Development of Diaryliodonium Salts
as Precursors to [18F]Fluoroarenes
Dr M. A. Carroll
School of Chemistry
CR-UK & EPSRC Cancer Imaging Programme at the Universities of Newcastle and Durham
in association with the MRC and Department of Health (England)
Outline
 Medical Imaging at Newcastle
 Fluorine-18 radiochemistry
 Diaryliodonium salts as precursors to [18F]fluoroarenes
 Fluorine-18 oncology/neuroscience tracers
 Summary
Imaging Facilities
 Clinical MRI (Philips 3T)
 Pre-clinical MRI (Varian 7T)
 Clinical PET-CT (Siemens Biograph 40)
 Pre-clinical PET (Philips), CT (Bioscan)
Why restricted to [18F]FDG?
Challenges
 No systematic studies to optimise radiolabelling process (>5 Ci)
 Few combination studies (different isotopes and techniques)
 Low material yield
 Low radiochemical yield + RCY(DC)
 Low specific activity (isotopic dilution)
 Label is incorporated where it is easy to introduce
– not necessarily where it is needed!
 Short half lives
– conventional synthetic routes/procedures not appropriate
 Metabolism
 Automation/translation to clinical setting
[18F]Fluorine Chemistry
Starting material is [18F]fluoride anion in [18O]H2O
 Aromatic fluorine
- enhanced metabolic stability
- restrictions on the aromatic ring
- restrictions on the substituents
X
X = NO2, [NMe3]+, Br, Cl
 Aliphatic fluorine
- limited metabolic stability
- restrictions on the position
- restrictions on other substituents
R
X
[18F]fluoride
R
18F
X = OTs, OTf, ONs, OMs, Br
 Fluorine ‘tags’
- can be aromatic or aliphatic
- requires suitable linking group
18F
[18F]fluoride
18F
X
Y
18F
X = NH2, OH, SH, COOH
Pike et al., Eur. J. Org. Chem., 2008, 2853 (review); Miller et al. Angew. Chem., 2008, 47, 8998 (review)
Radiopharmaceutical Production
 Radiochemical yield - RCY
 Decay corrected radiochemical yield – RCY(DC)
 Specific activity – radioactivity per mole of compound
cyclotron
EOB
1
2
3
EOS
1.
2.
3.
4.
5.
6.
4
5
6
ready
for
injection
EOB EOB
Transfer of 18F from cyclotron to radiosynthesis unit
Trapping and drying of [18F]fluoride
Reaction of [18F]fluoride to make imaging agent (may be multi-step)
Isolation/purification of imaging agent
Formulation
Transfer to scanner ready for injection (passed QC)
Technology: Selection Criteria
 [18F]fluoride is the starting material of choice
 [18F]fluoroarene preferred
 No restriction on the:- electronic nature of the target (hetero)aromatic ring
- steric constraints of the target (hetero)aromatic ring
- substitution pattern of the target (hetero)aromatic ring
 Compatible with multiple and sensitive functionality
 Single-step generic process
- technology fit with existing automation
Iodonium Route to [18F]Fluoroarenes
 Diaryliodonium salts may be prepared:- by direct aromatic substitution
- from aryltrialkylstannanes
- from arylboronic acids
ArI(OAc)2
R2
X
R1
R2
X
I
X = H, SnR3, B(OH)2
 [18F]Fluoride: high specific activity
 electron-deficient and electron-rich (hetero)aromatic rings
 no restriction on substitution pattern
 control of ring selectivity on fluorination
X
R1
R2
I
[18F]Fluoride
R1
R2
+
I
18F
For some examples see:Coenen et al. J. Am. Chem. Soc., 2007, 129, 8018; Carroll et al J. Label Compd. Radiopharm., 2007, 50, 452;
Wüst et al. Org. Biomol. Chem., 2005, 3, 503; Coenen et al. J. Label Compd. Radiopharm., 2004, 47, 429; Widdowson et al.
J. Label Compd. Radiopharm., 1997, 39, 65; Pike et al. J. Chem. Soc., Chem. Commun, 1995, 2215; Wuest et al. Steroids,
2003, 68, 177; Suzuki et al. Tetrahedron Lett., 2007, 48, 8632.
Synthesis of Ethyl-3-[18F]fluorobenzoate
COOEt
COOEt
CF3COO
or
ArI
ArF
18
F
S
Ar =
COOEt
fluoridea
Ar =
F
57%
1
:
0b
21-80% (n = 6)
70%
1
:
0b
4-35% (n = 6)
49%
11
:
1
7-23% (n = 6)
MeO
Ar =
OMe
a 19
F; CsF, TEMPO (10 mol%), DMF, 130 oC, 1.5 h: 18F; [18F]KF/K222, TEMPO (10 mol%),
DMF, 130 oC, 5 min. b Not detected
 All compounds in the initial studies, using our routine screening conditions,
provided the target 3-[18F]fluoro derivative in practical yields.
