アルツハイマー病診断薬 Single Photon Emission Computed Tomography(SPECT)用 amyloid-βリガンドに関する実験的研究

(1)

Title アルツハイマー病診断薬 Single Photon Emission ComputedTomography(SPECT)用 amyloid-βリガンドに関する実験的研究( 本文(Fulltext) ) Author(s) 陳, 忠正 Report No.(Doctoral Degree) 博士(獣医学) 甲第442号 Issue Date 2015-03-13 Type 博士論文 Version ETD URL http://hdl.handle.net/20.500.12099/51008 ※この資料の著作権は、各資料の著者・学協会・出版社等に帰属します。

(2)

HhrJɗ˷Ǌ˚ Single Photon Emission

Computed TomographyͶSPECTͷɊ amyloid-β

Ql.̀Aœͯɝɬɽ

;ͼͽ΀ŷ

Ŭ͂ŃŏŃŏ͈

̢ėɁĀŏɬɽɲ

ͶųŸɓɉŃŏͷ

͋ ƎȀ

(3)

ɡ ɡ Ǿ Abbreviation list 3 ʠ ˲ 4 Į ˡ 9 ʄ 1 ʀ SPECT Ɋ Q l ̾ ɛ É ˥ ģ 0 Aβ â ͓ ½ 4 0 ˯ Ģ Ɛ + ʻ Ȭ Ɛ 0 ǳ ˴ 1 ͺ ʶ ǘ + ɡ ɝ 1 2 2ͺ Ǧ ǉ > 3 ǌ ȕ 13 3ͺ ʚ ǫ 16 4ͺ ʬ ŝ 17 Ť Ƨ 18 Į ˡ 20 ʄ 2 ʀ Ȁ Ŵ g k * 0 DRM106 0 ½ Ü ù ƕ > 3 ʿ Ü ɶ ˞ Ɛ 0 ǳ ˴ 1 ͺ ʶ ǘ + ɡ ɝ 2 3 2ͺ Ǧ ǉ > 3 ǌ ȕ 23 3ͺ ʚ ǫ 26 4ͺ ʬ ŝ 27 Ť Ƨ 29 Į ˡ 30

(4)

ʄ 3 ʀ AD j K ^ . A DRM106 0 O k ] O U x I . > A ʿ Ü Aβ 0 ɭ ˻ 1ͺ ʶ ǘ + ɡ ɝ 37 2ͺ Ǧ ǉ > 3 ǌ ȕ 38 3ͺ ʚ ǫ 41 4ͺ ʬ ŝ 42 Ť Ƨ 4 3 Į ˡ 4 4 ʄ 4 ʀ AD j K ^ . A SPECT Ó + PET Ó + 0 ȋ ̕ 1 ͺ ʶ ǘ + ɡ ɝ 4 9 2ͺ Ǧ ǉ > 3 ǌ ȕ 50 3ͺ ʚ ǫ 53 4ͺ ʬ ŝ 54 Ť Ƨ 5 5 Į ˡ 5 6 ʟ Ƨ 6 6 ̃ ̖ 69 ċ ʬ ǆ ɀ 70 Summary 77

(5)

Abbreviation list

Aβ: Amyloid beta

AD: Alzheimer's disease

APP: Amyloid precursor protein ARG: Autoradiography

Bmax: Maximum specific binding BP: Binding potential

eq.: equation

FSB: (E,E)-1-fluoro-2,5-bis-(3-hydroxycarbonyl-4-hydroxy) styrylbenzene HPLC: High performance liquid chromatography

IC5 0: Half maximal inhibitory concentration

IMPY: 2-(4'-dimethylaminophenyl)-6-iodo-imidazo[1,2-a]pyridine) IP: Imaging plate

Kd: Dissociation constant

logD7.4: Distribution coefficient, measure of lipophilicity at pH 7.4 MRI: Magnetic resonance imaging

PiB: Pittsburgh compound B

PET: Positron emission tomography RI: Radioisotope

SPECT: Single photon emission computed tomography Tg: Transgenic

(6)

ʠ ʠ ˲ Ŷ Ƙ 24ŷ Ż ĉ Ɉ ÷ Ò ɤ 0 Ƕ ȓ . > A + ͹ ǐ ǥ * 1 ͹ ņ Ɛ 0 Ŷ ĳ ş ġ 1 89ȃ ͹ ɏ Ɛ 1 80ȃ E ̐ ͹ ɑ 0 ̼ ş ġ İ + - & ) A 8 # ͹ 65ȃ ² 0 Ͳ ʹ ʭ ª đ ʟ ª đ 0 20%E ć : A ̏ Ͳ ʹ ü ɰ ¶ E ̙ ) @ ͹ ɑ ɝ . ; ʫ ŷ ª đ 0 ñ ė 1 7%E ̏ ͹Ͳ ʹ ü ̤ ˞ ' ' A Ͷ www.mhlw.go.jp/toukei/saikin/hw/life/life13ͷ İ ͐ H h r J Ą ¶ 0 Ĺ Ğ Ͷ http://www.alz.co.uk/research/files/ WorldAlzheimerReport-Japanese.pdfͷ * 1 ͹ 2010ŷ . ɑ 0 ˻ ɪ ɘ Ƒ ʭ Ǆ 1 3,560 ª . ̩ ͹¬ Ƅ 20ŷ ȉ . È Ľ A + ¢ Ȩ B ) A 2013 ŷ ĉ Ɉ ÷ Ò ɤ ɬ ɽ Ƀ 0 ɛ ˡ * 1 ͹ǐ ǥ 0 65ȃ ² 0 Ͳ ʹ ʭ 0 ʑ 15%Ͷ ʑ 462 ª ͷ ˻ ɪ ɘ . ʩ Ƒ ) # Ͷ http://www.mhlw.go.jp/stf/kaiken/daijin/0000024488.htmlͷ ˻ ɪ ɘ + 1 ͹ Ͳ Ǿ ʿ Ǽ ʺ Ƅ ń ɝ - ĩ ̌ ɝ Ʒ Ð . > & ) » ͹ ǐ Ŵ Ɉ ș . ƽ ͑ E # ; 0 * A B 1 ͹ ˵ Ɨ ͑ ŗ < ˲ ˽ ͑ ŗ 0 9 - ? ͹ Ɇ ˱ ò ͹ è Ǌ ò + & # ˻ ɪ Ǽ ʺ < ª Ǳ Ŀ ü E ¸ ɖ Ƒ * A ¬ Ƅ ͹ ť ŋ Ͳ ʹ ü ɰ ¶ E ̙ A . # @ ͹ ˻ ɪ ɘ Ƒ ʭ 0 Ľ ó 1 Ř ǎ ̇ ʭ 0 ʙ ȥ ɝ ̈ Ƥ ͹ Ā ɚ ̇ Z v ^ 0 ̑ + & # ɰ ¶ ɝ ħ ͤ E # + ʬ ? B A ! B = ͹ ˻ ɪ ɘ 0 Ǒ ǡ ˷ Ǌ 1 ͹ ɗ ƕ 0 ̤ ˞ E ̥ ? A Ā ŏ ɝ ã ʨ ˞ A + ͹ > 3 Ƒ ʭ ˌ ̒ + Ř ǎ ̫ æ - ɰ ¶ ɝ Ş ƍ E + A + * A 0 * ͹ ̵ ˩ - ̀ ͤ + - & ) A ˻ ɪ ɘ 0 å ͦ + ) ͹H h r J Ĵ ˻ ɪ ɘͶ Alzheimer’s disease: ADͷ͹˝ ʉ Ɛ ˻ ɪ ɘ ͹ w Ť ½ Ĵ ˻ ɪ ɘ > 3 í ͢ ˖ Í ͢ ˖ Ŀ Ɛ ɘ ? B A ͹! 0 % ͹ʑ 70% AD. > A ; 0 * A AD1 ͹ͽ ͷ ɱ ʙ ʖ ʷ 4 0 amyloid-βͶ Aβͷâ ͓ ½ 0 ˘ ɻ ͹; ͷʿ 0 ɱ ʙ Ċ ʡ ʝ Ŀ ü

(7)

+ ɱ ʙ ʖ ʷ Ȅ ͹ Ϳ ͷ ʿ 0 ɱ ʙ ʖ ʷ 0 ʾ ˕ + & # ɗ Ɇ ŏ ɝ Ⱥ Ɗ E ɮ ̤ ˞ Ɛ 0 ɱ ʙ Ŀ Ɛ ɖ Ƒ * @1 ͷ_{͹ Ƒ ʭ 0 ˻ ɪ Ǽ ʺ 1 ̤ ˞ Ɛ . Ã B )}

AD0 ɛ ɘ Ǽ ź . ' ) 1 ǣ ˱ Ǔ - ̮ å ł ͹H J l P ^ V l ³ ˾ . ± ˡ B A P n _ . ĸ ( ) Ǹ - ˷ Ǌ Ȓ ɚ ȕ 0 ɬ ɽ ˞ D B ) A

H J l P ^ V l ³ ˾ + 1 ͹Aβ0 í ͮ ȹ ̌ * A APPͶ amyloid precursor proteinͷ β` T d a . > A æ Ǌ E Đ ͹ ! 0 Ƅ ? . ͹ γ` T d a . > @ æ Ǌ E Đ A + * ɉ Ɉ B A æ Ǌ * Ɉ # Aβ0 CǤ ʁ . 1 ł Ǹ Ɛ @ ͹ 40Ç H q ̲ ? - A AβͶ 1-40ͷ + ͹ 42 Ç H q ̲ ? - A AβͶ 1-42ͷ ɪ ? B ) A Ř ǎ Ɛ AD. ) ͹APP ̭ · ŋ < γ` T d a ̭ · ŋ 0 Ŀ ɕ ͹ ? . 1 APP̭ · ŋ 0 ̵ ˧ . > & ) AβÚ ½ 0 ɉ Ɉ ͹ Ⱥ . AβͶ 1-42ͷ 0 ɉ Ɉ Ľ ó A + ɮ B ) A Aβ , 0 > . ɱ ʙ · ̩ ͑ ŗ ɱ ʙ ʖ ʷ Ȅ E Ž ̎ ) A 0 . ' ) 1 ǣ $ Ǔ - ȴ ł ͹Ǆ Ç 0 Aβ q ̵ ė # O Y < Aβâ ͓ ½ 0 Ȋ Ɛ > 3 ̧ ð ̲ ü d K d t T ̌ 0 â ͓ ½ 0 ˘ ɻ ɢ Ʊ ɝ - ʖ ʷ Ȋ Ɛ E ɮ + < ͹ T U H 0 ș Ɛ ü . > A Ȳ ɘ č ƍ E # ͑ ŗ ; ʬ ? B ) AͶ Fig.1ͷ 8 # ͹AβĿ ɕ ̭ · ŋ E ̧ ð ɛ Ʉ # k ^ ] L n g TͶ Tgͷ K ^ . ) ; ͹ʫ ª ǈ 0 ˘ ɻ < ˻ ɪ Ǽ ʺ ͑ ŗ + & # ADǸ 0 ɘ ȼ 9 ? B A1 5 ͷ ʿ 0 Aβ â ͓ ½ ȑ ɧ 1 ͹͚ ē Ȭ Ɛ Aβ 0 â ͓ ½ * @ ͹ + ) β \ k Ƿ ̡ * Ƿ Ƙ B ) A 8 Ǆ Ç 0 q Ȭ Ɛ Aβ ˛ ɜ E ̵ ė ) O Y ȼ + A ? . O Y ̿ 0 â ͓ * ʡ ʝ ȼ +

(8)

- AD + AD ² Ł 0 ˻ ɪ ɘ E ˫ å A # : ͹ʿ Ü . ˘ ɻ # Aβ â ͓ ½ E ɭ ˻ A ƌ ˩ A ͹ u k 0 Ɉ ½ ʿ ʘ ʧ E Ɉ ǳ ) ˺ ǉ + A ɗ Ɇ ŏ ɝ ˷ Ǌ 1 Ĭ ͖ * A ǜ ̚ ͹Ⱥ ɕ ɝ s J O P + ) ͹ ʿ ʽ ͱ ȡ AβͶ 1-42ͷ0 » > 3 ʟ d K < ̲ ü d K ˛ ɜ 0 Ľ ó Ǟ ø - Ʃ ǹ + ) ȗ ɡ B ) A 3 4 ͷ_{͹ʿ ʽ ͱ ȡ 0 Ư ď 1 Ƒ} ʭ 4 0 Ã ˨ Ɛ Ń ǌ ͹ ͚ Ã ˨ ɝ - ƛ ȕ + ) ͹ magnetic resonance imagingͶ MRIͷ A ͹ AD Ƒ ʭ 0 ʿ ŕ Ʀ Ń < ʿ 0 ˔ ʣ E ˰ ŝ A + * A ; 0 0 ͹ ʿ 0 Ɓ ƕ Ŀ ü E ɮ - ç ǡ ȇ ͍ * 1 ˷ Ǌ * - 8 # ͹AD Ƒ ʭ * 0 Ǵ í ̮ > 3 ų ȼ Ī Ƅ ̮ 0 ˝ Ț < ʎ ± ̃ 0 » . ɧ ɡ ) ͹ single photon emission computed tomography Ͷ SPECT ͷ . > A ʿ ˝ Ț ̷ 0 Ȩ ő < ͹ ʿ ʎ ± ̃ 0 Ȩ ő 0

1 8

F-fluorodeoxyglucose E Ɋ # positron emission tomographyͶ PETͷ ˷ Ǌ ê Ɋ B ) A ͹ B ; ˝ ʉ Ɛ ˻ ɪ ɘ - , ¯ 0 ˻ ɪ ɘ + 0 ÿ é * ͹ Ⱥ ɕ Ɛ - 2012ŷ ̾ Ï B # İ ͐ H h r J ɗ ¶ ̆ Ͷ s T s ͹ P m e ͷ * 1 ͹ Aβâ ͓ ½ 0 ȑ ɧ E ͚ Ã ˨ ɝ . ƞ ƶ * B 2 ͹ AD0 ɛ ɘ E 5 ŷ ̿ ̥ ? ͹ Ƒ ʭ Ǆ E ă Ȧ A + ē ʺ * A + ɛ ˡ ) @ ͹ Ǒ ǡ ˷ Ǌ ȕ 0 ɭ ɿ Ǡ 8 B ) A Ͷ Fig.2ͷ ǰ Ā ŏ ǳ Ǯ 1 ͹ ƿ š Ɛ Ę º Õ ʔ Ͷ radioisotope΂ RIͷ E Ɋ # ɐ Ó ˷ Ǌ * A 0 å ̶ * 1 H J l J ] U + ) PET × ˞ ) @ ͹k Z + ) 11 C 0 Ĺ Ğ A 9 , 1 3 , 1 4 , 1 8 , 2 3 , 2 5 , 3 0 ͷ_͹ 11_{C 0 ă Ȧ ǡ 1 20 å ̿ * ͹ ͌ ͗ ŋ E ɛ Ɉ A Z J T k ˣ ʨ} ƌ ˩ * A ! 0 # : ͹ À Ɋ * A Ǎ ˶ ë ͇ B A 0 > - ȼ ȓ ͹2012 ŷ + 2013 ŷ . ͹ă Ȧ ǡ 110 å 0 1 8 F 0 Q l ̾ ɛ B

(9)

flutemetamol3 3 ͷ_{Ͷ Vizamyl͹GE Healthcare, ʋ İ ͷ ͹! B " B ʋ İ ͨ ģ}

Ā ˚ ģ ŨͶ FDAͷ. > & ) Ɲ ˻ B # ? . ͹2014 ŷ . 1 florbetaben Ͷ Neuraceq͹ Piramal Imaging, ^ J ^ ͷ ʄ 3 0 PET k Z + ) Ɲ ˻ B ͹1 8

