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In vivo imaging. NIH ： Roadmap for Medical Research ・ New Pathway to Discovery ・ Research Team of the Future ・ Re-engineering the Clinical Research Enterprise FDA ： Critical Path Initiative(2004) ・ effective application of basic researches to clinical researches - PowerPoint PPT Presentation
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In vivo imaging
NIH ： Roadmap for Medical Research・ New Pathway to Discovery・ Research Team of the Future・ Re-engineering the Clinical Research EnterpriseFDA ： Critical Path Initiative(2004)・ effective application of basic researches to clinical researches・ combination of drug discovery, diagnostic and therapy
NIH/NCI ： Cancer Imaging Program (CIP)
UK Clinical Research Collaboration promotion of clinical research
National Biomanufacturing CentreDevelopment of bio-drugs
EMIL (European Molecular Imaging Lab.) Network of researchers on cancer research
DiMI (Diagnostic Molecular Imaging)Research network of bioimaging
In vivo imaging technologies
Ｘ -ray Computer Tomography (CT)Positron Emission Tomography (PET) 18F, 11C, 124I, 64Cu etc
Single Photon Emission Computer Tomography (SPECT) 201Tl, 67Ga, 99mTc etc
Magnetic Resonance Imaging (MRI) Gd3+ Complex, SPIO
Fluorescence imaging （ near IR）Luminescence imaging (Bioluminescence)Ultrasound imagingLight scattering imaging
X-ray CT
X-ray source and detector are rotated around the subject of examination.During the permeation of irradiated X-ray into the subject, part of the X-ray is absorbed and the attenuated X-ray is detected. This absorption depends on a contents of the subject. Image is created with Fourier transform of this attenuated rate detected in 360°direction
Ⅹ-ray ＣＴ contrast agent
Monomer type Dimer type
Lipid type Lipiodol (Iodized poppy oil ） triglyceride
SPECTDetect g-ray emitted from RI-probe administered in body woth g-camera and its tomographic image is made.Detection of early phase in atherosclerosis, heart diseases or cancersEasy to handle, but the sensitivity and resolution are lower than PET due to the absorption of g-ray in the body.
SPECT contrast agent
99mTechnetium (99mTc)examethadim:(99mTc-HMPAO ） For brain functional imaging The absorption depends on the blood flow.
X-ray CT PET
Positron Emission Tomography (PET)Detection of metabolic level in central nervous system or tumor Half life 15O ： 2 min, 13N ： 10 min, 11C ： 20 min, 18F ： 110 minThe collapse of above atoms emits one positron. The positron gets pair annihilation with water molecule and emits two photon （ 511keV ） to opposite direction. Then the two photons are detected with photomultipliers set around the object.If two photons are detected at the same time in opposite direction, radiation source should exist in the line.
18FDG
18FDG
18FDG
P
× metabolism
Cancer cell
Tumor imaging using 18F-Fluorodeoxyglucose
Magnetic Resonance Imaging (MRI）
Detect of magnetic relaxation in water proton
NN N
O
OO
O
OO
OOO
O Gd3+
Contrast agent using dipole-interaction
・ Contrast agent using magnetic susceptibility
Gd-DTPA (Diethylenetriamine-N, N, N’, N’, N” -pentaacetic acid) complex
＞ 100 nm
Superparamagnetic
paramagnetic
T1-weighted spin-echo T2-weighted spin-echo T2*-weighted gradient-
echo
Ferric oxide Fe3O4
positive contrast
negative contrast
NN N
O
OO
O
OO
OOO
O Gd3+
OHH
Gd-DTPA (Magnevist)
Gd-DOTA
N
N N
N
Gd3+
OO-
O
O-
OO-
O
O-OH
HN
N N
