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
・combination of drug discovery, diagnostic and therapy
NIH/NCI：Cancer Imaging
Program (CIP)
UK Clinical Research Collaboration
promotion of clinical research
National Biomanufacturing Centre
Development 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
Magnetic Resonance Imaging (MRI) Gd3+ Complex, SPIO
Fluorescence imaging （near IR）
Luminescence imaging (Bioluminescence)
Ultrasound imaging
Light scattering imaging
etc
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
Monomer type
contrast agent
Dimer type
Lipid type
Lipiodol (Iodized poppy oil）triglyceride
SPECT
Detect 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 cancers
Easy 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.
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 min
The 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.
X-ray CT
PET
Tumor imaging using 18F-Fluorodeoxyglucose
Cancer cell
18FDG
18FDG
18FDG
P
×
metabolism
Magnetic Resonance Imaging (MRI）
Detect of magnetic relaxation in water proton
Contrast agent using dipole-interaction
N
N3+ N
O
O
Gd
ON
3+
O
O
O
Gd
O
O OO
O
O
OO
O
O O O O
O H
O
H
・ Contrast agent using magnetic susceptibility
N
N
Gd-DTPA (Diethylenetriamine-N, N, N’,
N’, N” -pentaacetic acid) complex
＞100 nm
Ferric oxide Fe3O4
paramagnetic
Superparamagnetic
positive contrast
negative contrast
T1-weighted spin-echo
T2-weighted spin-echo
T2*-weighted gradient-echo
Decrease of osmotic shock
O
O
O-
ON
N
O
N
Gd3+
O - OO
N
O O-
O
OO
Gd-DTPA
(Magnevist)
OO
O
N
Gd
N
O-
3+
O H
H
N
O-
O
Gd-DOTA
O
O
O-
-
O
N
HN
N
N
N
Gd3+
Gd
O-
NH
O
O OO OO
O
Gd-DTPA-BMA
N
O
O H
H
Gd-HP-DO3A
O-
O
O
OH
OOH
ON
OH
N
O
O
HN
N
3+
N
N
Gd3+
N
OH
3+
N
O
O OO OO
O
Gd-DTPA-BMEA
O-
NH
O
O
Gd
N
N
O-
O
O H
H
Gd-DO3A-butrol
Accumulation in hepatocyte
OEt
O
O
O-
-
O
O
N
O - OO
N
Gd3+
N
-
O O
Gd-EOB-DTPA
O
O
O
-
O
N
N
O
O-
O
Gd3+
-
O
N
-
O O
Gd-BOPTA
O
OO
High sensitivity-type
R
R
Lys Lys
Lys R
R
NH
CO 2O
H
N
HN
N
H
R
Lys HN
Lys
R
Lys
R
R
O
O
CO 2-
N
N
CO
- 2
N
CO2
N
O
N
(
N
N
OO2C - O2 C -O2 C
Gd3+
N
H
N)
0.2
O
R
NH Lys
Lys R
Lys
R
R
O
H
N
N
N
CO 2-
O
OH
CO2-
-O C
2
)
n
O
O
O2 C
N
Gd3+
H
N )0.8
+
(
-
N
Gd-DTPA pendant dendrimer
(
N
N
N
O
-O C -O C -O C
2
2
2
R
NH Lys
Lys R
Lys
R
R
CO 2-
NH
N
CO2 - CO 2-
H
N
O
R=
O
R
Lys HN
Lys
R
Lys
R
R
Gd-DTPA pendant polymer
R
R
Lys Lys
R
Lys R
O
NH
H+
N
Gd 3+
-O
2C
-
O2 C
Poly-ion complex type Gd-DTPA
N
-O C
2
N
N
-O C
2
O
N
H
Gd-complex adsorbing to albumin
Micelle type：atheroma, cancer
O
N
CO 2N
HN
N
O
N S CF2 CF2 CF 2CF2CF2 CF2 CF2CF3
O
N
