque-imaging agent for the diagnosis of Alzheimer's disease. , 2006, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.