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Fluorine-18 Radiochemistry
Pei Yuin Keng
Scholars Trained in Advanced
Radiochemistry Technology
1
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Outline 1. PET radioisotopes
2. Properties of fluorine
3. Basic principles in radiochemistry of short-lived isotopes
i. Quantities ii. Specific activity
iii. Radiolysis
4. Fluorine chemistry i. Source of Fluorine-18
ii. Electrophilic and nucleophilic fluorine reagents
5. Electrophilic fluorination (“F+”) 6. Nucleophilic fluorination (“F-”)
i. General workflow
ii. Aromatic nucleophilic substitution (SNAr)
iii. Aliphatic nucleophilic substitution (SN2) i. Mechanism
ii. Solvents
iii. Leaving groups, activating groups 2
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PET Radioisotopes
M.-C. Lasne et al. Topics in Current Chemistry. 2002. 22 3
3. Low positron energy- shortest diffusion ranges < 2.4 mm
1. Moderate half-lives
2. High specific activity
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F18: Ideal Positron-Emitting Radionuclide
4
18F
Slide from Clifton Shen, M248 2009
• Low positron energy and short range in tissue (high resolution)
• 97% β+ decay
• high specific activity
• can be produced in large amount in a cyclotron (>10 Ci)
• can be labeled in high radiochemical yields for PET tracers
• acceptable radiation dosimetry for multiple studies in a patient
• allow transportation from production site to PET imaging centers (T1/2= 109.7
min)
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Properties of Fluorine 1. F bioisostere with O (size and electronegativity)
2. F most electronegative (highest number of protons in nucleus)
O’Hagan et al. Chem. Soc. Rev. 2008, 37, 308-319
M.-C. Lasne et al. Topics in Current Chemistry. 2002. 22
3. C-F bond is the strongest and is highly polarized
Hydration energy 507 kJ/moles F- + Hδ+ HF (bonding): 565 kJ/moles
F- (H2O)n
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Properties of Fluorine
6
( 𝐹 𝑎𝑛𝑑 919 𝐹)9
18 Atomic number Atomic mass
# Neutrons + Protons
# Protons
19F 18F
1s2 2s2 2p5
Electron configuration chemical reactivity (electrons!!)
F F F e-
F
-
1s2 2s2 2p6 OCTET! 1s2 2s2 2p6 OCTET!
328 kJ/mole
(“F+”) F-F bond weakest (159 kJ/mole)
EXTREMELY REACTIVE
(“F-) Donate a pair of electron
(nucleophilic) or H acceptor (base)
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Where to Label? i.e.: PET probe design
7
2-FDG Glucose
6-fluoro-L-DOPA L-DOPA
Fluorine ~ H: size and valence e-
(isosteres)
~ O: electronegativity
(3) Stereoselectivity: spatial orientation
of F relative to other functional
groups?
(1) Chemoselectivitiy and (2)
regioselectivity: which carbon?
Synthetic method consideration
2-FDM
Thymidine derivatives
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ONLY IN RADIOCHEMISTRY
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Specific Activity 1. Specific activity
2. Amount
3. Radiolysis
4. Radiochemical yield
𝑅𝑎𝑑𝑖𝑜𝑎𝑐𝑡𝑖𝑣𝑖𝑡𝑦 (𝐶𝑖)
𝑀𝑎𝑠𝑠 (µ𝑚𝑜𝑙𝑒𝑠)
Molecules of F-18
Molecules of F-18 + F-19
Maximum theoretical SA of F-18 ion ~ 1710 Ci/µmole
In reality, SA F-18 ions ([18F]F- /[18O]H2O] obtained from the cyclotron ~
50-100 Ci/µmole
SA of [18F]FDG = 2-5 Ci/µmole
How to measure specific activity of fluorine-18?: [18F]F2? [18F]F-?
Casella VR et al. 1980. J Nucl Med 21:750
Coenen et al. 1986, Appl Radiat Isot 37:1135
Small M. et al., Anal Chem. 1975. Anal Chem 47, 1801
F19 x20-40
F19 x10-50
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10 M.-C. Lasne et al. Topics in Current Chemistry. 2002. 22
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F19
F18
F19
F19
F19 F19
Receptors
Why is SA important? For imaging receptors (cell surface receptors, brains…etc)
o limited number
o Irreversible binding
Fluorine-18/19
molecules
F18 F19 >>> ~1000x
General rule of thumb:
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What affects SA of F18 ion?