F-AZD4694Ͷ NAV4694, Navidea Biopharmaceuticals, H J l ͷ8 ͷ_{+ ǩ ý Ń ŏ ̾ ɛ #} 1 8 F-BF-227 1 0 ͷ_{; ȗ ɡ B ) A} - ͹ǐ ǥ . ) 1 ͹Ʉ ı 1 8 F-florbetapir 0 ˦ ̡ ȕ 0 9 ˚ £ Ɲ ˻ B ) AͶ http://www.hitachi.co.jp/New/cnews/month/2014/09/0908.pdfͷ ǌ ͹SPECTɊ Aβk Z 0 ł 11 2 3 I* @ ͹! 0 ȹ Ɇ ŏ ɝ ă Ȧ ǡ 1 13ǖ ̿ + ̼ İ Ü * 1 ͹PETˣ ʨ 1 2014ŷ Ʉ ı 485Ĕ ɹ Ò ) A 0 . Ş ͹ SPECTˣ ʨ 1 1,600Ĕ ɹ Ò ) A Ͷ ǋ Ā ɚ ͹ 2014͹ 41, 156-167ͷ ˏ ɝ . ͹ SPECTk Z 0 ˦ ̡ X ^ k » # : ͹ ɛ ũ ̞ İ . 1 SPECT ̫ A Ɂ Ā ŏ ͡ Ķ . ) 1 ͹ 2009 ŷ 2 ǝ 0 Ɂ Ā ɚ ȕ Ǎ ˞ ˬ ì 0 ƾ Ȁ . > & ) ͹ Ȼ ͹ ȿ > 3 ͬ . ' ) ͹ SPECT ǰ ɸ 0 i T p f K -99m Ͷ9 9 m Tc΃ ă Ȧ ǡ 6 ǖ ̿ ͷ À Ɋ ē ʺ + - & # ͹ ͩ ʲ ʭ 0 Ł ̮ ˢ Ǚ ̈́ ǿ 0 # : ͹ ǳ Ǯ Ƅ 24 ? 48 ǖ ̿ 0 ˢ ǳ ù ȹ 0 ͏ ͕ ʪ ú ( ? B ) A Ţ Ǩ ɝ 1 ͹ ʫ ʹ Ȼ 0 ə Ĝ ɘ . Ş ) ͹ H J l J ] U ǋ # - ˷ Ǌ 0 h . - A ē ʺ Ɛ A

PET Ɋ Aβ ˷ Ǌ ˚ . 1 ͹ | c f H c Ͷ benzothiazoleͷ Ƿ ̡ E Ǟ A f O x v TͶ thioflavine T, ThTͷ @ ͹ThT 1 β \ k Ƿ ̡ 0 Aβ â ͓ ½ + ʚ ė A + ɪ ? B ) A ͹ RI ǹ ̅ ü ė ȹ ˝ ȡ ʿ ̀ ̽ E ̟ ̧ A # : . 1 ͹ ThT 1 ˝ ȡ ʿ ̀ ̽ E 6 + F , ̟ ̧ * - ǽ ȴ A ! * ͹w g h s U Ń ŏ 1 ThT 0 Ȉ ǰ E ƨ '

(10)

H c Ͷ 1,3,4-DPODͷ ˼ ţ ½ 3 5 ͷ_{͹ O ˼ ţ ½} 2 6 ͷ_{͹ 1,4-] x L} n k H c ˼ ţ ½ 3 2 ͷ_{͹w ] | c x ˼ ţ ½} 6 , 3 1 ͷ_͹J e c [1,2-a]w ] ˼ ţ ½ Ĺ Ğ B ) A 2 0 , 2 1 , 3 7 ͷ_{Ͷ Fig.3ͷ! B ?} 0 * ͹ Ħ ˋ Ź ˺ ͯ 8 * ̤ F * # 0 1 6-iodo-2-(4'-dimethylamino-)phenyl-imidazo[1,2-a]pyridineͶ IMPYͷ * & # 2 9 ͷ_{͹ IMPY 1 ˋ Ź ˺ ͯ * ͹ AD Ƒ ʭ + Ì Ŵ ª 0 ÿ é *} - & # # : ͹ ! 0 Ƅ 0 ̾ ɛ ǿ B # 2 2 ͷ ǥ ɬ ɽ * 1 ͹ ʿ Ü Aβ â ͓ ½ . ˯ Ģ Ɛ E ƨ ' imidazopyridine ˼ ţ ½ E ĸ ǥ Ƿ ̡ + # ü ė ȹ . ɧ ɡ ͹ Aβ 0 ʿ Ü å ű E ǳ ä A # : 0 SPECT Ɋ Q l 0 ̾ ɛ E ɡ ɝ + ) ͹² 4 ʀ . ¥ @ ǳ ˴ E ó # ʄ 1 ʀ * 1 ͹SPECT Ɋ Q l ̾ ɛ É ˥ ģ * A DRK092͹DRM101͹ DRM102͹DRM105 > 3 DRM106 0 Aβ â ͓ ½ 4 0 ˯ Ģ Ɛ > 3 ʻ Ȭ Ɛ E in vitro ʐ * IMPY + ȋ ̕ #  ʄ 2 ʀ * 1 ͹ Aβ ˯ Ģ Ɛ + ʻ Ȭ Ɛ Ô B # DRM106 . ' ) ͹1 2 5 I * ǹ ̅ ½ E Ɋ ) ͹ Ȁ Ŵ g k * 0 ½ Ü ʘ ʧ å ű > 3 ʿ ʘ ʧ ~ ] p k Ƅ 0 ƣ ä ȡ 0 ± ̃ ș Ɛ ȹ E ́ 5 # ʄ 3 ʀ * 1 ͹ AD ɗ j TgͶ +ͷ K ^ E Ɋ ) ͹1 2 5 I * ǹ ̅ # DRM106 0 ʿ Ü Aβ â ͓ ½ 4 0 ͓ ɻ Ɛ . ' ) ͹ O k ] O U * ǳ ˴ # ʄ 4 ʀ * 1 ͹TgͶ +ͷ K ^ E Ɋ ) ͹1 2 3 I-DRM106 0 SPECT Ó E ͹ × ˞ A 1 1 C-PiB 0 PET Ó + ȋ ̕ # ² 0 ɬ ɽ E ̟ ) ͹ Aβ â ͓ ½ . Ⱥ ɕ ɝ . ͓ ɻ A ǋ # - SPECT Ɋ Q l + ) 0 Ǟ Ǡ - ̾ ɛ É ˥ ģ 0 ̬ ä E ˺ 9 #

(11)

Fig. 1. Proposed hypothesis of Aβ causing the neurotransmission failure and neuronal cell death is still unclear. Aβ oligomer, Aβ aggregates plaques plus hyper-phosphorylated tau proteins, as well as microglia activated neuronal inflammation exhibit direct neuron toxicity.

(12)

Fig. 2. Hypothetical model of dynamic biomarkers of the AD before onset to dementia: In vivo non-invasive detection of Aβ deposition by amyloid imaging is important for early diagnosis and medical intervention for AD at a mild cognitive impairment (MCI) prodromal stage, since Aβ deposition has been already accumulating in the brain for 25 years prior to AD onset. CSF: cerebrospinal fluid

(13)

Fig. 3. Chemical structures of radio-iodinated ligands for amyloid imaging with SPECT. *I represents radioactive iodine.

(14)

ʄ ʄ 1 ʀ SPECT Ɋ Q l ̾ ɛ É ˥ ģ 0 Aβ â ͓ ½ 4 0 ˯ Ģ Ɛ + ʻ Ȭ Ɛ 0 ǳ ˴ 1ͺ ʶ ǘ > 3 ɡ ɝ 1 2 3 Iǹ ̅ ƿ š Ɛ Ā ˚ ģ . ̫ # SPECTɊ ü ė ȹ 0 ȹ Ɇü ŏ ɝ Ⱥ Ɛ + ) ͹ ͽ ͷ ʿ Ü Aβâ ͓ ½ 4 0 ˯ Ģ Ɛ Ͳ + ͹ ; ͷ ̫ Œ - ʻ Ȭ Ɛ . > A ˝ ȡ ʿ ̀ ̽ ̟ ̧ Ɛ A + ͹ Ϳ ͷ ͚ Ⱥ ɕ ɝ - ʚ ė » + ͹ ƪ ? B A ʠ ˲ * ̛ 5 # + ͹× ˞ ) # IMPY1 Ì Ŵ ª + AD Ƒ ʭ * 0 ÿ é * - & # # : ͹ IMPY Ǟ A imidazopyridineͰ Ǳ Ͷ Fig. 3ͷ. ɧ ɡ ͹ B E Æ ͫ A + . > @ ͹ ˵ X ` z k E Ȫ # ü ė ȹ 0 ư ʕ E ˞ & # ǥ ɬ ɽ * 1 ǋ ˬ 0 ΁ ü ė ȹ Ͷ Table 1ͷ E ė Ƙ ͹ Aβâ ͓ ½ 4 0 ˯ Ģ Ɛ + pH7.4. A ʻ Ȭ Ɛ 0 å ̯ Ä Ǆ

Ͷ logD7.4ͷE in vitro ʐ * IMPY+ ȋ ̕ # ǋ ˬ ü ė ȹ 0 Aβ˯ Ģ Ɛ 1 ͹ IMPY0 AβͶ 1-40ͷ â ͓ ½ . Ş A ʚ ė 0 half maximal inhibitory

concentrationͶ IC5 0ͷ* ˹ Â # 8 # ͹Ǟ Ǡ É ˥ ü ė ȹ 0 ˱ ͕ ő ǄͶ Kd΂

Dissociation constantͷ > 3 Ⱥ ɕ ɝ ʚ ė 0 ʟ Đ ř ½ ȯ Ż Ͷ Bmax΂ Maximum specific bindingͷE ȏ : # - ͹ʻ Ȭ Ɛ 0 å ̯ Ä Ǆ 1 2 ? 3.50 ʊ ĭ * ˝ ȡ ʿ ̀ ̽ 0 ̝ ̧ Ɛ Ͳ + D & ) A ˯ Ģ Ɛ 0 Ʃ ǹ + ) IC5 0 > 3 Kd E Ɋ # Ɇ Ɍ E ͹ ² . ˾ Ǔ A ƿ š Ɛ Ę º Õ ʔ ǹ ̅ IMPY + AβͶ 1-40ͷâ ͓ ½ 0 ʚ ė ̮ º . Ş ) ͹ ʂ ė A ǋ ˬ ü ė ȹ E ó A + ͹ ǋ ˬ ü ė ȹ ; Ę Ǹ . AβͶ 1-40ͷ â ͓ ½ + ʚ ė A Ɛ ̌ E ƨ ' ! 0 ĺ ė ͹͚ RI ǹ ̅ 0 IMPY > @ ť ̷ * IC5 0 Ƈ ? B # ü ė ȹ 1 IMPY + ȋ 5 Ͳ AβͶ 1-40ͷâ ͓ ½ 0 ˯ Ģ Ɛ E Ǟ A + + - A B 1 ͹ 8 * ǋ ˬ ü ė ȹ + IMPY + 0 Ô ô E ɮ # ; 0 * @ ͹ǥ Ǩ 0 AβͶ 1-40ͷâ ͓ ½ + 0 ˯ Ģ Ɛ E ɮ ;

(15)

0 * 1 ͹^ T n U B # ǋ ˬ ü ė ȹ E RI ǹ ̅ A + - ͹ ł Ǆ 0 ǳ ½ E ́ 5 A + * A # : ͹ ǋ ˚ 0 ư ʕ ɬ ɽ * Ȑ Ɋ B ) A ƛ ȕ * A ? . ͹ ʚ ė ò 0 Ʃ ǹ + ) ͹ ʚ ė ő Ǆ 0 ̜ Ǆ * A ˱ ͕ ő Ǆ Kd + Bmax E ȏ : # ? ˳ ʈ B # binding potentialͶ BP = Bmax / Kdͷ ü ė ȹ 0 Đ ř ½ . Ş A ɥ 0 ˯ Ģ Ɛ 0 Ʃ ǹ * A 2ͺ Ǧ ǉ > 3 ǌ ȕ 2.1ͺ ˢ ǳ ü ė ȹ ˵ . ɮ imidazopyridine Ͱ Ǳ E Ǟ A 5 ɸ 0 ̾ ɛ É ˥ ģ 1 ͹ Ŝ ľ x J RI x G ǯ ż ¶ ɰ Ͷ ǩ ¨ ͷ * ė Ƙ B # Ͷ Table 1ͷ 5-[4-(6-Iodoimidazo[1,2-a]pyridin-2-yl)phenyl]-1,3-oxazole Ͷ DRK092ͷ 2-[4-(6-Iodoimidazo[1,2-a]pyridin-2-yl)phenyl]-1,3-thiazole Ͷ DRM101ͷ 3-[4-(6-Iodoimidazo[1,2-a]pyridin-2-yl)]-1,2,4-oxadiazole Ͷ DRM102ͷ  6-Iodo-2-[4-(1H-1,2,3,4-tetrazol-5-yl)phenyl]imidazo[1,2-a]pyridine Ͷ DRM105ͷ  6-Iodo-2-[4-(1H-3-pyrazolyl)phenyl]imidazo[1,2-a]pyridine Ͷ DRM106ͷ 8 # ͹ ȋ ̕ 0 # : . IMPY 2-(4'-dimethylaminophenyl)-6-iodo-imidazo[1,2-a]pyridine E À Ɋ #  - ͹ IMPY 0 1 2 5 I ǹ ̅ ½ 1 ͹ ¾ B ; Ŝ ľ x J RI x G ǯ ż ¶ ɰ * ¿ Ƙ B ͹ ʒ Ż 95͵ ² ͹ ȋ ƿ š ʺ 81.4 GBq/mmol * & # 2.2. AβͶ 1-40ͷ â ͓ ʡ ʝ . Ş A IC5 00 Ȩ ő

(16)

ǐ Ȍ ˦ ˚ ǯ ż ¶ ɰ ͹ǩ ¨ ͷ . ǜ ʗ ȯ Ż 100 mM. - A > . AβͶ 1-40ͷ E Ȭ ˱ ͹ ƫ ɠ - ? 4ǐ ̿ 37℃* J R | k # Ƅ ͹ Aβ Ͷ 1-40ͷâ ͓ ʡ ʝ 0 Ȭ ȡ E 4℃* Å Ō # À Ɋ ɢ í . ͹â ͓ ʡ ʝ Ȭ ȡ E PBS* 200È Ų ̴ ͹500 nM0 AβͶ 1-40ͷȌ Ȭ ȡ E ¿ ˦ # 0 Aβ Ͷ 1-40ͷȌ Ȭ ȡ 100 μlE 900 μl0 1͵ 0 M d q ͹20 mM0 H ^ X v ̲ > 31 2 5 I-IMPYͶ 0.1 nMͷ E Ě Ǟ # PBS+ ȣ ė ) k Z Ȭ ȡ . # ˢ ǳ ü ė ȹ 1 ͹ǜ ʗ ȯ Ż 0.06 nM ? 1000 nM8 * 8ȇ ͍Ͷ Ė n=3ͷ . Ų ̴ ͹ Ȥ ó Ƅ 0 ȣ ė ȡ E 37℃* 3ǖ ̿ č ƍ # GF/BQ ^ ʦ ʝ ȱ ʓͶ Whatman͹NJͷE ˣ ɧ # Brandel cell harvesterͶ Mode M-24R, Biomedical Research. Lab., Gaithesburg, MDͷE Ɋ ) ě Ž ȱ ̧ # ˺ ǉ E ě Ž ȱ ̧ # Q ^ ʦ ʝ ȱ ʓ . ͹ ȍ ß # 0.1 mM0 H ^ X v ̲ E Ě Ǟ # 2.0 ml0 PBS* 3Ī Ș ț ȱ ̧ # Ƅ ͹ γP K d Ͷ Wallac Wizard 1480; PerkinElmer Wallac Inc, Turku, FinlandͷE Ɋ )1 2 5_{IȨ ő Ɋ}

]Ͷ 35.5 keV; ŵ 16.1Έ 74.6 keVͷ. ė ) 1å ̿ Ȩ ő # Ƈ ? B # ˳ Ǆ ? ͹ GrahPad PrismͶ GraphPad Software, version 4.0, San Diego, CA,USAͷ E Ɋ # ^ R g f l å Ǫ . > @ IC5 0 ȏ : # 2 7 ͷ_{8 # ͹} ͚ Ⱥ ɕ ɝ Ɵ ëͶ 0%ͷ+ ǜ Ń Ɵ ëͶ 100%ͷ1 ! B " B ˢ ǳ ü ė ȹ 0 Ȭ Ŋ + ͚ ǹ ̅ IMPYͶ 500 nMͷ 0 Ȥ ó > @ ȏ : # Ͷ n=3ͷ 1 2 5 I-IMPY . Ş A IC5 00 Ȩ ő 1 ͹d t T ̌ u k Ĵ ė Ƙ AβͶ 1-40ͷ

E ͹ Kd + Bmax 0 Ȩ ő . 1 ͹ AβͶ 1-40ͷ > 3 AβͶ 1-42ͷͶ ǯ ż ¶ ɰ } z f l ɬ ɽ ƚ ͹ Ń ̓ ͷ E Ɋ #

