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Molecular imaging is a new discipline that helps understanding complex pathological processes by visualizing unique molecular signatures at the cellular, subcellular or gene level.
This technique Contributes diagnosis of cancer, neurological and cardiovascular
diseases Also contributes to shorten the time for developing new medicine at
lower cost Is expected to have a major economic impact due to earlier and more
precise diagnosis
Among imaging modalities, numerous studies have been made with PET. However, complementary development of PET and SPECT is required for widespread applications of this technique.
Molecular Imaging
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99m43Tc
The first artificially produced element with no stable
isotopes A transitional metal belongs to the second
transition series Its chemistry is close to that of rhenium
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99m43Tc
Is obtained by a generator system utilizing a radiation equilibrium between 99Mo and 99mTc
Emits a -ray of 140 keV with a half-life of 6 h, which is suitable to SPECT imaging
The most widely applied radionuclide in diagnostic nuclear medicine
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90Mo-99mTc Radiation Equilibrium
99Mo
99mTc
99Tc
β--Decay ,T1/2 = 65.9 h
Nuclear Isomer Transition-ray (140 keV)T1/2 = 6 h
β--Decay ,T1/2 = 2.1 x 105 y
99Ru( Stable )
Radiation Equilibrium
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99Mo - 99mTc Generator System
Separation of 99mTc from 99Mo
Only 99mTc is eluted from the column
Generation of 99mTc from 99Mo
0 1 2 3 4 5Days
Rad
ioac
tivi
ty (
%)
1
100
10
Decay Curve of 99Mo
Max 99mTc
AluminaColumn
Saline Vacuum Vial
99MoO42-/
99mTcO4-
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99m43Tc
Is obtained by a generator system utilizing a radiation equilibrium between 99Mo and 99mTc
Emits a -ray of 140 keV with a half-life of 6 h, which is suitable to SPECT imaging
The most widely applied radionuclide in diagnostic nuclear medicine
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PET tracer
Positron Range
The resolution of PET (Positron Emission Tomography) is affected
by positron range
PET recognizes the site of positron annihilation
Advantage of SPECT over PETSPECT (Single Photon Emission
Computed Tomography) recognizes the sites of tracer
accumulation
Impairs resolutionof PET
SPECT tracer
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123I-IBZM Moue Brain D2 Receptor
99mTc-MIBI Mouse Heart
mouse brain
salivaryglands
thyroid
striatum
eyes
I123-IBZMD2 receptor study
5mm
Fused Images
SPECT Images
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Simultaneous Dual Isotope Imaging of Perfusion and Dopamine D2 Receptors in Rat Brain
99mTc-HMPAO 123I-IBF
Images co-registered with MRI
MRI MRI
SPECT allows simultaneous images of cerebral blood flow and D2 receptor function
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SPECT/CT Images ( Murine Thyroid )
Single pinholeRadius of gyration: 25 mm
Acquired for 20 min (360 degree)
Multi pinholeRadius of gyration: 35 mm
Acquired for 10 min (360 degree)
99mTcO4- (50-80 μCi)
6 h post-injection
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Reticuloendothelial System 99mT-Sn colloid
Hepatobiliary excretion 99mTc-HIDA
Renal Function 99mTc-DTPA
Bone Function 99mTc-MDP
99mTc Radiopharmaceuticals in the 70’
At the initial stage of 99mTc radiopharmaceutical development, it was thought that Tc is a foreign substance and is recognized as such by the body
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Breakthrough in Tc Chemistry
TcO(V)3+
Tc(I)+
TcN(V) 2+
Tc
OH2
OH2
OH2
CO
OC
OC
R
O
TcOC
COCO
N
S S
O
Tc
NH
Tc Core Representative Tc Complex
Tc
S
S
S
S
N
RR
+
N N
OH
O
O
Tc
NH HN
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Chemical Design of 99mTc-Labeled Compound for Cerebral Blood Flow Measurement
Tc
ON N
N N
OH
O
Rapid conversion to a hydrophilic compound in the brain
GSH can easily attack the Tc center Neutral, compact and lipophilic complex that penetrates intact BBB