12 12
0
20
40
60
80
100
120
140
160
0 10 20 30 40
Sp
ec
ific
Ac
tivity
(C
i/u
mo
le)
Dose (mC)
Dose vs Specific Act
1. Radioactivity, bombardment time and dose
Solin O., Appl Radiat Isot. 1988, 39, 1065-1071
2. Ions contamination
from target
Higher radioactivity, higher SA?
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13
3. Contamination from materials
(b) Contamination from
reagents K2CO3 ~ 10 nmole of F19
K222 = ~ 30 nmole of F19
Precursor ~ negligible
(c) Contamination from QMA
resins SAX resin
Resin vs no resin: 5000 vs 700 mCi/umole
Berridge M.S. et al., JLRC. 2009, 52, 543-548
Pike V. et al., Curr Radiopharm. 2009, 2, 1.
Controlled experiments without Teflon tubing: 25-51 Ci/umole
In the presence of Teflon tubing average SA ~ 0.6 Ci/umole
(a)Radiolysis in Teflon
tubing and
components o Radioactivity levels o Incubation time
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Measure cold mass after probes decay.
1. Develop calibration curve
2. Commonly used detection techniques:
o HPLC (UV detection for UV-active molecules)
o Pulsed amperometric (carbohydrates, non-UV active molecules)
How to measure specific activity of labeled molecules?
14
Berridge M.S. et al., JLRC. 2009, 52, 543-548
FBA
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Only in radiochemistry
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1. Specific activity
2. Amount 3. Radiolysis
4. Radiochemical yield Theoretical specific activity 1710 Ci/µmole
1 Ci radioactivity ~ 60 nmoles fluoride ion
Typical reaction conditions
Precursors and reagent : 10-100 mmoles
Reaction rate of stoichiometry SN2 = [Substrate] x [nucleophiles]
Reaction rate of SN2 in radiochemistry = [Substrate]
Increased in [Substrate], increasing reaction rates
Detection? Rates? Concentrations?
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Basic Radiochemistry
16
1. Specific activity
2. Amount
3. Radiolysis
Conclusion: Toxic, unstable side products form by the presence of the higher
energy positron in a concentrated solution
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Only in Radiochemistry
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Each 18F decay (T1/2=109.8 mins, Emaxβ+ = 0.69 MeV)
releases positrons (β+) particles of 0.23 MeV
Buriova E et al., J Radioanalytical and Nucl Chem. 2005, 264, 595-602
18F
0.69 MeV
18O
β+ 0.23 MeV
e-
~0.4 mm
1. Specific activity
2. Amount
3. Radiolysis
4. Radiochemical yield
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General requirements of synthesis of short-lived radioisotopes
18
1. Fast, fast and fast. Rule of thumb: 3 half-life. For F18 <6 hours.
2. Non-stoichiometry reactions. Large excess of reagents/precursors to
increase the reaction rates
Organic Synthesis Stoichiometric reaction
[[18F]fluoride] ~ nM
Radiosynthesis Non-Stoichiometric reaction
[precursor] ~ mM
3. High temperatures to increase the reaction rates
4. Optimization of reaction conditions (time, temperature, solvents,
concentrations)
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Only in Radiochemistry
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1. Specific activity
2. Amount
3. Radiolysis
4. Radiochemical yield (RCY)
Definition RCY:
(1) Fluorination efficiency (radio-TLC or radio-HPLC) ** THIS IS NOT RCY!
(2) RCY yield= Percentage of (purified product/starting radioactivity)
• Decay corrected (corrected to (EOB, EOS)
• Non decay corrected
• Which one is more useful?
• Eg: decay corrected RCY = 20% with a synthesis time of 90 mins Non decay corrected RCY ~ 11%
(3) For reaction optimization/research and development
• Crude RCY %= [Total radioactivity collected x (conversion by
radio-TLC)]/(total starting radioactivity) • ** important – losses as volatile side radioactive products;
reoptimize conditions.