2.4ͺ å ̯ Ä Ǆ logD7.40 Ȩ ő

Lombardo > 3 Kerns?1 5 , 2 3 ͷ_{0 ǌ ȕ . Ɔ ͹UVǳ ä ĩͶ 2487 Dual λ͹}

(17)

x I ˣ ʨ Ͷ HPLC͹ Waters Corporation͹ Milford͹ MAͷ E Ɋ # 20 mM 4-morpholinepropanesulfonic acid [MOPS Ͷ pH7.4ͷ]Ȭ Ŋ * d q Ͷ R \ e ü ŏ ͹ ǩ ¨ ͷ 0 ȯ Ż E 60 ? 85%8 * ȇ ͍ ɝ . ́ ǅ ͹ ɶ ù ɣ E Ț ̠ 1.0 ml/min* Ȩ ő # Ė ˺ ǉ E 10 μlȗ Ù ͹˺ ǉ 0 Å ƨ ǖ ̿Ͷ tRͷ+ P ̟ ̧ ̾ ň ǖ ̿Ͷ t0ͷ ? eq. 1E Ɋ ) R t \ i I x G T d Ͷ k%ͷ E ȏ : #1 7 ͷ k% = Ͷ tR – t0ͷ / t0 Ͷ eq. 1ͷ ˢ ǳ ½ > 3 IMPY0 Ė d q ȯ Ż 0 R t \ i I x G T d 0 Ş Ǆ Ê Ͷ logk%ͷ ? d q 0% ȯ Ż 8 * ɢ ʡ * Ł Ƭ . > A logkw Ƈ ? B # Lombardo? 0 ǆ ɀ * À Ɋ B # ˚ ȹ > @ 19 ɸ ͦ E ̬ F * ǹ ȫ ċ ʬ ü ė ȹ + #1 6 , 2 4 ͷ_{! B " B 0 logkwÊ E Ý Ż Ȩ ő ͹}

! 0 logkwÊ + ǆ ɀ 0 logD7.4 Ê E À Ɋ ) ͹ɣ ̀ ż ͹eq. 2E ¿ Ƙ # 0 ż E À Ɋ ) ǋ ˬ ˢ ǳ ü ė ȹ 0 logkw Ê . ĸ ( ) logD7.4E ʈ ä # Ͷ Fig. 4.ͷ y = 0.9477x + 0.1072 Ͷ eq. 2ͷ 2.5ͺDRM1060 Aβ Ͷ 1-40ͷ > 3 AβͶ 1-42ͷâ ͓ ʡ ʝ . A Kd Ê + BmaxÊ AβͶ 1-40ͷ > 3 AβͶ 1-42ͷ 1 ͹! B " B 20 mM PBS * ǜ ʗ ȯ Ż 100 mM . - A > . Ȭ ˱ ͹ƫ ɠ - ? 4 ǐ ̿ 37℃ * J R | k ) ͹AβͶ 1-40ͷâ ͓ ½ Ȭ ȡ > 3 AβͶ 1-42ͷâ ͓ ½ Ȭ ȡ E Ƈ ) ͹4℃ . Å Ō # À Ɋ ǖ . PBS * 200 È Ų ̴ ) ! B " B Aβ Ͷ 1-40ͷ > 3 AβͶ 1-42ͷȌ Ȭ ȡ E ¿ ˦ # Q ^ f y . ! B

(18)

˺ ǉ + ) DRM106 E 100͹ 50͹ 25͹ 12.5͹ 6.25͹ 3.13͹ 1.57͹ 0.78͹ 0.39 > 3 0.2 nM͹ 8 # 100% ʚ ė ˺ ǉ + ) DRM106 E Ě 8 - PBS E 100 μl + ȣ ė # Ė ǳ ½ 0 ʟ ̷ E PBS * 1.0 ml . ́ ˦ ͹ 37℃* 1 ǖ ̿ J R | k # Ė ˺ ǉ 1 ͹GF/B Q ^ ʦ ʝ ȱ ʓ E ˣ ɧ # Brandel cell harvesterͶ Model M-24RͷE Ɋ ) ě Ž ȱ ̧ #  ? . ͹ Q ^ ʦ ʝ ȱ ʓ E 0.1 mM 0 H ^ X v ̲ E Ě Ǟ # 2.0 ml 0 ȍ ß # PBS * 3 Ī Ș ț ȱ ̧ # Ƅ ͹ γ P K d Ͷ Wallac Wizard 1480ͷ E Ɋ ) 1 2 5

I Ȩ ő Ɋ ] * 1 å ̿ Ȩ ő # Ƈ ? B # ˳ Ǆ Ê ? ͹ ͪ Ģ ǚ ʡ + Scatchard plot 1 GrahPad Prism Ver.4.00 Ͷ GraphPad SoftwareͷE Ɋ # ͚ ʡ Ɓ ǜ Ť ¤ ȕͶ Levenberg-Marquardt methodͷ . > @ ͹ Kd Ê > 3 Bmax Ê E ȏ : # 2 7 ͷ 2.6ͺ ʜ ˳ ˱ Ǫ Ė œ ͯ 1 Ȉ ͓ ī + - A Ȭ ȡ 1' 0 9 * & # # : ͹ʜ ˳ ˱ Ǫ 1 œ Ǎ - & # 3ͺ ʚ ǫ 3.1. AβͶ 1-40ͷ â ͓ ʡ ʝ . Ş A IC5 00 Ȩ ő + å ̯ Ä Ǆ logD7.4 ʈ ä # Aβ Ͷ 1-40 ͷ ʡ ʝ . Ş A Ė ˢ ǳ ü ė ȹ + IMPY 0 IC5 0+ logD7.4E Table 1. ɮ IC5 0Ê 1 , DRM092 Ͷ 1.08 nMͷ > DRM106 Ͷ Ͷ 1.86 nMͷ > IMPY Ͷ 2.93 nMͷ > DRM102 Ͷ 4.13 nMͷ > DRM101 Ͷ 6.87 nMͷ > DRM105 Ͷ 744.9 nMͷ 0 ͠ * & # logD7.4Ê 1 ͹IMPY Ͷ 4.03ͷ > DRK092 Ͷ 3.64ͷ > DRM106 Ͷ 3.20ͷ > DRM101 Ͷ 3.06ͷ > DRM102 Ͷ 3.12ͷ > DRM105 Ͷ 1.73ͷ 0 ͠ * & #

(19)

3.2. DRM1060 AβͶ 1-40ͷ > 3 AβͶ 1-42ͷ â ͓ ʡ ʝ . A Kd Ê + BmaxÊ

˵ ʚ ǫ E ĸ . DRM106 E ď @ ͹ AβͶ 1-40ͷ > 3 AβͶ 1-42ͷ â ͓ ʡ ʝ * 0 Kd Ê > 3 Bmax Ê E ȏ : # Ͷ Table 2ͷ AβͶ 1-40ͷ â ͓ ʡ ʝ 0 Ͳ ˯ Ģ Ɛ ̮ º * 1 ͹ Kd Ê > 3 Bmax Ê 1 ! B " B 1.5 nmol/L > 3 4.3 pmol/nmol͹ » ˯ Ģ Ɛ ̮ º * 1 140.3 nmol/L > 3 163.0 pmol/nmol E ɮ # 8 # ͹ AβͶ 1-42ͷ â ͓ ʡ ʝ 0 Ͳ ˯ Ģ Ɛ ̮ º * 1 10.1 nmol/L > 3 34.3 pmol/nmol͹» ˯ Ģ Ɛ ̮ º * 1 289.4 nmol/L > 3 339.4 pmol/nmol * & # 4ͺ ʬ ŝ SPECT Ɋ 0 ƿ š Ɛ Ā ˚ ģ 1 ͹ǹ ɝ ˊ ĩ 4 0 ͓ ɻ Ɛ Ͳ + + ͚ ǹ ɝ ͡ Ķ > 3 ! 0 ¯ 0 ˊ ĩ . ͓ ɻ . ̠ < . Ʈ Ȕ B A + Ǡ 8 B A B 8 * ͹ ʿ Ü Aβ â ͓ ½ E ɐ Ó ü A ɡ ɝ * ͹ ThT ͦ ¹ ü ė ȹ 0 imidazopyridine ˼ ţ ½ IMPY E 1 2 3 I * ǹ ̅ ͹AD Ƒ ʭ * ˋ Ź ˺ ͯ ˞ D B # ͹ ˋ Ź ˺ ͯ * 1 ͹ Ǟ ø Ɛ ɮ B - & # ! 0 Ɇ Ɍ + ) ͹Aβ â ͓ ½ 0 ˯ Ģ Ɛ ā å * & # + + ͹ʻ Ȭ Ɛ Ͳ # # : + ʬ ? B # ˯ Ģ Ɛ ſ + ǹ ɝ 0 Aβ â ͓ ½ + 0 ʚ ė ſ ͹ ɐ Ó ƺ Ƃ í . ʿ Ü ? Ƞ Ņ A + . - A 8 # ͹ ʻ Ȭ Ɛ Ͳ - A + ʿ ɶ ˞ Ɛ 0 ħ ͤ + ʿ ɜ ̌ 0 M ͜ . ͓ ɻ < # : ͹ ͚ Ⱥ ɕ ɝ - ʚ ė Ͳ ͹ ā å - X k ^ k Ƈ ? B - ? . ͹ ʻ Ȭ Ɛ Ͳ * ; » * ; ʿ Ü ɶ ˞ Ɛ » A Ñ ę

(20)

ƨ ę > 3 ʻ Ȭ Ɛ 0 ́ ǅ E ɡ ɝ + # ˼ ţ ½ ė Ƙ E ˞ & # -D % ͹ IMPY 0 Ǥ ʁ x L n ĸ 4 º 0 Í ̺ . ͚ ɇ ȼ ʨ Ƶ ĸ * A dimethylamino ĸ E ͹! 0 Í ̺ 0 ȳ ʔ Ċ ŋ E 5 Ĥ ɇ Ě ɾ ʔ ˧ ʔ ɇ ĸ + ) ɇ ȼ . į ő A + . > @ ͹Aβ ʡ ʝ ˯ Ģ Ɛ 0 ʝ ƨ ͹ę + å ŋ 0 ʻ Ȭ Ɛ 0 ́ ǅ E ˞ & # 5 ɸ 0 imidazopyridine ˼ ţ ½ E ˶ ˳ ė Ƙ ͹ ! 0 Aβ ʡ ʝ 0 ˯ Ģ Ɛ > 3 ʻ Ȭ Ɛ E ˹ Â # ! 0 ʚ ǫ ͹ 5 ɸ 0 imidazopyridine ˼ ţ ½ 1 ͹ 5 ) 0 Ş ȶ + A ü ė ȹ * A IMPY > @ ʻ Ȭ Ɛ » ͹ DRK092Ͷ 3.64ͷ + DRM105Ͷ 1.73ͷ ² Ł 0 3 ü ė ȹ 0 logD7.4 Ê 1 ͹ɡ ɝ + # 2.0-3.5 0 ː Ň - ʻ Ȭ Ɛ 0 ʊ ĭ Ü * & # 8 # ͹Aβ ʡ ʝ ˯ Ģ Ɛ 1 DRM105Ͷ IC5 0=744.87ͷE ͉ ͹ː Ň - ˯ Ģ Ɛ E ɮ ͹ Ⱥ . DRK092 + DRM106 1 ͹ IMPY > @ ; Ͳ Aβ ʡ ʝ ˯ Ģ Ɛ E ɮ # ǌ ͹ DRM105 0 Aβ ʡ ʝ ˯ Ģ Ɛ 0 Ń ŵ - » 1 ͹ ¯ 0 4 ɸ 0 Ě ɾ ʔ ˧ ʔ ɇ ĸ ſ ļ ĸ Ɛ E ɮ 5 Ĥ ɇ Ě ɾ ʔ ˧ ʔ ɇ ĸ * A 0 . Ş ͹ DRM105 0 ƨ ' 5-i k c ĸ 1 P ̲ ʆ Â ½ + Ġ 2 B A ̲ Ɛ ĸ * A + ! 0 Ɇ Ɍ * A + ʬ ŝ B # Aβ ʡ ʝ ˯ Ģ Ɛ IMPY 0 1.7 È E ɮ ͹ logD7.4 Ê 3.2 + IMPY > @ » Ê * & #

IMPY 0 AβͶ 1-40ͷ . Ş A Kd + Bmax 1 ͹ ! B " B 1.14 nmol/L + 0.14 pmol/nmol + Ĺ Ğ B ) A 5 ͷ_{0 Ǆ Ê ? ͹ IMPY 0 BP 1} 0.122 . Ş ͹DRM106 0 BPͶ 2.874ͷ> @ ; ͹23.6 È Ͳ & # 0 + ? ͹ DRM106 1 Aβ â ͓ ½ 0 ˯ Ģ Ɛ > 3 ʻ Ȭ Ɛ ? ͹ Q l + ) 0 É ˥ ģ 0 Ⱥ Ɛ E Ǟ A + ʬ ? B # Ť Ƨ SPECT Ɋ Q l ̾ ɛ É ˥ ģ E ̬ ơ A # : . ͹DRK092͹DRM101͹

(21)

DRM102͹ DRM105 > 3 DRM106 E ď @ ͹ Aβ â ͓ ½ 4 0 ˯ Ģ Ɛ > 3 ʻ Ȭ Ɛ E in vitro ʐ * ͹× ˞ ) A IMPY + ȋ ̕ # ! 0 ʚ ǫ ͹ DRM106 1 5 ' 0 ̾ ɛ É ˥ ģ 0 * ǜ ; É ˥ ģ + ) 0 Ⱥ Ɛ E Ǟ A + ʬ ? B #

(22)

Fig. 4. Standard curve for estimation of logD7.4 (left panel) and logD7.4 of the reference compounds (right panel). The partition coefficients were determined experimentally according to an HPLC method (Lombardo, 2001) previously published.

(23)

Table 1. The half maximal inhibitory concentration (IC5 0) of candidate

compounds for binding of 1 2 5

I-IMPY to synthetic human Ab (1-40) fibril and their lipophilic parameter (logD).

(24)

(25)

ʄ ʄ 2 ʀ Ȁ Ŵ g k * 0 DRM106 0 ½ Ü ù ƕ > 3 ʿ Ü ɶ ˞ Ɛ 0 ǳ ˴ 1ͺ ʶ ǘ > 3 ɡ ɝ ʄ 1 ʀ . ) ͹ SPECT Ɋ Q l 0 É ˥ ģ + ) ͹ Aβ â ͓ ½ 4 0 ˯ Ģ Ɛ > 3 ʻ Ȭ Ɛ . A in vitro ʐ 0 ʚ ǫ ? ͹ imidazopyridine ˼ ţ ½ DRM106 E ̬ ơ # DRM106 0 ȹ Ɇ ü ŏ ɝ Ɛ ȼ E Table 3 . ɮ # 8 # ͹ Q l 0 ȹ Ɇ ü ŏ ɝ Ⱥ Ɛ . ó ) ͹ ȅ ɒ Ɛ ͹ ± ̃ ȹ 0 Ɉ Ƙ < Ő Ú Ɛ . ; ȗ Ɠ E Ɯ ƌ ˩ A IMPY 0 K ^ . A ½ Ü ù ƕ 1 ͹ʿ . ) 2 å * 2.88%ID͹30 å * 0.26͵ ID * @ ͹ː Ň - ʿ ɶ ˞ Ɛ + T H ^ ɪ ? B ) A 3 7 ͷ_{͹ IMPY 1 ʿ} Ü ± ̃ ȹ @ ͹ Q l + ) ̀ ͤ ȅ A 4 ͷ_{8 # ͹IMPY 0 g k} ą Ī Ȋ Ɛ ˺ ͯ 0 Ƙ ʤ * 1 ͹ˋ Ź ¢ ƒ Ɋ ̷ 20 μg/ manͶ 60 kgͷ0 ʑ 1,000 È Ɋ ̷ 30 μg/kg . ) ; ͹ Ȋ Ɛ 1 ˻ : ? B - & # 3 ͷ_{ǌ * ͹ É} ˥ ģ DRM106 * 1 ͹ Ɉ ½ 0 ǹ ɝ ˊ ĩ * A ʿ 4 0 ɶ ˞ Ɛ ͹ ʿ T H ^ < ʿ ² Ł 0 ˊ ĩ 4 0 ͚ Ⱥ ɕ ɝ - ͓ ɻ . ' ) 1 Ǔ - ȴ ł ǥ ʀ * 1 ͹ Ȁ Ŵ 0 ͔ ͒ g k . 1 2 5 I-DRM106 E ą Ī ͙ ʼ Ü Ơ ͹ ʙ ǖ ɝ . ˺ ǉ E Ư ď ) ͹ Ú ̒ ˊ ĩ ʘ ʧ 4 0 å ű E ǳ ˴ # ! 0 Ƅ ͹ ʿ 4 0 ɶ ˞ Ɛ E ˱ Ǫ # ? . ͹ ʿ ʘ ʧ E Ư ď ͹ ʿ . A DRM106 ± ̃ ȹ 0 Ǟ ȵ E ́ 5 # 2ͺ Ǧ ǉ > 3 ǌ ȕ 2.1ͺ À Ɋ ù ȹ