O O-O
O-
OO-O-
O
O Gd3+
O
O-
NN N
O OO-OO-O
O
Gd3+
O
O-
NHHN
NN N
O OO-OO-O
O
Gd3+
O
O-
NHHN
O O
Gd-DTPA-BMA
Gd-DTPA-BMEA
N
N N
N
Gd3+
OO-
OH
OO-
O
O-OH
H
Gd-HP-DO3A
N
N N
N
Gd3+
OO-
OH
OO-
O
O-OH
H
OH
OH
Gd-DO3A-butrol
Decrease of osmotic shock
Accumulation in hepatocyte
NN N
O O-O
O-OO-O-
O
O Gd3+
O
O-
OEt
Gd-EOB-DTPA
NN N
O O-O
O-OO-O-
O
O Gd3+
O
O-O
Gd-BOPTA
HN
O
NH
O
HN O
CO2-
NN
N
CO2-
CO2-
CO2- CO2
-
CO2-
Gd-DTPA pendant polymer
N
NO
O
ON
NH
HN NH
NH
NH
HN
Lys
Lys
Lys
Lys
Lys
Lys
LysLys
LysLys
Lys
Lys
Lys
Lys
Lys
Lys
Lys
Lys
R
R R
R
R
RR
R
R
R
R RR
R
R R
R R
R
R
R R
R
R
R =
N N
N N
CO2-
-O2C CO2-
O
NH
O
Gd3+
Gd-DTPA pendant dendrimer
High sensitivity-type
+
N N
-O2CO
N
-O2C -O2C
HN
O
HN N N N
HN
O-O2C -O2C -O2C
O
HN
(()
)0.2
0.8
Gd3+
OO H+
N
( )n
Poly-ion complex type Gd-DTPA
NH
OHCO2
-
O
N
-O2C
N
N
-O2C
-O2C
-O2C
-O2C
Gd3+
Gd-complex adsorbing to albumin
Micelle type ： atheroma, cancer
N N
N N
CO2-
-O2C CO2-
O
HNN
ON S
O
OCF2CF2CF2CF2CF2CF2CF2CF3
Gd3+
Micell forming Gd-DOTA (Gd fluorine)
NN
C17H35
N
CO2-
CO2-
CO2-
CO2-
Gd3+
Gd-AAZTA-C17
N N
N N
CO2-CO2
-
-O2C
Gd3+
N
O
Gd-DO3A-diph bind to LDL
PAMAM dendrimer
Gd-DO3A-diphアビジンと結合して巨大複合体ＥＰＲ効果でがんに蓄積
ミセル型造影剤：アテローム、がん
N N
N N
CO2-
-O2C CO2-
O
HNN
ON S
O
OCF2CF2CF2CF2CF2CF2CF2CF3
Gd3+
Micell forming Gd-DOTA (Gd fluorine)
NN
C17H35
N
CO2-
CO2-
CO2-
CO2-
Gd3+
Gd-AAZTA-C17
N N
N N
CO2-CO2
-
-O2C
Gd3+
N
O
Gd-DO3A-diphBind to LDL
NN N
O O-O-
OO-O -
O
Gd3+
O
O-
OO
HN
OO
HN
4-8
N
O
O
NH
O
ONH
O
(CH2)4S
NHHN
O
S
PAMAM dendrimer
Gd-DO3A-diph
NN N
O
OO
O
OO
OOO
O Gd3+
Imaging unit
+ Molecular probe
Sensing unit
Functionalized Contras Agents1: for endothelial injury or disorder using dye molecule
2: for cancer cells using sigma receptor-specific ligand
Functionalized Contrast Agents
Gd3+
N
N
N
N
CO2-
-O2C
CO2-
O
HN N
H
O
NH2
O
CO2-
グルタミントランスポータ結合造影剤
Ligand-conjugated type
NN
NN
CO2-
-O2C
CO2-
O
HN
HN
Gd3+O
OH
OH
HT-DOTA-Gd Macrophage targetingMyeloperoxidase binding
Glutamine transporter -binding
Enzyme substrate-type
NN N
O OO-O
O-O-
O
Gd3+
O
O-
NHHN
OO
OC17H35
OO
OC17H35
NN N
O OO-O
O-O-
O
Gd3+
O
O-
NHHN
OHO
OOH
esterase
Water insoluble: MRI silent Water soluble: MRI signal on
Esterase-responsive system
N N
N N
CO2- CO-
2
-O2C HOH2O
Gd3+
b-galactosidase
b-Galactosidase-responsive system
N N
N N
CO2- CO-
2
-O2C O
OOH
OHOH
OH
Gd3+
Contrast agent for endothelium damage
NN N
O OO-O
O-O-
O
Gd3+
O
O-
HNO N
N
HOH2N SO3Na
SO3Na
Screening of dyes with specific adsorption to endothelium damage
Evans Blue: 10mg/ml Congo Red: 10mg/mlTrypan Blue: 10mg/ml
Thioflavin T: saturated Primuline: saturated
Crystal Violet: saturated
Sirius Red: 10mg/ml
NN
OHNH2SO3Na
SO3Na
N NOH NH2
SO3Na
SO3NaEvans Blue
NN
NH2N N
NH2
SO3Na SO3NaCongo Red
NN
OHNH2N N
OH NH2
SO3NaSO3NaSO3NaSO3Na
Trypan Blue
S
SNH2
S
S
SO3Na
Thioflavin T
S
NN
Cl+
Primuline
NN N NSO3Na
SO3Na
NH
NN N NSO3Na
SO3Na
NHO
Sirius Red
N N
N
Cl
+
Crystal Violet
aorta
Left: normal aortaRight: injured aorta
Before administration 60 min after the administration
Balloon treatment + EB-DTPA-Gd
Before administration 60 min after the administration
Normal + EB-DTPA-Gd
Balloon treatment + Gd-DTPA
Before administration 60 min after the administration
Detection of atheroma
②③
①摘出標本(Sudan Red染色)
③
①
②
③
①
②
(①～③：動脈硬化部位)
Detection of arteriosclerosis
N NOH NH2
SO3H
SO3H
NNN
O
NH
O O O O
O
OH
O
O
Gd3+
ANDD-Gd
Spasm occurs in atheloma
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