0 10 20 30 40 50 60 70 mm
TLC
0 10 20 30 40 50 60 70 mm
0
50
100
150
200
250
300
350
400
450
500
550
600 C/mm
Front
Origin
Reg #1
Reg #2
88% [18F]FLT
Unreacted [18F]F-
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F18 LABELING METHOD
20
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Fluorinating agents
Fluorine Chemistry
21
19F 18F
1s2 2s2 2p5
MF
Selectfluor
Diethylaminosulfur
Trifluoride (DAST)
XeF2
HF
S
O O
NS
O O
F
Fluorobenzenesulfonimide
(NFSI)
Pyridine
hydrofluoride
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[18F]F-Labeling Methods
22
1. Direct labeling (i) Electrophilic Substitution
“[18F]F+” Substrates-EDG [18F]F-Substrates-EDG
Substrates-EWG “[18F]F-” [18F]F-Substrates-EWG
(ii) Nucleophilic Substitution
3. Via prosthetic groups
[18F]F-Substrates-coupling group
Peptide or protein
+ [18F]F
2. Via built-up procedures
OR
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ELECTROPHILIC FLUORINATION
23
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Mechanism Electrophilic Fluorination
24
Nucleophile R-F
F L
C C F LC C
F
F
F-F, FClO3, XeF2, CF3OF and CsSO4F
H = -104kcal/mol
Cl-Cl C CC C
Cl
ClH = -31kcal/mol
• Very reactive
• Mechanism(?)
• Highly
exothermic
• Electron rich
substrate
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Electrophilic Fluorination
25
F F
R R
F
1. Non selective (F2, XeF2,
CH3COOF source)
OH
HO
COOH
NH2
18F
OH
HO
COOH
NH2
18F
OH
HO
COOH
NH2
18F
12% 1.7% 21%
2. Selective precursor (HgOCOCF3 or Sn(CH3)3)
OBoc
BocO
COOEt
NH2
Sn(CH3)3
OH
HO
COOH
NH2
18F
[18F]F2
HBr
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Electrophilic fluorination
26
Reaction of fluorine gas
with 3,4,6-tri-O-acetylglucal
8%; 2 hrs
1976: First synthesis of [18F]FDG at Brookhaven National Lab.
U of Pennsylvania, the 1st [18F]FDG PET imaging of the brain
1978: Preclinical studies of [18F]FDG for myocardial metabolism
1980: Preclinical studies of [18F]FDG for tumor metabolism
Poor stereoselectivity2-FDM
(3:1 ratio)
Poor RCY; only 25% (max) is
labeled
Low specific activity- [18F]F2
gas doped with F2
(1) Separation
(2) Hydrolysis
[18F]FDG synthesis
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N-[18F]F Radiofluorination
27
[18F]F2
Electrophilic fluorination agent
Reactive, but more selective
Easier to handle –solid, liquid
Not as corrosive as F2 gas.
-OTf 2 -OTf
NFSI
Selectfluor
Gouverneur, V. et al, Angew Chemie Int Ed. 2012, 51, 2-14
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[18F]Selectfluor bis(triflate)
28 Gouverneur, V. et al. Angew Chem Int Ed. 2010, 49, 6821
LiOTf, MeCN, -10 °C
[18F]F2
Isotopic exchange with BF-4
Electrical discharge methodology: Higher SA of [18F]F2
Higher SA 8 Ci/µmole
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Summary Electrophilic Fluorination
29
1. [18F]F2 gas:
i. Gaseous, difficult to handle
ii. Low specific activity, doped with F2 gas
iii. Need dedicated cyclotron and radiochemistry lab
2. Extremely reactive.
3. Aromatic substrates (electron rich substrates)
4. New, milder, and more selective N-[18F] fluorination
agent
5. Improve specific activity of [18F]F2 by gas discharge
method (SA
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NUCLEOPHILIC FLUORINATION
30
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PET Probes from Nucleophilic Fluorination
31
Aliphatic Aromatic
FDG
FDDNP
FAC family
FLT
FMISO
Fallypride
FDOPA
N
HN S
ON
O
18F
SFB
[18F]Altanserine
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[18F]F Nucleophilic Sources
32
Alkaline metal fluoride
(1) MF (M: K, Cs, Ag)
LiF < NaF < KF < CsF
Increasing nucleophilicity
Increasing solubility
Increasing ionic strength
Common alkali metal fluorides
NO
ON
O
O
O
OK+ 18F-
KF/Cryptand
Tetraalkylammonium fluoride
N
18F-
[18F]fluoride ion/[18O]H2O
K2.2.2/ K2CO3
or
TBAOH/TBAHCO3
(2) HF
Metal cations that render
nucleophilicity Al, In, Ni, Cu, Zn, Ca, Na
(1) Role of PTC?
(2) Role of base?
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Phase Transfer Catalyst (PTC)
33
Role of Cryptand and tetraalkylammonium salt?
R-X R-F N
X
N
X
Organic phase
Aqueous phase
N
F-
N
F-
F-
Starks, C.M. J. Am. Chem. Soc. 1971, 93, 195
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Which PTC or Base?