(26)

ͩ ʲ ǡ ̿ ͹ ͇ ɑ ȱ ̧ x I d # Ȍ ̨ Ȍ + ƿ š ʡ ȭ ˓ # W g Ȃ ͦ Ɋ ͩ ǉ Ͷ FR-2͹ ǯ ż ¶ ɰ x m s \ x G ͹ Ă ˖ ͷ E ˌ Ɍ . Ƹ ď # ǥ œ ͯ 0 ù ȹ œ ͯ z k X 1 ͹Ŝ ľ x J RI x G ǯ ż ¶ ɰ ù ȹ œ ͯ ŉ Ĥ ¶ . Ɲ ˻ B # Ͷ Ë 071004ͷ 2.2ͺ1 2 5 I-DRM106 Ơ ȡ 0 ́ ǅ 1 2 5 I-DRM106 1 40 mM H ^ X v ̲Ͷ R \ e ü ŏ ͷ > 3 0.05 w/v% Tween80Ͷ R \ e ü ŏ ͷĚ Ǟ Ɉ Ɇ ͨ ļ ȡ * 0.37 MBq/ratͶ 1.85 MBq/kg͹ Ơ ȡ ̷ 200 μLͷ . - A > . ́ ǅ # Ơ ̷ 1 ͹ ¢ Î ˺ ͯ 0 ʚ ǫ E ĸ . ˶ ő # À Ɋ # 1 2 5 I-DMR106 0 ȋ ƿ š ʺ 1 81.4 MBq/nmol͹ ƿ š ʡ ü ŏ ʒ Ż 1 95͵ ² 0 ; 0 E À Ɋ # 2.3ͺ œ ͯ ǌ ȕ ͔ ͒ g kͶ n = 3ͷ0 Ŧ ͙ ʼ Ü . 1 2 5 I-DMR106 E 0.37 MBq/ratͶ 1.85 MBq/kgͷ 0 ñ ė * Ơ ͹ Ơ 2, 5, 15 > 3 30 å Ƅ + 1, 2, 4, 8, 24 > 3 48 ǖ ̿ Ƅ . J b x Ͷ x N ͹H g k ] t ͹ǩ ¨ ͷͳ ̰ * Ǌ ͢ ƿ ˝ # Ú ˝ > 3 ŧ E Ư ď ͹! 0 Ƅ ͹ɍ ȼ ˄ ͹ ʿ ͹ ɦ Ʌ ͹ r e ˄ ͹ ɞ ˇ ͹ ʹ ˄ ͹ Ƌ ˊ ͹ ʳ ͹ ʰ ˊ ͹ ˀ ˊ ͹ ˉ ˊ ͹ ʴ ͹Ť ˂ ͹Ń ˂ ̮ ͹Ń ˂ ̮ ͹ï ˁ ͹ˁ ˊ ͹ʻ ʱ ͹ʍ Ů ͹ʍ Ů ½ ͹ Ĉ Ů ͹ŋ Ŗ ͹Ͱ ͹Ͷ Ń ˅ ̮ ͷʇ ʯ > 3 ˆ ʸ E ƹ ä ͹̵ ̷Ͷ ɍ ȼ ˄ 1 ͉ ͷ E ͗ ŋ ń ɴ Ͷ PG-802͹ k k l ǯ ż ¶ ɰ ͹ ǩ ¨ ͷ * Ȩ ő #

Ė ˺ ǉ 0 ƿ š ʺ 1 ͹γ P K d Ͷ Wallac Wizard 1480ͷE Ɋ ) 1 2 5

I Ȩ ő Ɋ ] * 1 å ̿ Ȩ ő ͹ Ė ˊ ĩ 0 1 2 5

I-DMR106 0 ʘ ʧ Ü ƿ š ʺ ȯ Ż Ͷ %ID/gͷ E ˵ eq. 4 * ʈ ä #

(27)

%ID/g = ˺ ǉ 0 P K k Ǆ /Ơ # ʟ P K k Ǆ /˺ ǉ 0 ̵ ̷ Ͷ gͷ ×100 Ͷ eq. 4ͷ

Ė ˊ ĩ 0 1 2 5

I-DMR106 ʘ ʧ Ü ƿ š ʺ å ű ɂ Ͷ %IDͷ 1 eq. 5 * ʈ ä # %ID = Ú ˺ ǉ 0 P K k Ǆ /Ơ # ʟ P K k Ǆ ×100 Ͷ eq. 5ͷ 2.4ͺ ʿ * 0 DMR106 0 ± ̃ ȹ 0 ǳ ˴ g k ʿ ʘ ʧ E Ư ď Ͷ 0.3 gͷ ͹ Q ^ ~ ] m [ . Ù B ͹ ʘ ʧ ȩ ̵ ̷ . Ş ) 2 È ̷ 0 40 mmol/L H ^ X v ̲ Ͷ R \ e ü ŏ ͷ 0.1w/v% Tween80Ͷ R \ e ü ŏ ͷĚ Ǟ Ɉ Ɇ ͨ ļ ȡͶ Ø ˦ ˚ ͹ǩ ¨ ͷE Ȥ ó ͹ĳ . - A 8 * ~ ] m J _ # 0 ~ ] p k ? 50 μL E ď @ ͹ Mini-Uniprep x I d f y Ͷ Whatman Inc. NJ, ʋ İ ͷ . Ù B ͹ H ` k n k Ͷ R \ e ü ŏ ͷ 50 μL E Ȥ ó ƻ ƥ # x I d f y 0 z ] E Ƣ ) Z z E C ̧ ͹ f s ̮ å . ȱ ȡ E Ī Ď # ȱ ȡ . ͪ Ģ H ^ X v ̲ M d q Ͷ R \ e ü ŏ ͷ Ȭ ȡ 25 μL E Ȥ ó ȣ Ģ # ̜ ɣ \ P W ˙ Ū T k U x I Ɋ z kͶ Whatman Inc. NJͷ0 ʁ ? 2 cm 0 º ʨ . ̹ ʅ * Ċ ʡ E ˵ ͹ Ė Z z 10 μL E Ċ ʡ . ʆ ̿ ͏ . Ļ ű # ͧ # z k E ũ ̾ Ɋ ř ĩ . Ù B ͹ ˙ Ū T k U x I ũ ̾ Ȭ Ŋ d q /Ȍ Ͷ 80:20ͷ Ȭ ȡ ʑ 15 cm ũ ̾ # ũ ̾ . ˩ # ǖ ̿ 1

(28)

r ͹ ǩ ¨ ͷ * ˪ BAS-MS2340 J ] U z k Ͷ IP; Ŝ ľ x J ͷ+ 39 ǐ ̿ ͘ Ø # IP 1 BAS-1800 ɐ Ó ˱ Ǫ \ ^ i Ͷ Ŝ ľ x J ͷ E Ɋ ) ˱ Ó Ż 200 mm * ˿ 9 ̘ F $ 3ͺ ʚ ǫ 3.1. 1 2 5 I-DRM106 0 ʘ ʧ Ü ƿ š ʺ ȯ Ż Ͷ %ID/gͷ > 3 ʘ ʧ Ü ƿ š ʺ å ű ɂ Ͷ %IDͷ ͒ Ɛ g k 0 ʚ ǫ E Table 4 > 3 5 . ͹͔ Ɛ g k 0 ʚ ǫ E Table 6 > 3 7 . ɮ # Ⱥ . ˝ ȡ > 3 ʿ ƿ š ʺ ȯ Ż 0 ʚ ǫ 1 Fig.5 . ɮ # ʿ ƿ š ʺ ȯ Ż Ͷ Fig.5, lower panelͷ 1 ͹ ͒ Ɛ * 0.453%ID/g͹ ͔ Ɛ * 0.532%ID/g + ǜ ; Ͳ Ê E ɮ ͹! 0 Ƅ ̠ < . Ȧ ť # Ơ 30 å Ƅ . ͹ ͒ Ɛ 1 0.08%ID/g͹ ͔ Ɛ 1 0.09%ID/g * ͹ ̠ < . ʿ ? Ƞ Ņ # ɍ ȼ ʡ ͹ r e ˄ ͹ ɦ Ʌ > 3 ɞ ˇ . 1 Ơ Ƅ ͹ ̠ < . ƿ š ʺ å ű # r e ˄ 1 ͹ ͔ ͒ g k + ; . Ơ Ƅ 5 å ͹ ͒ Ɛ * 0.699%ID/g͹͔ Ɛ * 1.15%ID/g͹ǜ ł 0 ƿ š ʺ ͓ ɻ E ɮ # ͹ 1 ǖ ̿ Ƅ . ͒ Ɛ * 0.076%ID/g͹ ͔ Ɛ * 0.108%ID/g͹ ǜ ç 0 1 ñ 8 * » # 8 # ͹ ʿ + ȋ ̕ ) < < Ͳ ƿ š ʺ ȯ Ż E ɮ # ɦ Ʌ 0 ƿ š ʺ 0 ͓ ɻ 1 Ơ 2 å Ƅ 0 ͒ Ɛ * 0.183%ID/g͹͔ Ɛ * 0.203%ID/g E ɮ ͹ ! 0 Ƅ ̠ < . Ƞ Ņ # ͹ ʿ 0 ƿ š ȯ Ż > @ < < Ͳ & # ɍ ȼ ʡ . 1 ͹͔ ͒ + ; . Ơ Ƅ 30 å Ƅ > @ ʢ < . ƿ š ʺ å ű ɂ Ľ ó ͹ 48 ǖ ̿ Ƅ * ; ͹ ͒ Ɛ * 0.586%ID͹ ͔ Ɛ * 0.326%ID ɮ B # ɞ ˇ 4 0 ƿ š ʺ 1 ͹ Ơ ɢ Ƅ ? Ͳ ͓ ɻ E ɮ ) ͹ ! 0 Ƅ ʢ < . Ƞ Ņ # ͹ 48 ǖ ̿ Ƅ * ; ͒ Ɛ * 0.0421%ID/g͹ ͔ Ɛ * 0.0243%ID/g + ¯ 0 ͢ ͣ ̮ ʘ ʧ . ȋ 5 ) Ͳ ȯ Ż 0 ȅ ɒ ˻ : ? B # ʰ ˊ 0 ƿ š ʺ ͓ ɻ 1 Ơ 5 å Ƅ ǜ ; Ͳ ͹ ͒ Ɛ * 2.81%ID/g͹ ͔

(29)

Ɛ * 3.32 %ID/g * & # ! 0 Ƅ ͹̠ < . Ƞ Ņ # ʴ 4 0 ͓ ɻ 1 ͹ ͒ Ɛ * Ơ 30 å Ƅ . 0.729%ID/g ͹ ͔ Ɛ g k * Ơ 2 ǖ ̿ Ƅ . 1.2%ID/g * ǜ Ͳ 0 å ű ɂ + - @ ͹ ! 0 Ƅ ʢ < . Ȧ ť # Ť ˂ 4 0 ƿ š ʺ 0 ͓ ɻ 1 ͹ Ơ 2 ǖ ̿ Ƅ 8 * ǒ ͹ ͒ Ɛ * 12.2%ID/g͹ ͔ Ɛ * 15.5%ID/g * & # ! 0 Ƅ ȋ ̕ ɝ ʢ < . Ƞ Ņ # Ń ˂ ̮ 4 0 ƿ š ʺ 0 ͓ ɻ 1 Ơ 4 ǖ ̿ Ƅ . ͒ Ɛ g k * 11.2%ID/g͹ ͔ Ɛ * 14.5%ID/g͹Ń ˂ ̮ 4 0 ƿ š ʺ 0 ͓ ɻ 1 Ơ 8 ǖ ̿ Ƅ . ͒ Ɛ g k * 15.2%ID/g͹ ͔ Ɛ * 16.1%ID/g + ǜ ; Ͳ Ê E ɮ # ï ˁ ͹ ˁ ˊ ͹ Ɉ Ȇ ĩ ͹ ˆ ʸ ͹ Ƌ ˊ ͹ ʳ ͹ ˀ ˊ ͹ ˉ ˊ ͹ Ͱ ͹ ʇ ʯ Č 3 ʻ ʱ ʘ ʧ . 1 Ơ Ƅ ̠ < . ƿ š ʺ å ű ͹ ! 0 Ƅ ̠ < . Ƞ Ņ # ƿ š ʺ ȯ Ż Ͳ ʘ ʧ 1 ȵ & # 1 2 5 I-DRM106 Ơ # Ƅ 48 ǖ ̿ 0 ˘ ŧ * ŧ 4 Ʈ Ȕ ɂ E ͹ ͒ Ɛ * 1 13.2͵ ID͹ ͔ Ɛ * 1 13.4͵ ID * & # Ɛ Ű 1 9 ? B - & #

˝ ȡ ƿ š ʺ ȯ ŻͶ Fig.5, upper panelͷ1 ͹Ơ 2 å Ƅ * ǜ ; Ͳ Ê E ɮ ͹ ͒ Ɛ * 0.350% ID/g͹ ͔ Ɛ * 0.561%ID/g * & # ! 0 Ƅ 0 Ƞ Ņ 1 ͹ ǜ ç 0 ͽ ǖ ̿ * ̠ < * @ ͹ ! 0 Ƅ 1 ʢ < * ͹ ¤ ɣ Ɛ E ɮ # 3.2. ʿ * 0 DMR106 0 ± ̃ ȹ 0 ǳ ˴ ͒ Ɛ 0 ʿ 0 ± ̃ ȹ ˱ Ǫ ʚ ǫ E Fig.6. ɮ # 2ǖ ̿ 8 * ± ̃ ȹ 0 Ō ı E ɮ ĥ A ï s l 1 ˰ ŝ B ͹ 120å * ǳ ä ͇ ɑ ² + - & # 4ͺ ʬ ŝ

(30)

Ɛ 0 t d E ɮ # 0 + ? ͹1 2 5 I-DRM106 0 Ʈ Ȕ 1 Ơ 24 ǖ ̿ í Ƅ + ʬ ? B # ͺ - ͹ Ɛ Ű 1 ˫ ? B - & # Ͷ Fig. 5ͷ 1 2 5 I-DRM106 1 ˝ ȡ ʿ ̀ ̽ ? ʿ . ̟ ̧ < ͹2 å * ǜ Ͳ 0 ͓ ɻ E ɮ # ͹ ˘ ɻ Ɛ 1 - ̠ < . ʿ ? Ƞ Ņ # 0 Ⱥ Ɛ 1 ʿ . Aβ â ͓ ½ ȑ ɧ ) B 2 ͹ Aβ E ɐ Ó ü A # : 0 X k ^ k Ƈ < + ʬ ? B # 8 # ͹ ˙ Ū T k U x I 0 ʚ ǫ ? 1 2 5 I-DRM106 ² Ł 0 ï s l - & # # : ͹1 2 5 I-DRM106 0 ʿ Ü ± ̃ ȹ 1 Ɉ Ƙ B - + ʬ ? B # Ͷ Fig. 6ͷ ɍ ȼ ˄ . 1 ͹ < < Ͳ å ű ˫ ? B # ɍ ȼ ʡ 1 J O ü K ʔ E ď @ ̘ 9 T3< T40 ė Ƙ E ˞ & ) A ! 0 # : ͹ 1 2 5 I-DRM106 0 ± ̃ ̧ ɷ * ̦ ͕ B # J O ü 1 2 5 I ɍ ȼ ˄ ʖ ʷ . ʺ ù ɝ . ď ̘ 8 B # + Ʋ ŝ B # ͢ ̮ * 1 ͹ r e ˄ ͹ ɦ Ʌ ͹ ° ͎ ʇ ʯ < ɞ ˇ 0 ƿ š ʡ ͓ ɻ ʿ 0 ɐ ̌ . Ƃ ͝ E A # : ͹ B ? 0 ʘ ʧ 4 0 ͓ ɻ 1 Ň 8 - ¬ Ī Ƈ ? B # ʚ ǫ E ĸ . A + ͹ Ơ 1 ǖ ̿ Ƅ . 1 ͹ B 0 ʘ ʧ ? ; 6 7 Ƞ Ņ # + ? ͹ɐ Ó 4 0 Ƃ ͝ 1 ť - + ʬ ? B # - ͹ ʰ ˊ 0 ˊ ĩ ȯ Ż 0 » . ¸ Ť ˂ + Ń ˂ 0 ˊ ĩ ȯ Ż Ľ ó ͹ ŧ Ʈ Ȕ 1 13%ID í Ƅ * A + ? ͹1 2 5 I-DRM106 0 Ń ̮ å 1 ͹ ʰ ˊ ? 0 ʵ Ȏ E ʙ Ɍ ) ʏ . Ʈ Ȕ B A + ʬ ? B # r e ˄ . ' ) 1 ͹ u k * 1 Ō ı - ˊ ĩ * A # : ͹ ! 0 Ɠ ğ . ' ) 1 Ǔ * A 8 # ͹ í ˋ Ź Ȋ Ɛ j d 1 ǥ ǆ . 1 ɮ ) - ͹ DRM106 0 Ő Ú Ɛ ˚ Ɇ ˺ ͯ * 1 ͹ g k . Ş ) 25 μg/kg 0 ą Ī ͙ ʼ Ü Ơ Ͷ ˋ Ź ¢ ƒ ǜ Ń Ơ ̷ 6 ng/kg 0 4,165 È ͷ. ) ; ͹ Ǭ ɱ ʙ ʐ 0 ɕ Ŵ 1 ˻ : ? B ͹ 5 μg/kgͶ ˋ Ź ¢ ƒ ǜ Ń Ơ ̷ 0 833 È ͷ 0 ͙ ʼ Ü Ơ