N
CO2 -
O2 C
3+
N Gd
C17 H35
O
Gd3+
-
CO2 CO2 -
Micell forming Gd-DOTA (Gd fluorine)
CO2 -
N
N
CO2Gd-AAZTA-C17
PAMAM dendrimer
CO 2N
CO2 N
Gd3+
-O C
2
N
N
N
O
Gd-DO3A-diph
bind to LDL
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
O
N
CO 2N
HN
N
CO2 CO2 -
O
N S CF2 CF2 CF 2CF2CF2 CF2 CF2CF3
O
3+
N Gd
Gd3+
-
N
N
CO2Gd-AAZTA-C17
CO2 -
O2 C
N
N
C17 H35
O
CO2 -
Micell forming Gd-DOTA (Gd fluorine)
O
ON
O
CO 2N
CO2
-
O - OO
PAMAM dendrimer
H
N
N
Gd3+
N
O O-
O
OO
H
N
O
O
4-8
N
Gd3+
-O C
2
N
N
N
O
O
Gd-DO3A-diph
Bind to LDL
O
S
O
N
O
Gd-DO3A-diph
HN
N
H
NH
O
O
N
H
(CH 2 )4
S
Functionalized Contrast Agents
N
N
3+
O
Gd
O
O
O
N
O
O O
O
O
+
Molecular probe
O
Imaging unit
Sensing unit
Functionalized Contras Agents
1: for endothelial injury or disorder using dye molecule
2: for cancer cells using sigma receptor-specific ligand
Ligand-conjugated type
CO2CO2-
O
N
-
O2C
N
Gd3+
NH2
H
N
N
N
H
O
O
N
CO2-
グルタミントランスポータ結合造影剤
Glutamine
transporter -binding
CO2 N
-
O2 C
N
Gd 3+
N
O
N
H
N
H
N
O
OH
OH
CO 2-
HT-DOTA-Gd
Macrophage targeting
Myeloperoxidase binding
Enzyme substrate-type
O
O
-
O
O
N
N
Gd3+
HN
O - OO
O
-
esterase
N
NH
O O-
O
O
HN
O-
O
O
O
O
O
O
C 17 H35
N
Water insoluble: MRI silent
C17H 35
O-
O
-O
O
2C
OHOH
3+
N Gd N
N
N
OH
HO
2O
3+
N Gd N
b-galactosidase
O
N
O-
NH
O
O
Water soluble: MRI signal on
-O C
2 H
O
Gd3+
HO
Esterase-responsive system
OH
N
N
N
CO 2- CO- 2
CO2 - CO-2
b-Galactosidase-responsive system
O
OH
Contrast agent for endothelium damage
O
H2 N
HO
ON
O
O - OO
SO3 Na
N
Gd3+
N
O O-
H
N
O
O
N
N
SO3 Na
Screening of dyes with specific adsorption to endothelium damage
Trypan Blue: 10mg/ml
Evans Blue: 10mg/ml
NH 2
OH
OH
N N
SO 3 Na
Congo Red: 10mg/ml
N
NH 2
N
NH 2
NH 2
N
N
N
OH
OH
N N
NH 2
NH 2
N N
N
SO 3 Na
SO 3 Na
SO 3 Na
SO 3 Na
SO 3 Na
Trypan Blue
Evans Blue
SO 3 Na
SO 3 Na
SO 3 Na
Primuline: saturated
Thioflavin T: saturated
SO 3 Na
N+
S
S
SO 3 Na
Congo Red
Sirius Red: 10mg/ml
SO 3 Na
Cl
N
S
SO 3 Na
N
N
N
N
S
NH 2
S
NH
Primuline
O
Thioflavin T
NH
N
N
+
SO 3 Na
Cl
N
N
N
SO 3 Na
Sirius Red
Crystal Violet: saturated
N
Crystal Violet
N
Balloon treatment + EB-DTPA-Gd
60
min
administration
Before administration
aorta
after
the
Normal + EB-DTPA-Gd
Before administration
60
min
administration
after
the
Balloon treatment + Gd-DTPA
Left: normal aorta
Right: injured aorta
Before administration
60
min
administration
after
the
Detection of arteriosclerosis
Detection of atheroma
Spasm occurs in atheloma
摘出標本(Sudan Red染色)
O
O
OH
HO
N
N
H
N
N
N
NH 2
N
①
SO 3H
O
O
O
O
O
Gd
O
①
SO 3H
3+
ANDD-Gd
②
②
③
③
(①～③：動脈硬化部位)