34
NO
ON
O
O
O
OK+ 18F-
KF/Cryptand
Tetraalkylammonium fluoride
R = methyl, ethyl, butyl
CsF
1. Solubility, (2) Stability, (4) Hygroscopic (likes water)
N......K+….N
F-
[18F]fluoride ion/[18O]H2O
Kryptofix (K2.2.2)
K2CO3 Tetrabutylammonium
carbonate
or bicarbonate
Cesium carbonate
or bicarbonate
Thermal decomposition of TBAF
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Role of Base
35
Role of base (1) Prevent formation of H[18F]F volatile, lost radioactivity
(2) Counter ion for [18F]fluoride ion complexation– phase transfer
(3) Side reactions and decomposition of PTC
(4) Base hydrolysis of precursor (base sensitive)
(5) Base catalyzed side reactions
Molar ratio Kryptofix >base (K2CO3 and KHCO3)- decomposition, and 2 K+
Choice of base
Base pKb
K2CO3 3.8
KHCO3 7.6
K+ oxalate 10
H2O 14
Mo
re b
asic
Kryptofix/K/oxalate system ALONE- resulted in 30% loss of radioactivity as H[18F]F
Add 30-50 ug of K2CO3 to prevent radioactivity losses during drying
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Literature example, the role of base
36
K222/K+/CO3 K222/K+/oxalate
K2CO3 (20-50 ug)
Radiochemical yield ~ 1%
Direct nucleophilic fluorination of butyrophenone neuroleptics
Potassium oxalate
Katsifis, A. et al. Appl Radiat Isot. 1993, 44, 1015
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Typical workflow of F18 ion radiochemistry
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Phase Transfer Catalysis and azeotropic distillation in
Radiochemistry?
38
R-X R-F N
X
N
X
Organic phase
Aqueous phase
N
F-
N
F-
F-
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Nucleophilic Aliphatic Substitution (1) SN2 substitution mechanism Radiolabelled product
Inversion of
stereochemistry
Precursor
Product
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Stereochemical Consequences
40
Kinetic
differences of
cell uptake
Chemo/Stereo
consequences
Probe different
biological functions
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41
Nucleophilic Aliphatic Substitution 3. Solvents (Dielectric constant? acidic H? H-bonding?)
Polar Protic Polar aprotic Non-polar
Choice: Solubility, boiling point, dielectric constant
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2. Side reactions
42
(1) Undesirable reaction: E2 elimination mechanism Side product
i. Optimal ratio of phase transfer
catalyst:base:precursor
ii. Choice of base eg: potassium oxalate iii. Higher temperature higher elimination byproducts
iv. Better leaving group are more sensitive to elimination
side reaction, especially with increasing temperatures
v. Elimination rate in 2o LG >> 1o LG
Nucleophilic Aliphatic Substitution
(K2CO3, Kryptofix, KHCO3, TBAHCO3…etc)
Antiperiplanar
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F18-F19 exchange
43
Lowers RCY. Importance of leaving group. Less reactive LG (mesylate) 0 yield
Side reaction
Roeda D. et al., Current Radiopharm. 2010, 3, 81-108
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Side reaction with leaving group
44
N
O
N
OH
HH
O
CH3
F
H
H
N
O
N
O
HH
O
CH3H
H
S
O
O
FHO
HCl
[18F]fluoride ion
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45
Nucleophilic Aliphatic Substitution Example: Side reaction in [18F]FLT
Roeda D. et al., Current Radiopharm. 2010, 3, 81-108
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Nucleophilic Aliphatic Substitution
46
4. Precursor design: Leaving group
S
O
O
F3C O
S
O
O
OO2N
S
O
O
H3C O
S
O
O
OH3C
Triflate (Tf)
Nosylate (Ns)
Tosylate (Ts)
Mesylate (Ms)
Krel
1.4 x 108
4.4 x 105
3.7 x 104
3.0 x 104
I-
Br-
CF3CO2-
Cl-
F-
p-nitrobenzoate
CH3CO2-
91
14
2.1
1
9 x 10-6
5.5 x 10-6
1.4x 10-6
rea
ctiv
ity
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Literature Survey: FLT synthesis
47
Nosylate (Ns)
Tosylate (Ts)
Mesylate (Ms)
Leaving group, R =
19.8
7.8
5.3
Fluorination yield
K2.2.2/K2CO3
MeCN
105 C
10 mins
rea
ctiv
ity
Eisenhut, M. et al. Nuc Med Biol. 2002, 263-273
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The n.c.a. [18F]FDG synthesis
48
+ glucose
No other side
products!