(31)

. ) Ġ ě ʐ + Ƌ ˝ ʉ ʐ . 1 Ƃ ͝ ˻ : ? B - & # # & ) ͹ DRM106 1 Ɉ ½ 0 X H s g i Ǽ ʺ . 1 Ƃ ͝ - & # ? . ͹ DRM106 0 ˏ Ȋ Ɛ ˺ ͯ * 1 ͹ g k 0 ą Ī Ơ + 28 ǐ č ƈ Ơ E ¾ B ; 25 μg/kg . ) ; ͹ ɕ Ŵ - ɗ Ŀ E ˻ : - & # J o 0 ą Ī Ơ Ͷ 25 μg/kgͷ + 28 ǐ č ƈ Ơ Ͷ 5 μg/kgͷ . ) ; ͹ ˗ Ǔ - Ŀ ü 1 ˰ ŝ B - & # ² ͹1 2 5 I-DRM106 0 g k ½ Ü ù ƕ 0 Ƙ ʤ ? ɍ ȼ ˄ 4 0 å ű 9 ? B A ; 0 0 ͹ ! 0 ¯ ˊ ĩ . ɕ Ŵ - ͓ ɻ 1 9 ? B - & # Ť Ƨ DRM106 0 Ɉ ½ Ü å ű E ́ 5 A # : . ͹ Ȁ Ŵ SD g k E Ɋ ) 1 2 5 I-DRM106 E ą Ī ͙ ʼ Ü Ơ ͹ʙ ǖ ɝ . ½ Ü å ű > 3 ʿ ± ̃ ș Ɛ E ́ 5 # ! 0 ʚ ǫ ͹ DRM106 0 ː Ň - ʿ ɶ ˞ + ̠ < - T H ^ ɮ B # 8 # ͹ ʿ Ü ± ̃ ˱ Ǫ * 1 DRM106 0 ± ̃ ȹ 1 ˻ : ? B - & # ? . ͹ ! 0 ¯ 0 ˊ ĩ . ɕ Ŵ - ͓ ɻ E ˻ : - & # ͺ

(32)

Fig.

5. Radioactivity levels in blood (upper panelͷ and the brain (lower panelͷ of normal female and male SD rats given intravenously 125

I-DRM106 .

Values represent the mean of 3 rats.

(33)

Fig.

6. Metabolic stability of DRM106 in normal male SD rats. The brain samples were

collected at scheduled time points after i.v. injection of 125_{I-DRM106. Thin-layer}

chromatography analysis clearly demonstrated that no overt metabolite was observed in the brain at 120 min later.

(34)

(35)

Table 4. Biodistribution of 125

I-DRM106 in normal male SD rats calculated in tissue weight concentration.

(36)

(37)

I-DRM106 in normal female SD rats calculated in tissue weight concentration.

(38)

Table 7. Biodistribution of 1 2 5

(39)

ʄ ʄ 3 ʀ AD j K ^ . A DRM106 0 O k ] O U x I . > A ʿ Ü Aβ 0 ɭ ˻ 1ͺ ʶ ǘ + ɡ ɝ í 1-2 ʀ . ) ͹ É ˥ ģ DRM106 1 ͹ in vitro ʐ * Ô B # Aβ â ͓ ½ 4 0 ˯ Ģ Ɛ > 3 ̫ æ - ʻ Ȭ Ɛ E ɮ ͹ ' in vivo ʐ * 1 Ȁ Ŵ g k ʿ 4 0 ː Ň - ɶ ˞ Ɛ ͹ T H ^ > 3 Ő ő Ɛ E ɮ + E Ǔ ? . # ǥ ʀ * 1 ͹ ˚ ø ˚ Ɇ ɬ ɽ 0 ɇ + ) ͹ ó ʹ . > @ ʿ Ü . Aβ â ͓ ½ ȑ ɧ A AD j * A PS-1ki/JU-Tg2576Ͷ Tgͷ K ^ E ď @ ͹1 2 5

I-DRM106 E Ơ Ƅ ͹O k ] O U x I Ͷ ARGͷ. > @ ex vivo ʐ * Aβ â ͓ ½ 0 ȑ ɧ E Ƴ ä A + E ˺ 9 # ! 0 Ƅ ͹ ARG 0 Ń ʿ ɞ ̌ /ʡ ǧ ½ X k ^ k E ʈ ä # 8 # ͹ƺ Ƃ 0 ˍ ̫ ǖ ̿ E ƞ ƶ A # : ͹Ơ Ƅ 0 ʙ ǖ ɝ - Ŀ ü ; ́ 5 # ? . ͹ARG * À Ɋ # ʿ æ ȸ 0 Aβ ȑ ɧ E Congo-red ǭ ˑ * ɭ ˻ # ǥ ɬ ɽ * Ɋ # Tg K ^ 1 ͹^ K L j 0 Ř ǎ Ɛ AD Ƒ ʭ ? ɛ ˫ B # H J l d t T 0 í ͮ ½ 0 Ŀ ɕ ½ Ͷ Lys670→Asn, Met671→LeuͷE C57BL/6 K ^ . ţ Ù # ; 0 * ͹ʋ İ Mayo ̉ ī * ¿ ä B # ; 0 * A 8 ͹ C57BL/6J×SJL 0 F1 ± Ͷ B6SJLF1ͷ + § ̯ ʥ Ȇ Ƅ ͹ ? . JU ʐͶ JU/Ct-C,Aͷ K ^ + 29 ± ² 0 ƙ § ̯ ) ͹Ŀ ɕ Aβ 0 APPͶ × ͮ ˛ ɜ ͷE JU K ^ . { i * ƨ ' Ç ½Ͷ JU-Tg2576 K ^ + ɵ A ͷE ʝ ƨ # JU-Tg2576 K ^ 1 ͹ȧ ͠ - Ɛ Ǳ + ½ Ĵ Ń ͹ǐ Ŵ ʉ Ɇ + œ ͯ ǔ - A $ * 1 - ͹

(40)

0 Ŀ ɕ ½Ͷ Ile213→Thrͷ @ ͹ B E gene-targeting . > @ knock-in # ù ȹ . PS-1ki K ^ A 2 8 ͷ * . ͹ Aβ-APP Ŀ ɕ ½ + PS-1 0 Ŀ ɕ ½ . > A e y k ^ ] L n g T ù ȹ * 1 ͹ ʿ Ü Aβ ȑ ɧ ó ̠ ü B A + ˸ Ǔ B ) @ ͹ 8 # Aβ ɛ Ʉ ̷ Ľ ó A + ; è Ǔ ) A 2 1 , 2 8 ͷ_{B ? j d E ĸ . ͹À Ɋ # PS-1ki/JU-Tg2576} Tg [Tg Ͷ +ͷ] K ^ 1 ͹͒ Ɛ JU-Tg2576 K ^ + Ŀ ɕ PS-1ki 0 ~ ̭ · ŋ E ƨ ' ͔ Ɛ K ^ + § ̯ Ͷ F1ͷ ) ¿ ä # ˹ Â . 1 ARG Ó ͹ ARG 0 Ń ʿ ɞ ̌ ʡ ǧ ½ X k ^ k > 3 Aβ + Ⱥ ɕ ɝ . č ƍ A Cong-red ǭ ˑ E Ɋ # 2ͺ Ǧ ǉ > 3 ǌ ȕ 2.1ͺ À Ɋ ù ȹ 19 ǝ ʹ ͔ Ɛ PS-1ki/JU-Tg2576 [TgͶ +ͷ ] K ^ Ͷ ʄ Û ͹ ǩ ¨ ͷ + Ş ȶ + ) H J l ȑ ɧ 0 ȵ Ę ˃ 0 ͒ Ɛ TgͶ −ͷ K ^ E ţ Ù ͹ Ɋ # Ͷ n = 4ͷ ˏ ɝ . ͹ TgͶ +ͷ ù ȹ 0 H J l ɛ Ʉ ̷ 1 ͔ Ɛ . ł + D & ) A # : ͹͔ Ɛ E À Ɋ # ͩ ʲ ǡ ̿ ͹ K ^ 1 ͇ ɑ ȱ ̧ Ȍ ̨ Ȍ + ƿ š ʡ ȶ š ͩ ǉ Ͷ FR-2͹ ǯ ż ¶ ɰ x m s \ x G ͹ Ă ˖ ͷ E ˌ Ɍ . Ƹ ď # ǥ œ ͯ 0 z k X 1 ͹ Ŝ ľ x J RI x G ù ȹ œ ͯ ŉ Ĥ ¶ * Ɲ ˻ B # Ͷ Ë 050208ͷ 2.2ͺ1 2 5 I-DRM106 Ơ ȡ 0 ́ ǅ 1 2 5_{I-DRM106Ͷ Ŝ ľ x J RI x G ͷ 0 ȹ Ɇ ü ŏ ɝ Ɛ ȼ > 3} Ȭ ˱ ȕ 1 ͹ g k 0 ͟ Ͷ ʄ 2 ʀ “2.2.”ͷ * ˵ ̛ # ǌ ȕ + Ę Ǹ * A Ơ ̷ 1 ͹ ¢ Î ˺ ͯ 0 ʚ ǫ E ĸ . 1.3 MBq/mouseͶ Ơ ȡ ̷ 200 μLͷ . ˶ ő # 1 2 5 I-DRM106 0 ƿ š Ɛ ü ŏ ʒ Ż 1 95͵ ² * & #

(41)

2.3ͺ ʿ æ ȸ * 0 ARG 0 ¿ ˦ 1 2 5 I-DRM106 0 1.3 MBq/mouse E TgͶ +ͷ > 3 TgͶ −ͷ K ^ . ą Ī ͙ ʼ Ü Ơ ͹ Ơ 1͹ 2͹ 5 > 3 8 ǖ ̿ Ƅ . r d Ͷ x ` ͹ ȁ ɋ ˚ ģ ů ǵ ǯ ż ¶ ɰ ͹ Ń ̓ ͷ 0 Ȣ ͳ ̰ * Ǌ ͢ ƿ ˝ ˎ Ȅ # Ͷ n =1 ͷ ʿ E ƹ ä ͹ Ȟ ͬ E Ǻ Ǌ # ʿ Þ ȼ Ǌ y g T E û ĵ Ͷ Tissue-TecR_{O.C.T. Compound Sakura Finetechnical, ǩ ¨ ͷ ) ͹ l}

J H J ^ + { R Z Ͷ ̀ ǩ ü ŏ ͹ ǩ ¨ ͷ * á ʚ # á ʚ æ ȸ E T O ^ d g kͶ T O k FSE; Thermo Fisher Scientific Inc, MA. USAͷ * 15 μm . ˙ æ ͹ ^ J l Q ^ . ̊ @ ° ͹ ͧ Ƅ ͹ ^ J l Q ^ . ̊ @ ° # ʿ æ ȸ E ˙ ˈ x I * ˪ ͹ J ] U z k Ͷ IP͹ MS2340͹ Ŝ ľ x J ǯ ż ¶ ɰ ͷ + 19 ǐ ̿ ͘ Ø # ͘ Ø # IP E ͹FLA-3000G ɐ Ó ˱ Ǫ \ ^ i Ͷ GE Healthcare UK, Amersham Place, Englandͷ. > @ 50 μm 0 å ˱ ʺ * ARG E ˿ 9 ď & # Ę Ǹ . ͹ ^ J l Q ^ . ̊ @ ° # ʿ æ ȸ E ˙ ˈ x J * ˪ ͹ X ʡ x J Ͷ BioMax MS͹X e g T ė Ę ¶ ɰ ͹ǩ ¨ ͷ. 19 ǐ ̿ ͘ Ø ͹ˌ ù Ʉ Ó ˣ ʨͶ FPM100΃Ŝ ľ x J ͹ǩ ¨ ͷ. ) Ʉ Ó # ͘ Ø ǖ ̿ . ' ) 1 ¢ Î ǳ ˴ 0 ʚ ǫ ? ˶ ő # ! 0 Ƅ ͹ À Ɋ # ʿ æ ȸ E Congo-red * ǭ ˑ # 2.4ͺ ARG 0 Ń ʿ ɞ ̌ /ʡ ǧ ½ X k ^ k 0 ʈ ä J ] U z kͶ IPͷ* Ƈ ? B # ARG ? H J l â ͓ ½ ȑ ɧ A Ń ʿ ɞ ̌ > 3 H J l â ͓ ½ ȑ ɧ - ʡ ǧ ½ . ̀

(42)

T U K l 0 Ê E Ž ) ȏ : # ɥ 0 ƿ š ʺ ȯ Ż ΆͶ P-BGͷ /mm2_· ' ) 1 ͹ Ç 0 ù ȹ 0 Ń ʿ ɞ ̌ 0 Ê E ʡ ǧ ½ 0 Ê * ͉ ) ͹ Ń ʿ ɞ ̌ ʡ ǧ ½ 0 ƿ š ʺ ȋ E ʈ ä # ƿ š ʺ ȋ = Ń ʿ ɞ ̌ 0 ƿ š ʺ ȯ Ż ͻ ʡ ǧ ½ 0 ƿ š ʺ ȯ Ż Ͷ eq. 6ͷ ? . ͹ ˭ ˮ ɝ ˹ Â 1 ͹ X ʡ x I 0 ARG E Ɋ ͹ Congo-red ǭ ˑ Ó + 0 ˎ Ɛ E ΀ ȇ ͍ Ͷ excellent, good, fair, poorͷ * ˹ Â #

2.5ͺ Congo-red ǭ ˑ O k ] O U x I . À Ɋ # ʿ æ ȸ E 10% Ɛ ʢ ˠ ~ ȡ * 5 å ̿ į ő ͹ɢ % . ̲ ʢ ˠ ȡͶ PBSͷ. 20 ɳ ̿ Ȯ Ș ț # ! 0 Ƅ ͹ Congo-Red Ŋ ǭ ȡ Ͷ 80%M d q 1000 mL . ļ ü m k K 20.0 g E ̧ ͪ Ģ ) ͹x I d ȱ ̧ Ƅ ͹ȱ ȡ E 0.1%Ȍ ̲ ü m k K ȡ * pH 10.06 . ́ ǅ ͷ. 20 å ̿ ȟ Ȯ ͹Congo-Red ǭ ˑ ȡ Ͷ Congo-Red 0.60 g E 500 mL 0 80͵ M d q * Ȭ ˱ ͹ > ƻ ƥ ) ? ͹ ļ ü m k K 7.50g E Ȥ ó ͹ 15 ǖ ̿ ȣ Ģ # 0 Ȭ ȡ E x I d ȱ ̧ ͹ ȱ ȡ E 0.1%Ȍ ̲ ü m k K Ȭ ȡ * pH 10.06 . ́ ǅ ͷ. 20 å ̿ ǭ ˑ # ? . ͹70%M d q . 20 ɳ ̿ Ȯ ) ? ͹ 95%M d q . 3 å ̿ ' ė ˳ 3 Ī ȟ ʾ ˑ # ǜ Ƅ . ͹ R \ . 5 å ̿ ' ė ˳ 3 Ī Ȯ # 0 % ͹ P s Q ^ * ʿ æ ȸ E Š Ù ̻ ǳ # - ͹ À Ɋ # Ɛ ʢ ˠ ~ ȡ ͹ ļ ü m k K ͹ Ȍ ̲ ü m k K ͹ M d q > 3 R \ Ͷ R \ e ü ŏ ͷ͹PBSͶ ǐ Ȍ ˦ ˚ ͹ǩ ¨ ͷ+ Congo-redͶ Aldrich Chemical Company͹

(43)