No retention in the brain
N N
OH
O
O
Tc
NH HN
Structural modification
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Chemical Design of 99mTc-Labeled Compound for Cerebral Blood Flow Measurement
NHN
S S
Tc
OEtOOC COOEt
Rapid hydrolysis of an ester group togenerate a hydrophilic compound
The properties of the 99mTc complex (stable, neutral and lipophilic) are masked so that the pharmacokinetics is governed only by the functional groups
Neutral, compact and lipophilic complexes that penetrates intact BBB
No retention in the brain
NH
S S
O
Tc
N
Structural modification
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N
COOCH3
H3C
11C-Cocaine
N
COOCH3
H311C
Cocaine
Chemical Design of 99mTc-Labeled Probes( Dopamine Transporter )
PET Probe
SPECTProbe
N
COOCH3
F
NN
SS
O
Tc
O
H3C
Cl
N
Tc
O
N
SS
123I-CocaineN
COOCH3
H3C
123I
The chemical structure of 99mTc-labeled cocaine analogs differs significantly from that of cocaine These compounds still possess substrate specificity to dopamine transporter of the brain
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99mTc-Labeled Probe for Assessing Fatty Acid Metabolism in the Heart
OH
O
C
[11C]palmitic acid
OH
O
123I
15-(p-[123I]iodophenyl)pentadecanoic acid ([123I]IPPA)
TcOCCO
CO
OH
O
Transported and recognized as a substrate for -oxidation by the myocardium
J. Med. Chem. 50 (3), 543-549, 2007
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Present Design of 99mTc-Labeled Probes
: Targeting unit
Ligand (10-4 M)
Tc
Tc
ComplexationMonovalentLigand
Tc(10-7 M) 99mTc-Labeled Probe (10-7
M)
TcDivalentLigand
MonovalentComplex
Divalent Complex
Avidity
Conjugate a chelating molecule with a targeting unit (e.g., tropane, peptide) A large excess ligand is used to obtain 99mTc labeled compound with high radiochemical yields in short reaction times Divalent ligands provide divalent 99mTc complexes that possess higher avidity to target molecule than monovalent counterpart
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99mTc-Labeled RGD Peptides for Tumor Imaging
N
SH
O
HON
HS
O
OH
OHN O NH
5
c(RGDfK)c(RGDfK)
5
Divalent RGD Ligand
N
S
N
S
O
OHO
OO
HN O
c(RGDfK)
O NH
c(RGDfK)
5 5
Tc
Divalent 99mTc-Labeled RGD
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SPECT Images
Tumor(U87MG cell
s )
Non purified 99mTc-TMEC-RGD2
(contained 10-4 M ligand)
HPLC-Purified 99mTc-TMEC-RGD2
(No excess ligand)
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Problem
BloodTarget
(peripheral)Capillary
Wall
The presence of excess ligand impairs the accumulation of 99mTc labeled probes in the target
Tc Tc
Tc
: 99mTc-labeledprobes
: Ligand
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Dilemma Excess ligands are used to prepare 99mTc-labeled probes in
order to achieve high radiochemical yields in short reaction times
The presence of excess ligands reduces target accumulation of 99mTc-labeled probes by competing for the target molecule
Removal of excess ligands from the 99mTc-labeled probes by HPLC or solid-phase extraction method is possible
HOWEVER, such manipulation impairs the advantages of 99mTc-labeled probes simple and sterile preparation loss of 99mTc-labeled probes during the purification process (HPLC
separation, evaporation and reconstitution)
ANY OTHER APPROACH ?
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Preparation of 99mTc-Labeled Probes
Kit( Ligand + SnCl2)
99mTcO4-
99mTc-LabeledProbe
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Dilemma Excess ligands are used to prepare 99mTc-labeled probes in
order to achieve high radiochemical yields in short reaction times
The presence of excess ligands reduces target accumulation of 99mTc-labeled probes by competing for the target molecule
Removal of excess ligands from the 99mTc-labeled probes by HPLC or solid-phase extraction method is possible
HOWEVER, such manipulation impairs the advantages of 99mTc-labeled probes simple and sterile preparation loss of 99mTc-labeled probes during the purification process (HPLC
separation, evaporation and reconstitution)
ANY OTHER APPROACH ?