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NUCLEOPHILIC AROMATIC SUBSTITUTION
49
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Precursor Requirements
50
(a) Activating effect: EWG: 3-NO2 < 4-CH3CO < 4-CN < 4-NO2
(b) Leaving group: I < Br < Cl <F < NO2 < N+Me3
(C-F bond making is RLS. Polar effects favors addition step)
(c) Solvent effect: DMSO > DMAc (N,N,-dimethylacetamide) > sulfolane >>
acetonitrile
Effect of activating (X) and leaving groups
(Y) on nucleophilic aromatic fluorination
(80 °C) (120 °C)
Meisenheimer complex;
delocalization electron onto EWG
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51
Side Reactions in SNAr Side reactions
Trimethylammonium triflate LG
Most reactive
Easy to separate (charged)
Fluorobenzaldehyde site specific peptide
(Prosthetic group) conjugation; away
from the binding sites
O-NH2
Amino-oxy functionalized peptide
Oxime formation
Li, X. et al. Bioconjugate Chem. 2008, 19, 1684-1688 Solin, O. et al. J Fluorine Chemistry, 2012, 143, 49-56
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Nucleophilic Aromatic Substitution of substrate without EWG?
52
OH?
* High temperature, harsh reagent, corrosive, explosive
Low yield
Balz-Shciemann reaction
H3CO
H3CONHCOCH3
COOEt
N
N
BF4
FDOPA
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[18F]F-Nucleophilic Heteroaromatic Substitution
53
LUMO of pyridine at ortho and para position lower than benzene
No need activating group
Coenen, H.H. 2007. Basic Fluorine-18 Labeling Methods
Gouverneur, V. et al. Angew Chem Int Ed. 2012, 51, 2-14
Irie, T. et al. App Radiat Isot. 1982. 33 445.
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Summary Nucleophilic Substitution
54
1. Preferred method
2. High specific activity of [18F]F- vs [18F]F2 (1740 Ci/umole
vs 0.1 Ci/umole)
3. Easy to handle (liquid vs gas)
4. [18F]F- Can be transported and distributed to nearby
imaging clinicic (Decentralized model of PET probe
production)
5. SN2, leaving group, solvent, phase transfer catalyst and
base
6. Side reactions, optimization
7. Activated substrate and good leaving group for SNAr
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INDIRECT F18-LABELING
55
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Commonly used [18F]Prosthetic groups
56 N
O
F18
N
O
O
F18
O
N
N
O
O
H
O
H
F18
F18
H
N
18F
O
H
n
18F
N3
n
18F
O
ON
O
O
18F
O
HO
18F
O
HN
3H2N
COOH
HS
OH2N
N3
NH2
Chemoselectivity
Site-specific conjugation
Banister et al. Current Radiopharm, 2010, 3, 68-80
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CHALLENGES IN F18 RADIOCHEMISTRY
57
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Radiochemistry Requirements
• High-cost
• Low-throughput
• Bulky
• Complicated
• Need skillful personnel
• Limited flexibility
Slide adapted from Clifton Shen M248
Expensive, bulky synthesizer
1-synthesizer, 1-probe
workflow
Hot cells. Pb shielding Automation
Robotic arms
Dedicated radiochemistry lab
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A Typical Workflow of PET imaging
PET radiopharmacies PET/CT imaging clinics
[18F]FDG
Produce
[18F]fluoride
Produce
tracer
Dispense
doses
Clinical PET imaging center
Preclinical PET research center
[18F]FDG
[18F]FDG
Centralized PET probes production
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PET radiopharmacies PET/CT imaging clinics
[18F]F- ion
DeCentralized Production of PET Probes
Produce
[18F]fluoride Dispense
doses
Produce tracer
Clinical PET imaging center
Preclinical PET research center
[18F]FDG
[18F]FLT
[18F]FDOPA
[18F]FDG
[18F]FAC
[18F]SFB-Db
Produce tracer
New technologies, simplified chemistry, higher kinetics, higher reaction selectivity
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References
61
L. Cai, S. Lu, and V. W. Pike, “Chemistry with [18F]Fluoride Ion (Eur. J. Org.
Chem. 17/2008),” European Journal of Organic Chemistry, vol. 2008, no. 17,
pp. 2843-2843, Jun. 2008
Roeda D. et al., Current Radiopharm. 2010, 3, 81-108
M.-C. Lasne et al. Topics in Current Chemistry. 2002. 22
Banister et al. Current Radiopharm, 2010, 3, 68-80
Gouverneur, V. et al, Angew Chemie Int Ed. 2012, 51, 2-14