WI, ʋ İ ͷ E Ɋ # 3ͺ ʚ ǫ 3.1. ʿ æ ȸ * 0 ARG 1 2 5 I-DRM106 E Ơ # TgͶ +ͷ > 3 TgͶ −ͷ0 J ] U z k 0 ARG E Fig.8 . ɮ # 1 2 5 I-DRM106 . > A TgͶ +ͷ K ^ 0 Aβ â ͓ ½ ȑ ɧ Ó 1 ǖ ̿ ? 8 ǖ ̿ 8 * ƀ Ƴ ä B ͹Aβ â ͓ ½ 0 ȑ ɧ ̮ º + Ǔ ɨ - X k ^ k E ĝ # Aβ â ͓ ½ ȑ ɧ B ) - ʡ ǧ ½ ̮ º > 3 TgͶ −ͷ K ^ 0 ʿ Ü . 1 ͹ ɕ Ŵ - ƿ š ʺ 0 ͓ ɻ ˰ ŝ ǖ ̿ E ̟ ) 9 ? B - & # 3.2. ARG 0 Ń ʿ ɞ ̌ /ʡ ǧ ½ X k ^ k ȋ Ń ʿ ɞ ̌ Ş ʡ ǧ ½ ȋ E eq. 6 0 ż * ȏ : ͹ Table 8 . ɮ # TgͶ +ͷ . A ƿ š ʺ ȋ 1 ͹ 1 ǖ ̿ * 4.66 + - & # Ƅ ͹ 2 ǖ ̿ ? 8 ǖ ̿ 8 * 10 í Ƅ E ʝ ƨ ͹TgͶ −ͷ K ^ * 1 1 í Ƅ 0 ș Ɛ ȋ * ʝ ƨ B # 3.3. Congo-red ǭ ˑ Ó TgͶ +ͷ > 3 TgͶ −ͷ0 X ʡ x J 0 ARG > 3 Congo-red ǭ ˑ Ó E Fig. 9 . ɮ # TgͶ +ͷ 0 ARG 1 ͹ Congo-red ǭ ˑ . A Aβ â ͓ ½ 0 ȑ ɧ . > ˎ ) #

(44)

ARG ɐ Ó 1 ͹ Congo-red ǭ ˑ Ó + > ˎ # Ơ Ƅ 1 ǖ ̿ . ʿ ǲ ° ̚ 0 ɜ ̌ . ͚ Ⱥ ɕ ɝ - ͓ ɻ E ˻ : # ; 0 0 ͹ 2 ǖ ̿ ² ͆ * 1 Ƞ Ņ # 4ͺ ʬ ŝ ǥ ʀ * 1 ͹ IMPY 0 H J l J ] U . ̀ A Ǐ Ĺ * Ɋ ? B ) # Tg K ^ 2 1 ͷ_{E À Ɋ #}1 2 5 I-DRM106 E TgͶ +ͷ > 3 Tg Ͷ −ͷ K ^ . ą Ī ͙ ʼ Ü Ơ ͹ʙ ǖ ɝ . ARG E ¿ Ƙ A + + ; . ͹ Ę æ ȸ E Ɋ ) Congo-red ǭ ˑ E ˞ & # TgͶ +ͷ K ^ 0 Aβ â ͓ ½ ͌ Ɛ å ű + Congo-red ǭ ˑ 0 ͌ Ɛ å ű 1 ͚ Ŵ . ˎ ) # Ş ȶ 0 TgͶ −ͷ K ^ 0 ʿ . ͚ Ⱥ ɕ ɝ - ʚ ė 1 ͹ ˰ ŝ B - & # ARG ɐ Ó 0 ő ̷ ˹ Â . Ń ʿ ɞ ̌ /ʡ ǧ ½ E Ɋ # + * ͹ Aβ â ͓ ½ ł Ō ı A Ń ʿ ɞ ̌ + ͹ 6 + F , ȑ ɧ - ʡ ǧ ½ 0 Aβ â ͓ ½ 0 å ű ȋ . > & ) ͹Ŕ ˰ ɝ - ˹ Â ē ʺ * & # Ex vivo ˺ ͯ ʚ ǫ  ? ͹Ƕ / Ń ʿ ɞ ̌ /ʡ ǧ ½ 2 ² * B 2 ͹in vivo 0 ˹ Â . ) ; Aβ â ͓ ½ 0 X k ^ k Ƈ ? B A + ʬ ? B ) @ ͹ ¬ Ī 0 ȋ Ͷ 1 ǖ ̿ * 4.66͹ 2 ǖ ̿ ? 8 ǖ ̿ 8 * 10 í Ƅ E ʝ ƨ ͷ 1 ͹ in vivo ˹ Â . ā å ʮ A ʚ ǫ * & # + ʬ ? B # 1 2 5 I-DRM106 E Ơ # TgͶ +ͷ K ^ * 1 ͹ Ơ Ƅ 8 ǖ ̿ 8 * Ͳ X k ^ k Ƈ ? B # + ? ͹SPECT 0 ƺ Ó ē ʺ - ǖ ̿ ɭ Å B # + ʬ ? B # ? . ͹ Ń ʿ ɞ ̌ Ş ʡ ǧ ½ ȋ ? Ơ Ƅ ͽ ǖ ̿ 0 Ǒ ǖ ȴ ? SPECT 0 ƺ Ƃ ē ʺ * A + ; Ǔ ? + - & # # $ ͹in vivo SPECT Ó 0 ƺ Ƃ . ͐ ) 1 ͹1 2 5

I-DRM106 0 1 2 5 I E 1 2 3 I Ͷ ă Ȧ ǡ 13 ǖ ̿ ͷ. ʨ Ƶ A ƌ ˩ A Ex vivo œ ͯ * À Ɋ # 1 2 5 I 0 ă Ȧ ǡ 60 ǐ . Ş ͹1 2 3 I 0 ă Ȧ ǡ 1 13 ǖ ̿ * A # : ͹Aβ â ͓ ½ *

(45)

0 ƿ š ʺ ș Ɛ 1 ɫ - @ ͹ ƺ Ƃ ̫ ǡ 1 Ǒ + ʬ ? B #

² 0 ʚ ǫ E ʬ Ɩ A + ͹Aβ â ͓ ½ * 0 ƿ š ʺ ș Ɛ ſ - A í . ͹  ' ͚ Ⱥ ɕ ɝ - ʚ ė ť - ǖ ȴ . 1 ͹in vivo SPECT Ó 0 ǜ ̫ ƺ Ó ǖ ̿ Ͷ Ơ Ƅ 1-2 ǖ ̿ ͷ + ʬ ? B #

- ͹Aβ â ͓ ½ 0 ǭ ˑ . 1 Congo-red E À Ɋ # ͹Congo-red ǭ ˑ 1 Ȍ Ȭ Ɛ Ͳ ͹ ǭ ˑ Ƽ ¿ ř ǔ * A ˑ ʔ 1 ˜ Ø ǭ ˑ + ȋ 5 ) Ɣ Ż » # : thioflamine S < (E,E-1-fluoro-2,5-bis-(3-hydroxycarbonyl-4-hydroxy)styrylbenzeneͶ FSBͷ 0 ˜ Ø ǭ ˑ . ± Ǜ B ' ' A ͹ č ƍ ř ǔ + ê ȴ A Ť Ƨ DRM106 0 Aβ â ͓ ½ Ƴ ä ʺ E ˹ Â A # : ͹1 2 5 I * ǹ ̅ # DRM106 E AD j * A ͔ Ɛ TgͶ +ͷ K ^ + ͊ Ɛ Ş ȶ + ) Ę ˃ 0 ͒ Ɛ TgͶ −ͷ K ^ . ͙ ʼ Ü Ơ Ƅ ͹ Aβ â ͓ ½ 4 0 ͓ ɻ Ɛ . ' ) ARG * ˱ Ǫ # ! 0 ʚ ǫ ͹ TgͶ +ͷ K ^ 0 ARG 1 Congo-red ǭ ˑ + > ˎ # 0 + ? ͹ DRM106 1 ʿ 0 Aβ â ͓ ½ . Ⱥ ɕ ɝ . ͓ ɻ A + ɮ B #

(46)

Fig. 7. Scheme showing the method for quantitative analyses of radioactivity of cortical area in a brain coronal section. Amyloidsis-associated accumulations of 1 2 5

I-DRM106 radioactivity were estimated as a photostimulated luminescence (PSL) per mm2

for the ratios of cerebral cortex to striatum. cerebral cortex, striatm

(47)

Fig. 8. Representative imaging plate autoradiograms in the brain of a 19-month-old female PS-1ki/JU-Tg2576 (Tg+) or age-matched male non-Tg [Tg (-)] mouse receiving a bolus injection of 1.3 MBq/mouse of

1 2 5

I-DRM106 via the tail vein. The animals were euthanized at 1, 2, 5, and 8 hr post-injection, and the brains were immediately removed for autoradiography analysis.

(48)

Fig. 9. X-ray film autoradiograms (left panel) of 1 2 5

I-DRM106 with Congo-red staining (right panel) in the brain of a 19-month-old female Tg (+) or age-matched male Tg (-) mouse receiving a bolus injection of 1.3 MBq/mouseof 1 2 5

I-DRM106 via the tail vein. The animals were euthanized at 1, 2, 5, and 8 hr post-injection, and the brains were immediately removed. The coronal images (approximately 0.2 mm anterior to the bregma) were performed, and the same brain sections were stained with Congo red after autoradiography. 1 2 5

I-DRM106 radioactivity accumulations in Aβ plaques were consistent with Congo red staining.

(49)

Table 8. Ratio of 1 2 5

I-DRM106 radioactivity in the cerebral cortex to striatum areas of a Tg (+) or Tg (-) mice (n = 1 for each time point) receiving a bolus injection of 1.3 MBq/mouse via the tail vein. The animals were euthanized at 1, 2, 5, and 8 hr post-injection, and the brains were immediately removed. Post administration (hr) Tg (+) Tg (-) 1 4.66 0.72 2 10.35 0.81 5 9.75 1.01 8 11.67 0.96

(50)

(51)

ʄ ʄ 4 ʀ AD j K ^ . A SPECT Ó + PET Ó + 0 ȋ ̕ 1ͺ ʶ ǘ + ɡ ɝ ʠ ˲ * ̛ 5 # + ͹Aβ â ͓ ½ 0 ǰ Ā ŏ J ] U ɬ ɽ 1 ͹PET × ˞ ) A B 8 * 0 ɬ ɽ * 1 ͹ k Z + ) ͹ ̟ Ŵ 11 C Ɋ ? B ) # ͹ă Ȧ ǡ 20 å ̿ + ɫ ͹8 # ͌ ͗ ŋ E ɛ Ɉ A Z J T k ˣ ʨ ƌ ˩ * ͹ À Ɋ * A Ǎ ˶ ͇ ő B ) A ̟ Ŵ ͹ ˋ Ź . A PET 0 ƿ š Ɛ ǰ ɸ . 1 ͹ ă Ȧ ǡ 110 å ̿ 0 1 8 F Ȑ Ɋ B ) # ͹Good Manufacturing Practice . ) ä ˒ í . M l k R \ ǳ Ǯ ˩ ȏ B A # : ͹ ˦ ̡ ? ä ˒ 8 * 0 ǖ ̿ E ˩ ͹ Á ʛ * A ʊ ĭ Ⱦ - A ǌ ͹ SPECT * À Ɋ B A K ʔ k Z 1 ͹ ȹ Ɇ ŏ ɝ ă Ȧ ǡ ȋ ̕ ɝ ̼ Ͷ 13 ǖ ̿ ͷ͹ ˣ ʨ ; Ÿ Ǘ Č ) A + ? ͹SPECT Ɋ ˷ Ǌ ˚ 0 ǌ PET Ɋ ˷ Ǌ ˚ > @ ; Ȑ Ɋ Ɛ 1 Ͳ PET Ɋ Aβ ˷ Ǌ ˚ . 1 ͹ | c f H c Ƿ ̡ E Ǟ A f O x v E Ȉ ǰ + # 1 1 C-PiB @ ͹ʿ ɶ ˞ ; ː Ň * A ǌ ͹1 2 3 I-SPECT Ɋ Aβ Q l ü ė ȹ + ͹ Ħ ˋ Ź ˺ ͯ 8 * ̤ F $ 0 1 IMPY2 9 ͷ_* A ͹AD Ƒ ʭ 0 Ȁ Ŵ ̮ º + Aβ â ͓ ½ E ÿ é * ͹̾ ɛ 1 ǿ B # 2 2 ͷ_{ʄ 3 ʀ . ) ͹}1 2 3 I-DRM106 1 ͹ AD j * A PS-1ki/JU-Tg2576 [TgͶ +ͷ ] K ^ . ) ͹ Ȁ Ŵ ̮ º + Aβ â ͓ ½ + E ÿ é A + * A + è Ǔ # ! * ͹ǥ ʀ * 1 ͹TgͶ +ͷ > 3 TgͶ −ͷ K ^ E Ɋ ) ͹Ę Ç ½ * 1 2 3 I-DRM106 0 SPECT Ó + 11 C-PiB 0 PET Ó 0 ɐ Ó E ȋ ̕ #

(52)

2ͺ Ǧ ǉ > 3 ǌ ȕ 2.1ͺ À Ɋ ù ȹ

28 ǝ ʹ ͔ ͒ Tg2576 [TgͶ +ͷ ] K ^ Ͷ Taconic Farms, NY, ʋ İ ͷ + Ş ȶ + ) H J l ȑ ɧ 0 ȵ Ę ˃ 0 ͒ Ɛ TgͶ −ͷ K ^ E Ɋ # Ͷ n = 2ͷ Ç ½ ID ɔ ĕ 1 ͹ ˵ 0 + @ * A ͔ Ɛ TgͶ +ͷ K ^ : 1-2 ͒ Ɛ TgͶ +ͷ K ^ : 3-4 ͒ Ɛ TgͶ −ͷ K ^ : 5-6 ͩ ʲ ǡ ̿ ͹ K ^ 1 ͹ ͇ ɑ ȱ ̧ Ȍ ̨ Ȍ + ƿ š ʡ ȶ š ͩ ǉ Ͷ FR-2͹ ǯ ż ¶ ɰ x m s \ x G ͹ Ă ˖ ͷ E ˌ Ɍ . Ƹ ď # ǥ œ ͯ 0 z k X 1 ͹Ŝ ľ x J RI x G ù ȹ œ ͯ ŉ Ĥ ¶ . Ɲ ˻ B # Ͷ Ë 121008͹ Ë 121105ͷ 2.2ͺ 1 2 3 I-DRM106 + 11 C-PiB 0 Ơ ȡ 0 ́ ǅ 1 2 3 I-DRM106 Ͷ Ŝ ľ x J RI x G ͷ 1 ͹ 0.9͵ Ͷ v/vͷ | ] H X Ͷ R \ e ü ŏ ͷ + 0.09 v/v% ļ ̲ Ͷ R \ e ü ŏ ͷ Ě Ǟ Ɉ Ɇ ɝ ͨ ļ ȡ * 714 GBq/μmol . - A > . ́ ˦ # Ơ ̷ 1 ͹¢ Î ˺ ͯ E ĸ . 340-350 MBq/mouseͶ Ơ ȡ ̷ 800 μLͷ . ˶ ő # À Ɋ # 1 2 3 I-DRM106 0 ƿ š Ɛ ü ŏ ʒ Ż 1 ͹ 95͵ ² * & # 11 C-PiBͶ ƿ š ʡ Ā ŏ ʟ ė ɬ ɽ ƚ ͷ1 ͹0.3͵ tween80 Ͷ R \ e ü ŏ ͷ Ě Ǟ Ɉ Ɇ ɝ ͨ ļ Ȍ * 291 GBq/μmol . - A > . ́ ˦ # Ơ ̷ 1 ͹ ¢ Î ˺ ͯ 0 ʚ ǫ E ĸ . 30.0 ± 6.8 MBq/mouseͶ Ơ ȡ ̷ 200 μLͷ . ˶ ő # À Ɋ # 11 C-PiB 0 ƿ š Ɛ ü ŏ ʒ Ż 1 ͹ 95͵ ² * & #

(53)

2.3ͺ1 2 3 I-DRM106 > 3 11 C-PiB E Ɋ ) 0 ƺ Ó ǜ ç . ͹11 C-PiB E Ɋ ) PET ƺ Ƃ A # : ͹ù ȹ E 1.5͵Ͷ v/vͷ J b x Ͷ M ^ P J , x G [ ͹ǩ ¨ ͷͳ ̰ ͹30 G 0 Ȃ ɲ Ɋ ȗ š ̸ Ͷ i ͹ ǩ ¨ ͷ E Ŧ ͙ ʼ Ü . ɒ ʨ ͹ M f f y Ͷ PE 10, ŀ ɡ ˦ ¿ ƚ ͹ ǩ ¨ ͷ E ) 1 ml 29 G J ] L T d ȗ š ĩ Ͷ i ͷ > @ 11