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New Chemical Design of 99mTc-Labeled Probes
Change the paradigm from “Development of 99mTc-labeled probes that provide information similar to those by PET or Radioiodinated Compounds”
to
“Development of radiolabeled probes that can be best achieved by using 99mTc”
that is 99mTc-labeled probes utilizing chemical properties of
Tc, the properties as a transitional metal
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New Concept for Designing 99mTc-Labeled Probes
Synthesis of multivalent (divalent or trivalent) 99mTc- labeled probes from monovalent ligand The target accumulation of 99mTc-labeled probes would be less impaired by the presence of excess ligands
TcDivalent Complex
Tracer amount
Trivalent ComplexTracer amount
Tc
MonovalentLigand
10-5 – 10-4 M
TcTc
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99
mTc
Blood
Divalent 99mTc-labeled probes exhibit higher avidity than monovalent ligands to target
99mTc
99m Tc
Rationale behind the Chemical Design
Higher target accumulation
Target
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99mTc
99
mTc
99mTc
99mT
c
99mTc99mTc99mTc
Target
99mTc
Divalent 99mTc-labeled probes exhibit slower dissociation from target than monovalent ligands
Dissociation
No dissociation
Higher Retention
Blood
99m Tc
Rationale behind the Chemical Design
99mTc
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Validation of the Chemical Design
NH
SH
O
HO HN-c(RGDfK)
O
5
N
SH
O
HON
HS
O
OH
OHN O NH
5
c(RGDfK)c(RGDfK)
5
MonovalentLigand
Divalent Ligand
NH
S
HN
S
O
OHTc
O
OO
HN Oc(RGDfK)
O NHc(RGDfK)
5 5
N
S
N
S
O
OHO
OO
HN Oc(RGDfK)
O NHc(RGDfK)
5 5
Tc
Divalent99mTc Complex
Divalent 99mTc Complex
99mTc(V)-GH
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Multivalent 99mTc-Labeled Probes
99mTc Core Ligand LinkerTargeting Molecule
99mTcOD-Penicillamine
Hydroxyamamide
Alkyl
Ethylene glycol
Peptide
RGD Peptide Folate Oligo-aspartic acid Antibody Others
99mTcN Dithiocarbamate
[99mTc(CO)3
(OH2)3]+ Isonitrile
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Mixed Ligand [99mTc(CO)3(OH2)3]+ Compound
M: Tc/ReR: Targeting Unit
Trivalent Compound Divalent Compound withpharmacokinetic modifier (R’)
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Synthesis of 99mTc-Labeled RGD Peptide
CN-Hx-c(RGDfK)
Divalent compound
M: 99mTc/Re
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SPECT Images
99mTc-(CN-Hx-RGD)2 (300 µCi) 2 h post-injection
MultipinholeRadius of gyration: 25 mm.
Acquired for 20 min (360 degree)
Tumor
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Synthesis of 99mTc-Labeled RGD Peptide
CN-Hx-c(RGDfK)
CN-EG3-c(RGDfK)
Divalent compound
Trivalent compound
High hepatic accumulationM: 99mTc/Re
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Conclusions The monovalent penicillamine derivatives provided divalent
99mTc-labeled compounds in high yields The pharmacokinetics was manipulated by changing linkage
structures between penicillamine and c(RGDfK)
The divalent 99mTc-[Pen-SSG-c(RGDfK)]2
visualized tumor in mice by SPECT/CT without removing excess ligands
The use of 99mTc(CO)3(OH2)3 core provided divalent or trivalent 99mTc-labeled compounds in high yields
The pharmacokinetics was also manipulated by changing linkage structures between CN and c(RGDfK)
The present chemical design of 99mTc-labeled multivalent compounds would constitute a new strategy to develop molecular probes for SPECT