C-PiB E Ơ # micro PET 0 focus 220 animal scanner Ͷ Siemens Medical Solutions, Malvern, PA͹ʋ İ ͷE Ɋ ) Ơ ɢ Ƅ ? 60 å ̿ ƺ Ƃ # Ú ) 0 ƺ Ó ɐ Ó 0 ? ͹20-50 å 0 Þ ȼ Ǌ Ó > 3 ɩ ȼ Ǌ Ó E 0.5 mm T ` 3D . Ý Ƿ Ƙ # ! 0 Ó E PMOD® image analysis software Ͷ PMOD Group, Zurich, ^ J ^ ͷ E Ɋ ) ĉ 0.5 mm 0 ʿ MRI i z k . ̵ / ė ) x ] ɐ Ó E ¿ Ƙ # Ú ) 0 ǳ Ǯ ʗ ¡ Ƅ ͹ ù ȹ 1 ˮ ̳ #

PET ƺ Ó 1 ǝ Ƅ ͹ Ę K ^ E Ɋ ) 1 2 3_{I-DRM106 0 SPECT ƺ}

Ó E œ Ǎ # PET œ ͯ + Ę Ǹ . ͹ ɭ Å B # Ŧ ͙ ʼ 0 Ơ J > @ 1 2 3

I-DRM106 E Ơ # SPECT Ó 1 ͹Ť ù ȹ Ɋ SPECT ˣ ʨͶ Inveon

T M

platform, Siemens Medical Solutions USA, Knoxville, TN͹ʋ İ ͷ E Ɋ ͹ǳ ä ĩ . ɢ ƃ 1.0 mm 0 5 ɼ f w ~ X d E ˣ ɧ ͹ Ī ̓ ă ƃ 30 mm * ͹ step-and-shoot l * 4° ' 360°E 90 ÇͶ 45΅ 2ͷ. å ñ ) ƺ Ƃ # 8 # ͹1 2 3 I 0 M p S . ė D ) K J l K ŵ E 159 keV 0 20% + ͹Ơ ɢ Ƅ ? ǜ ç 0 60 å ̿ 8 * . 1 ɐ Ó E 20 ɳ ̿ ͹ 60 å ² ͆ 1 1 ɐ Ó E 40 ɳ ̿ Ȩ ő # Ę 0 ǧ ´ * ɐ Ó E ȋ ̕ A ɡ ɝ * ͹ ƺ Ó ǖ ̿ 0 1 2 3_{I 0 ȹ Ɇ ŏ ɝ ă Ȧ}

(54)

Ƿ Ƙ B # Þ ȼ Ǌ Ó + ɩ ȼ Ǌ Ó E PMOD® image analysis software Ͷ PMOD Group, Zurich, SwitzerlandͷE Ɋ ) K ^ 0 ʿ 0.5 mm ĉ MRI i z k . ͹ x ] ɐ Ó E ¿ Ƙ #

1 2 3

I- DRM106 0 SPECT Ó > 3 11

C- PiB 0 PET Ó 0 Ń ʿ ɞ ̌Ͷ Ͳ Aβ â ͓ ½ å ű Ķ ͷ + Ť ʿ Ͷ » Aβ â ͓ ½ å ű Ķ ͷ + 0 ȋ E ȏ : SPECT Ó + PET Ó 0 ƿ š ʺ ȋ 0 ɣ ̀ Ɛ E ˹ Â # 2.4. SPECT ƺ Ó Ƅ 0 ʿ æ ȸ 0 ¿ ˦ ʿ Ü . Aβ â ͓ ½ 0 Ō ı E ɭ ˻ A # : ͹ ʄ 3 ʀ * œ Ǎ # ʿ æ ȸ 0 ¿ ˦ E ˞ & # 8 ͹SPECT ƺ Ó Ƅ ͹ù ȹ 1 J b x Ȣ ͳ ̰ * Ǌ ͢ ƿ ˝ ˎ Ȅ # ʿ 0 ă Ʌ Ƌ ̮ ? ɩ ȼ Ǌ . û ĵ ͹ l J H J ^ + { R Z * á ʚ # - ͹² ͆ 0 ¿ Ƙ ƛ ͠ 1 ͹ʄ 3 ʀ “2.3.” . ȫ ) ˞ & # 2.5ͺ FSB ǭ ˑ Aβ â ͓ ½ 0 Ͳ Ɣ Ż ˜ Ø ǭ ˑ î FSBͶ Ę « ü ŏ ɬ ɽ ƚ ͹ȷ ǥ ͷE À Ɋ # 1͵ FSB Ͷ 1 mg /100 μl DMSOͷ. ͹M d q E ó ) ͹0.001% FSB Ȭ ȡ E ́ ǅ # ʿ æ ȸ E 0 ǭ ˑ ȡ Ü . 30 å ̿ ȟ ͹ ɢ % . ͪ Ģ ȳ ̲ f K Ȍ Ȭ ȡ Ͷ R \ e ü ŏ ͷ . ȟ # Ƅ ͹ 50͵ M d q . ) ̔ Ș & # 0 æ ȸ E BZ-9000 ˜ Ø ͥ Ɖ ̻ Ͷ R M ^ ͹ Ń ̓ ͷ * UV ØͶ ö ̎ Ȗ ̼ λex=390 nm, ˜ Ø Ȗ ̼ λem=511 nmͷ* ˰ ŝ # - ͹˭ ˮ ɝ ˹ Â 1 ͹11 C-PiB 0 PET Ó , 1 2 3 I-DRM106 0 SPECT Ó . A FSB ʘ ʧ ǭ ˑ Ó + 0 ͦ ¹ Ɛ E ΀ ȇ ͍Ͷ excellent, good, fair, poorͷ * œ Ǎ #

(55)

2.6ͺ ʜ ˳ ˱ Ǫ

˳ Ǆ Ê 1 Ŷ ĳ Ê * ˡ ͹ SPECT+ PET0 ɣ ̀ Ɛ 1 ͹ Pearson 0 t k g T ǳ ő * ɣ ̀ Ä Ǆ Ͷ rͷ E ȏ : ͹ P < 0.05* Ǟ Ɠ Ű @ + è Ǌ  # 3ͺ ʚ ǫ 3.1. 1 2 3 I-DRM106 E Ɋ ) 0 SPECT ɐ ƺ Ó TgͶ +ͷ > 3 TgͶ −ͷ K ^ . 1 2 3_{I-DRM106 E ͙ ʼ Ü Ơ # ĺ ė} 0 ± ˡ ɝ Þ ȼ Ǌ Ó E Fig.10 . ͹ ɩ ȼ Ǌ Ó E Fig.11 . ɮ # ɐ Ó + ; TgͶ +ͷ + TgͶ −ͷ K ^ 0 ʿ ? ƿ š ʺ ƅ . Ƞ Ņ ) # Ơ Ƅ 60-90 å . ͚ Ⱥ ɕ ɝ - ʚ ė washout B ͹ɐ Ó ? TgͶ +ͷ K ^ + TgͶ −ͷ K ^ 0 ÿ é ē ʺ * & # 3.2. Ç ½ é 0 11 C-PiB 0 PET Ó , 1 2 3 I-DRM106 0 SPECT Ó > 3 FSB ʘ ʧ ǭ ˑ Ó Ç ½ é 0 Ơ Ƅ 60-90 å 0 PET Ó ͹SPECT Ó > 3 FSB ǭ ˑ Ó E Fig.12-17 . ɮ #  TgͶ +ͷ K ^ 0 Ė Ç ½ 1 ͹PET Ó > 3 SPECT Ó + ; FSB ʘ ʧ ǭ ˑ Ó 0 Ń ʿ ɞ ̌ + Ȟ ͬ . ˎ # ɐ Ó Ƈ ? B # ͹ TgͶ −ͷ K ^ * 1 Ú ) 0 Ç ½ * ͌ Ɛ Ƴ ä 1 ˰ ŝ B - & # ˭ ˮ ɝ 0 ˹ Â ʚ ǫ E Table 10 . ɮ # ¾ B 0 Ç ½ . ) ; ͹11_{C-PIB 0 PET Ó}

+ 1 2 3

(56)

3.3. 1 2 3

I-DRM106 0 SPECT Ó > 3 11

C-PiB 0 PET Ó 0 ɣ ̀ Ɛ Ę Ç ½ . A SPECT Ó 0 Ń ʿ ɞ ̌Ȟ ͬ Ş Ť ʿ 0 ƿ š ʺ ȋ + Ę ͡ Ķ 0 PET Ó 0 binding potential + 0 ɣ ̀ E Fig.18 . ɮ # PET Ó + SPECT Ó 0 ɣ ̀ Ä Ǆ r = 0.95Ͷ P < 0.01ͷ * Ͳ ɣ ̀ Ɛ ɮ B # 4ͺ ʬ ŝ SPECT Ɋ ƿ š Ɛ Q l É ˥ ģ 1 2 3 I-DRM106 0 ƺ Ó + 11 C-PiB E Ɋ # PET Ó Ę Ǹ 0 ɐ Ó E Ƴ ä * A ͹TgͶ +ͷ > 3 TgͶ +ͷ K ^ 0 Ę Ç ½ E Ɋ ) ȋ ̕ # ! 0 Ƅ ͹ FSB ʘ ʧ ǭ ˑ E ¿ Ƙ Aβ â ͓ ½ 4 0 ȑ ɧ 0 ɭ ˻ E ˞ & # ǥ ɬ ɽ * À Ɋ # TgͶ +ͷ K ^ 0 Aβ â ͓ ½ ś Ż 1 ͹ 12 ǝ ʹ ? AD Ǹ H J l 0 ȑ ɧ ɗ Ɇ ʘ ʧ ŏ ɝ . ɭ ˻ B ) @ 1 5 ͷ_{͹ u} k 0 AD Ƒ ʭ 0 ʿ . ˫ ? B A ; 0 + Ę Ǹ 0 | * A # & ) ͹ AD j + ) ͹Ÿ À Ɋ B ) A ǌ * ͹11 C-PiB 0 PET Ó * 1 ͹ ʿ Ü Aβ â ͓ ½ 0 ʚ ė ̮ º AβN 3 Ͷ P E ͷ ť - + 0 Ĺ Ğ 1 9 ͷ_; A ¬ Ī 0 œ ͯ ʚ ǫͶ Fig. 12-17ͷ* 1 ͹TgͶ +ͷ K ^ * 0 11 C-PiB 0 PET Ó > 3 1 2 3

I-DRM106 0 SPECT Ó 1 ͹ ¾ B ; Ń ʿ ɞ ̌ Aβ â ͓ ½ . Ͳ ƿ š ʺ 0 ˘ ɻ Ƴ ä B # ˏ ɝ . ̟ Ŵ ͩ ʲ B # ͚ Tg K ^ 0 Ŷ ĳ ş ġ 1 Ɉ Ƅ 24 ǝ + B ) @ ͹ʿ Ü . Aβ â ͓ ½ ä Ʉ A ǖ ǡ . Ȅ ¦ ł ɛ A ¬ Ī 0 œ ͯ * 1 ͹ 28 ǝ ʹ 0 ʫ ʹ TgͶ +ͷ K ^ E À Ɋ # # : ͹ PiB + 0 ʚ ė ̮ º AβN 3 Ͷ P E ͷ ɣ Ş ɝ . Ľ # + ʬ ? B # 2 5 ͷ_{8 # ͹ ¬ Ī À Ɋ #} 11 C-PiB 0 ȋ ƿ š ʺ 1 ͹ 291 GBq/μmol + Ͳ ģ ̌ 0 ǹ ̅ ½ * @ ͹ 0 + Aβ â ͓ ½ 0 ǳ ä ʺ .

(57)

Ś # ē ʺ Ɛ ʬ ? B # 2 5 ͷ_{8 # ͹˭ ˮ ɝ ˹ Â * 1 ͹PET Ó SPECT} Ó 0 B ; ͹ FSB ǭ ˑ + > ˎ # # $ ͹ ¬ Ī 0 œ ͯ 1 ͹ ʿ æ ȸ 0 ĉ 16 μm . Ş ) ͹PET Ó + SPECT Ó 0 ^ J ^ ĉ 0.5 mm * & # + . ' ) 1 ͹ ʬ Ɩ . Ù B ) 5 * A 8 # ͹SPECT Ó + PET Ó . A Ń ʿ ɞ ̌ + Ť ʿ 0 ƿ š ʺ ȋ 1 ͹Ͳ  ɣ ̀ Ͷ r = 0.95, P<0.01ͷ ˻ : ? B ͹ B 0 ɐ Ó ; ͹ TgͶ +ͷ + TgͶ −ͷ K ^ 0 Aβ 0 ͓ ɻ 0 ̪ E č Ǖ # + ʬ ? B # ² ͹1 2 3 I-DRM106 0 SPECT ǳ Ǯ 1 11 C-PiB E k Z + ) ê Ɋ # PET ǳ Ǯ + Ę ʆ 0 Aβ â ͓ ½ 0 ǳ ä ʺ E Ǟ A + ʬ ? B # Ť Ƨ 1 2 3 I-DRM106 E Ɋ # SPECT Ó + 1 1 C-PiB E Ɋ # PET Ó E ȋ ̕ A ɡ ɝ * ͹Ę 0 j ù ȹ E Ɋ ) Aβ â ͓ ½ 0 Ƴ ä ʺ E ˹ Â # TgͶ +ͷ K ^ * 1 B 0 ɐ Ó ; Ń ʿ ɞ ̌ . å ű A Aβ â ͓ ½ Ƴ ä B # ͹ TgͶ −ͷ K ^ * 1 Ƴ ä B - & # 8 # ͹ SPECT Ó + PET Ó . A Ń ʿ ɞ ̌ + Ť ʿ 0 ƿ š ʺ ȋ 1 ͹Ͳ ɣ ̀ ˻ : ? B ͹ SPECT + PET 0 B 0 ɐ Ó ; ͹ TgͶ +ͷ + TgͶ −ͷ K ^ 0 Aβ â ͓ ½ 0 ͓ ɻ 0 ̪ E č Ǖ # 0 + ? ͹ 0 + ? ͹

1 2 3

I-DRM106Ͷ SPECTͷ + 1 1

C-PIBͶ PETͷ 1 ͹ Ę ɷ Ż . Aβ â ͓ ½ E ǳ ä * A + ɮ ĥ B # ² 0 ɬ ɽ ? ͹DRM106 1 SPECT Ɋ Q l + ) Ǟ Ǡ - ̾ ɛ É ˥ ģ * A + ʬ ? B #

(58)

Fig. 10. Representative coronal SPECT images of 1 2 3

I-DRM106 on MRI templates in a 28-month-old Tg (+) (#2, left panels) or age-matched Tg (-) mouse (#6, right panels) receiving a bolus injection of 340-350 MBq/mouse of 1 2 5_{I-DRM106 via the tail vein. The upper to lower panels were shown as}

time-dependent washout radioactivity from the brain. The respective panels represent coronal images at 2 mm posterior to the bregma.

(59)

Fig. 11. Representative sagittal SPECT images of 1 2 3

I-DRM106 on MRI templates in a 28-month-old Tg (+)(#2, left panels) or age-matched Tg (-) mouse (#6, right panels) receiving a bolus injection of 340-350 MBq/mouse of 1 2 5

I-DRM106 via the tail vein. The upper to lower panels were shown as time-dependent washout radioactivity from the brain.

(60)

Fig. 12. Sagittal 11

C-PiB PET image (upper panel), 1 2 3

I-DRM106 SPECT image (middle panel) and FSB staining (lower panel) in a female 28-month-old Tg Ͷ +ͷ mouse Ͷ #1ͷ receiving a bolus injection of 340-350 MBq/mouse of 1 2 5

I-DRM106 and 30.0 ± 6.8 MBq/mouse of 11

C-PiB via the tail vein.

(61)

Fig. 13. 11

I-DRM106 SPECT image (middle panel) and FSB staining (lower panel) in a female 28-month-old Tg (+) mouse (#2) receiving a bolus injection of 340-350 MBq/mouse of

(62)

Fig. 14. 11

I-DRM106 SPECT image (middle panel) and FSB staining (lower panel) in a male 28-month-old Tg (+) mouse (#3) receiving a bolus injection of 340-350 MBq/mouse of

(63)

Fig. 15. 11

I-DRM106 SPECT image (middle panel) and FSB staining (lower panel) in a male 28-month-old Tg (+) mouse (#4) receiving a bolus injection of 340-350 MBq/mouse of

(64)

Fig. 16. 11

I-DRM106 SPECT image (middle panel) and FSB staining (lower panel) in a male 28-month-old Tg (-) mouse (#5) receiving a bolus injection of 340-350 MBq/mouse of

(65)

Fig. 17. 11

I-DRM106 SPECT image (middle panel) and FSB staining (lower panel) in a male 28-month-old Tg (-) mouse (#6) receiving a bolus injection of 340-350 MBq/mouse of

1 2 5

I-DRM106 and 30.0 ± 6.8 MBq/mouse of 11

(66)

Fig. 18. Correlation of the binding between 1 2 3

I-DRM106 SPECT and

11

C-PiB PET. The data of individual mouse (n = 6), which received both

11

C-PiB and 1 2 3

I-DRM106, were used for correlation analysis.

(67)

(68)

ʟ ʟ Ƨ ˻ ɪ ɘ + 1 ͹ Ͳ Ǿ ʿ Ǽ ʺ Ƅ ń ɝ - ĩ ̌ ɝ Ʒ Ð . > & ) » ͹ ǐ Ŵ Ɉ ș . ƽ ͑ E # ɖ Ƒ * ͹ ǐ ǥ * 1 Ͳ ʹ ü . ¸ Ľ ó ) A Ʉ ı ͹ 65 ȃ ² 0 ǐ ǥ ª 0 15͵ ͹ 462 ª ˻ ɪ ɘ . ʩ Ƒ ) @ ͹ ! 0 70͵ H h r J ɗͶ ADͷ. > A + ʬ ? B ) A AD 0 Ǒ ǡ ˷ Ǌ 1 ͹ ɗ ƕ 0 ̤ ˞ E ̥ ? A Ā ɚ ã ʨ ˞ A + < Ƒ ʭ ˌ ̒ + Ř ǎ ̫ æ - ɰ ¶ ɝ Ş ƍ E + A + ē ʺ . - A + ? ͹ Ĩ ʞ 0 ̀ ͤ . - & ) A AD 1 ͹ɱ ʙ ʖ ʷ 4 0 amyloid-βͶ Aβͷ0 ˘ ɻ ɱ ʙ ɗ Ɇ ŏ ɝ Ŀ ü 0 Ⱥ Ɗ 0 ' * A ͹ ʿ ʘ ʧ E ˺ ǉ + A # : Ɉ í 0 ɭ ő ˷ Ǌ 1 ē ʺ * A ! 0 # : ͹ ˘ ɻ # Aβ E ͚ Ã ˨ ɝ . ƞ ƶ A + * B 2 ͹AD E Ǒ ǡ . ˷ Ǌ A + * A + ʬ ? B A AD 0 ǰ Ā ŏ ˷ Ǌ . 1 1 1_{C-Pittsburgh compound B E Ɋ # positron}

emission tomographyͶ PETͷ × ˞ ) A ͹ ł 0 PET Ɋ k Z 1 ȹ Ɇ ŏ ɝ ă Ȧ ǡ ɫ ͹ ˣ ʨ ; Ͳ Â * A # : Ö å Ǘ Č ) A + 1 - ǌ * ͹ single photon emission computed tomographyͶ SPECTͷ * À Ɋ B A K ʔ k Z Ͷ1 2 3 Iͷ 1 ͹ ȹ Ɇ ŏ ɝ ă Ȧ ǡ ȋ ̕ ɝ ̼ Ͷ 13 ǖ ̿ ͷ ͹ ˣ ʨ ; Ǘ Č ) A + ? ͹ SPECT * Aβ E Ⱥ ɕ ɝ . Ƴ ä A Q l ̾ ɛ * B 2 ˋ Ź ˷ Ǌ . A Ǟ Ɋ Ɛ 1 Ͳ + ʬ ? B A ! * ǥ ɬ ɽ * 1 ͹ ʿ Ü Aβ â ͓ ½ . ˯ Ģ Ɛ E ƨ ' imidazopyridine ˼ ţ ½ E ĸ ǥ Ƿ ̡ + # ü ė ȹ . ɧ ɡ ͹Aβ â ͓ ½ 0 ʿ Ü å ű E ǳ ä A # : 0 SPECT Ɋ Q l 0 ̾ ɛ E ɡ ɝ + ) ͹² 4 ʀ . ¥ @ ǳ ˴ E ó # ʄ 1 ʀ * 1 ͹ SPECT Ɋ Q l E ̬ ơ A ɡ ɝ * ͹ ̾ ɛ É ˥ ģ

(69)

DRK092͹ DRM101͹ DRM102͹ DRM105 > 3 DRM106 . Ş ) ͹ Aβ 4 0 ˯ Ģ Ɛ > 3 ʻ Ȭ Ɛ Ͷ logD7.4ͷ E in vitro ʐ * ǳ ˴ # ! 0 ʚ ǫ ͹Aβ â ͓ ½ ˯ Ģ Ɛ > 3 ʻ Ȭ Ɛ ? ͹DRM106 1 5 ' 0 ̾ ɛ É ˥ ģ 0 * ǜ ; É ˥ ģ + ) 0 Ⱥ Ɛ E Ǟ A + ʬ ? B # ʄ 2 ʀ * 1 ͹ ʄ 1 ʀ * ̬ ơ B # DRM106 0 ½ Ü ù ƕ + ʿ ɶ ˞ Ɛ E ́ 5 A # : . ͹ Ȁ Ŵ - Sprague-Dawley g k E Ɋ ) 1 2 5 I * ǹ ̅ # DRM106Ͷ 0.37 MBq/ratͷ0 ½ Ü ʘ ʧ å ű > 3 ʿ ʘ ʧ 0 ± ̃ ș Ɛ E ǳ ˴ # - D % ͹ ͙ ʼ Ü Ơ 2͹ 5͹ 15͹ 30 å ͹ 1͹ 2͹ 5͹ 8͹ 24 > 3 48 ǖ ̿ Ƅ . Ė ʘ ʧ 0 ƿ š ʺ ȯ Ż Ͷ %ID/gͷ ͹ ʘ ʧ Ü ƿ š ʺ å ű ɂ Ͷ %IDͷ > 3 ʿ Ü ± ̃ ȹ 0 thin layer chromatography t d E ́ 5 # ! 0 ʚ ǫ ͹ DRM106 0 ː Ň - ʿ ɶ ˞ Ɛ + ̠ < - T H ^ ɮ B # 8 # ͹ ʿ Ü ± ̃ ˱ Ǫ * 1 ͹ DRM106 0 ʿ Ü ± ̃ ȹ 1 ˻ : - & # ʄ 3 ʀ * 1 ͹DRM106 0 Aβ â ͓ ½ Ƴ ä ʺ E ˹ Â A # : ͹AD j 0 ͔ Ɛ TgͶ +ͷ K ^ + ͊ Ɛ Ş ȶ + ) Ę ˃ 0 ͒ Ɛ TgͶ −ͷ K ^ E Ɋ ) ͹1 2 5 I * ǹ ̅ # DRM106Ͷ 1.3 MBq/mouseͷ ͙ ʼ Ü Ơ Ƅ 0 Aβ â ͓ ½ 4 0 ͓ ɻ Ɛ . ' ) autoradiogram * ˱ Ǫ # ! 0 ʚ ǫ ͹ TgͶ +ͷ K ^ 0 autoradiogram 1 Congo-red ǭ ˑ + > ˎ # 0 + ? ͹ DRM106 1 ʿ 0 Aβ â ͓ ½ . Ⱥ ɕ ɝ . ͓ ɻ A + ɮ B # ʄ 4 ʀ * 1 ͹1 2 3 I-DRM106 E Ɋ # SPECT Ó + 1 1 C-PiB E Ɋ # PET Ó E ȋ ̕ A ɡ ɝ * ͹ Ę 0 j ù ȹ E Ɋ ) Aβ â ͓ ½ 0 Ƴ ä Ɛ E ˹ Â # SPECT Ó 1 ͹1 2 3 I * ǹ ̅ # DRM106Ͷ 345 MBq/mouseͷ

(70)

œ ͯ ù ȹ Ɋ PET ˣ ʨ * ƺ Ƃ # ! 0 ʚ ǫ ͹ TgͶ +ͷ K ^ * 1 B 0 ɐ Ó ; Ń ʿ ɞ ̌ . å ű A Aβ â ͓ ½ Ƴ ä B # ͹TgͶ −ͷ K ^ * 1 Ƴ ä B - & # 8 # ͹SPECT Ó + PET Ó . A Ń ʿ ɞ ̌ + Ť ʿ 0 ƿ š ʺ ȋ 1 ͹Ͳ ɣ ̀Ͷ r = 0.95, P΄ 0.01ͷ ˻ : ? B ͹SPECT + PET 0 B 0 ɐ Ó ; ͹TgͶ +ͷ+ TgͶ −ͷ K ^ 0 Aβ â ͓ ½ 0 ͓ ɻ 0 ̪ E č Ǖ # 0 + ? ͹1 2 3 I-DRM106Ͷ SPECTͷ+ 1 1 C-PIB Ͷ PETͷ 1 ͹ Ę ɷ Ż . Aβ â ͓ ½ E ǳ ä * A + ɮ ĥ B # ² 0 ɬ ɽ ? ͹ imidazopyridine ˼ ţ ½ E ĸ ǥ Ƿ ̡ + # DRM106 1 ͹ Aβ â ͓ ½ . Ⱥ ɕ ɝ . ͓ ɻ A ǋ # - SPECT Ɋ Q l + ) Ǟ Ǡ - ̾ ɛ É ˥ ģ * A + ʚ ̂ A

(71)

̃ ̃ ̖ ǥ ɺ E ʗ A . # @ ͹ ǥ ̂ ǆ 0 Ͳ ́ > 3 Ʃ ţ E ̋ & # ų Ÿ ɓ ɉ Ń ŏ ū ɋ ō ǂ ƭ . ̄ F * Ɣ ̃ 0 Ɠ E ˡ 8 8 # ͹ ǥ ̂ ǆ ¿ Ƙ . Ş ͹ õ ˲ ͹ Ʃ ţ ͞ 8 # ų Ÿ ɓ ɉ Ń ŏ ¼ Ǣ ɢ ǻ à ǂ ƭ ͹ ŭ ƛ Ń ŏ Ē Ȱ Ģ ǂ ƭ ͹ ǩ ¨ ̗ ů Ń ŏ ɋ œ ǂ ƭ ͹ Ŭ ͂ Ń ŏ Ȟ ̶ ŷ ž ǂ ƭ . Ȣ ̃ # 8 ? . ͹ ŏ ˟ ̂ ǆ ķ ʅ . # @ ʗ ň Ʃ ţ # $ # Ƚ ɿ ˞ ǀ ȕ ª ƿ š ʡ Ā ŏ ʟ ė ɬ ɽ ƚ Ŏ Ǉ µ ɬ ɽ Ĥ ͹ǩ ý Ń ŏ ū đ ǁ ǟ Ć ľ ͹Ƚ ɿ ˞ ǀ ȕ ª Ā ˚ ĸ ɟ ɬ ɽ ƚ ū ǃ Ć ľ ͹ Ŝ ľ x J RI x G ǯ ż ¶ ɰ ʃ Ċ ˤ ˞ Ć ľ ͹ Ĳ ǩ Ģ ì Ć ľ ͹ ¼ ̶ ȝ © Ć ľ . ɯ Ɏ 8 8 # ͹ Aβ Q l E ƴ Á # $ # Ŝ ľ x J RI x G ǯ ż ¶ ɰ ͹ AD j ù ȹ E ƴ Á # $ # ʄ Û ǯ ż ¶ ɰ . ɯ Ɏ 8

(72)

ċ ʬ ǆ ɀ

1. Braak, H., Braak, E. (1991). Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. (Berl). 82, 239-259. 2. Camus, V., Payoux, p., Barre, L., Desgranges, B., Voisin, T., Tauber,

C., La Joie, R., Tafani, M., Hommet, C., Chetelat, G., Mondon, K., de La Sayette, V., Cottier, J. P., Beaufils, E., Ribeiro, M. J., Gissot, V., Vierron, E., Vercouillie, J., Vellas, B., Eustache, F., Guilloteau, D. (2012). Using PET with 18F-AV-45 (florbetapir) to quantify brain amyloid load in a clinical environment. Eur. J. Nucl. Med. Mol. Imaging 39, 621-631.

3. Chang, K. W., Chen, C. C., Lee, S. Y., Wang, H. E. (2009). Acute toxicity of two Alzheimer's disease radiopharmaceuticals: FDDNP and IMPY. Drug Chem. Toxicol. 32, 429-437.

4. Chen, C. J., Bando, K., Ashino, H., Taguchi, K., Shiraishi, H., Shima, K., Fujimoto, O., Kitamura, C., Mastushima, S., Uchida, K., Nakahara, Y., Kasahara, H., Minamizawa, T., Jiang, C., Suhara, T., Higuchi, M., Yamada, K., Ji, B. (2014). Synthesis and biological evaluation of novel radioiodinated imidazopyridine derivatives for amyloid- imaging in Alzheimer disease. Bioorg. Med. Chem. 22, 4189-4197.

5. Chen, C. J., Bando, K., Ashino, H., Taguchi, K., Shiraishi, H., Shima, K., Fujimoto, O., Kitamura, C., Morimoto, Y., Kasahara, H., Minamizawa, T., Jiang, C., Zhang, M. R., Suhara, T., Higuchi, M., Yamada, K., Ji, B. (2014). Biological evaluation of the radioiodinated imidazo[1,2-a] pyridine derivative DRK092 for

(73)

amyloid-β imaging in mouse model of Alzheimer's disease. Neurosci Lett. 581, 103-108.

6. Cheng, Y., Ono, M., Kimura, H.,Ueda, M., Saji, H. (2012). Technetium-99m labeled pyridyl benzofuran derivatives as single photon emission computed tomography imaging probes for beta-amyloid plaques in Alzheimer's brains. J. Med. Chem. 55, 2279-2286.

7. Choi, S. R., Golding, G., Zhuang, Z., Zhang, W., Lim, N., Hefti, F., Benedum, T. E., Kilbourn, M. R., Skovronsky, D., Kung, H. F. (2009). Preclinical properties of 18F-AV-45: a PET agent for Abeta plaques in the brain. J. Nucl. Med. 50, 1887-1894.

8. Cselényi, Z., Jönhagen, M. E., Forsberg, A., Halldin, C., Julin, P., Schou, M., Johnström, P., Varnäs, K., Svensson, S., Farde, L. (2012). Clinical validation of 18F-AZD4694, an amyloid-beta-specific PET radioligand. J. Nucl. Med. 53, 415-424.

9. Engler, H., Forsberg, A., Almkvist, O., Blomquist, G., Larsson, E., Savitcheva, I., Wall, A., Ringheim, A., Langstrom, B., Nordberg, A. (2006). Two-year follow-up of amyloid deposition in patients with Alzheimer's disease. Brain. 129, 2856-2866.

10. Furumoto, S., Okamura, N., Furukawa, K., Tashiro, M., Ishikawa, Y., Sugi, K., Tomita, N., Waragai, M., Harada, R., Tago, T., Iwata, R., Yanai, K., Arai, H., Kudo, Y. (2013). A 18F-labeled BF-227 derivative as a potential radioligand for imaging dense amyloid

(74)

11. Hampel, H., Wilcock, G., Andrieu, S., Aisen, P., Blennow, K., Broich, K., Carrillo, M., Fox, N. C., Frisoni, G. B., Isaac, M., Lovestone, S., Nordberg, A., Prvulovic, D., Sampaio, C., Scheltens, P., Weiner, M., Winblad, B., Coley, N., Vellas, B. (2011). Biomarkers for Alzheimer's disease therapeutic trials. Prog. Neurobiol. 95, 579-593.

12. Hsiao, I. T., Huang, C. C., Hsieh, C. J., Hsu, W. C., Wey, S. P., Yen. T. C., Kung, M. P., Lin K. J. (2012). Correlation of early-phase 18F-florbetapir (AV-45/Amyvid) PET images to FDG images: preliminary studies. Eur. J. Nucl. Med. Mol. Imaging. 39, 613-620. 13. Ikonomovic, M. D., Klunk, W. E., Abrahamson, E. E., Mathis, C. A.,

Price, J. C., Tsopelas, N. D., Lopresti, B. J., Ziolko, S., Bi, W., Paljug, W. R., Debnath, M. L., Hope, C. E., Isanski, B. A., Hamilton, R. L., DeKosky, S. T. (2008). Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer's disease. Brain. 131, 1630-1645.

14. Ito, H., Shinotoh, H., Shimada, H., Miyoshi, M., Yanai, K., Okamura, N., Takano, H., Takahashi, H., Arakawa, R., Kodaka, F., Ono, M., Eguchi, Y., Higuchi, M., Fukumura, T., Suhara, T. (2014). Imaging of amyloid deposition in human brain using positron emission tomography and 18F-FACT: comparison with 11C-PIB, Eur. J. Nucl. Med. Mol. Imaging. 41, 745-754.

15. Kawarabayashi, T., Younkin, L. H., Saido, T. C., Shoji, M., Ashe K. H., Younkin, S. G. (2001). Age-dependent changes in brain, CSF, and plasma amyloid (beta) protein in the Tg2576 transgenic mouse model