(Carroll et al J. Nucl. Med., 2008, 49S, 303P)
[18F]Fluorobenzaldehyde, [18F]FBA
CF3COO
I
OHC
18F
[18F]fluoride
OMe
OHC
Heteroaromatics: 3-[18F]Fluoropyridine
CF3COO
I
N
OMe
RCY = 55 - 63%
ICl2
18F
18
[ F]fluoride
N
Carroll et al., US12/647,169
Carroll et al. J. Labelled Compd. Radiopharm., 2007, 50, 452; WO2007/141529;
N
Rapid Purification: Fluorous SPE
CF3COO
I
18F
18
[ F]fluoride
O
I
+
C6F13
C6F13
O
COOEt
COOEt
Reproducibility: Radical Scavengers
 The addition of a radical scavenger e.g. TEMPO improved reproducibility
Steric Effect
IPh
X
18
[ F]fluoride
Carroll et al J. Fluorine Chem., 2007, 128, 127. WO2005/061415A1
Carroll et al., J. Labelled Compd. Radiopharm., 2008, 51, 259
18F
4-[18F]SFB: Typical Approach
COOEt
COOEt
O
COOH
O
[18F]Fluoride
O
N
O
18F
NMe3
18F
18F
4-[18F]SFB
 4-[18F]SFB: Most commonly used prosthetic group
 Multi-step, multi-pot synthesis
 Difficult to automate
Iodonium Route - challenge
 Reduce the number of reaction steps
 Selective reaction of [18F]fluoride in the presence of the active ester
 Generic approach to all regioisomers
Okaryi., Eur. J. Nucl. Med., 2001, 28, 929 (review)
4-[18F]SFB: Iodonium Approach
O
O
CF3COO
O
O
O
S
K[18F]/K222
N
O
O
I
DMF 130 oC
18
N
O
F
4-[18F]SFB RCY= 4-23% (n = 8)
 4-[18F]SFB: The first single-step synthesis
 Selective for both 19F and 18F
 Other non-participating aromatic rings may be used
 Suitable for automation
Optimisation of process (yield/automation) and
application as a prosthetic group is currently underway
Carroll et al., J. Nucl. Med., 2008, 49S, 298P; US12/647,169
Radiochemistry Laboratory
FIRST PET radiochemistry facility in the North East
 Located:
School of Chemistry
 Research & pre-clinical
production of fluorine-18
radiopharmaceuticals
 2 PET research hotcells
 Refurbishment Q1 2009
 Operational (18F) Q4 2009
 Future proof design
- additional hotcells
- PET & SPECT isotopes
Synthetic
Radiochemistry
 Batch production
- Eckert & Zeigler Modular Lab
- Multi-step, flexible system
 Microwave
- Resonance Instruments
ABT:
Biomarker Generator
‘mini-cyclotron’
• 7.5 MeV Positive Ion
Cyclotron
• 3 Internal targets
• Production Rate of 1.0
mCi/min [18F]fluoride
• 1.16 T Magnet
• 2-5 µA Beam current
• 250 µL Target Volume
[18F]Fluorine Targets in Oncology
 Hypoxia
 Glucose metabolism
 Cellular proliferation
O
HO
HO
NH
OH
OH
O
N
OH
18F
18
N
F
N
HO
O
O
NO2
18F
[18F]FDG
[18F]FMISO
 PARP
O
 Choline transport
 Amino acid transporters
H
N
HO
NHMe
18F
[18F]FLT
N
COOH
18F
TsO
18
F
O
N
H
[18F]AG140699
[18F]FEC
[18F]FET
NH2
[18F]Fluorine Targets in Neuroscience
 5HT1A
 β-amyloid
 D2
OMe
N
OMe
N
18
N
N
OMe
H
N
18F
F
MeHN
N
[18F]AV45
O
O
O
O
O
18F
18F
OH
S
[18F]MPPF
 5HT2
H
N
 dopamine
transporters
18F
S
18F
HO
MeO
COOH
N
COOMe
HO
N
COOH
[18F]FPIB
N
 dopamine metabolism
N
O
MeHN
[18F]Fallypride
18F
NH2
HO
18F
NH2
Cl
O
[18F]Altanserin
[18F]FDOPA
[18F]FMT
[18F]FECNT
 ‘peripheral’
benzodiazepine
N
OMe
F
N
18F
18F
[18F]DAA1106
N
H
 α4β2 nicotinic
[18F]FMeNER-d2
 neurokinin
 mGluR5
type-1 receptors
18
N
N N
[18F]NS10743
F
O
S
N
O
O
O
N
[18F]Flumazenil
 α7 nicotinic
18F
O
O
OMe
OPh
Ph
D D
COOEt
N
O
18
 noradrenaline transport
 benzodiazepine
N
H
O
18F
Me
18
N
CN
N
[18F]nifene
F
CF3
NH
HN
N
N
N
N
[18F]MTEB
[18F]SPA-RQ
Biomacromolecules: peptides, antibodies, oligonucleotides
O
O
 ‘amine/alcohol’ selective
COOH
O
N
18F
O
18F
[18F]SFB
O
 ‘thiol’ selective
O
N
O
18F
CHO
18F
NH2
N
H
18F
 other
O
18F
 ‘carboxylate’ selective
Br/I
N
N
H
O
18F
O
18
N3
18F
NH2
F
H
N
Br
18F
O
O
18F
N
PET Radiochemistry - Summary
 ALL of the major methods for incorporation
of fluorine-18 have been achieved (SN2, 19F/18F, SNAr, iodonium)
 [18F]Fluorination has been achieved, both batch and microfluidic systems
 Microwave and conventional heating have been employed
 Pre-clinical production of a range of imaging agents:
- [18F]FEC, [18F]FET, [18F]MPPF, [18F]SFB, [18F]FBA, [18F]DAA1106, [18F]MTEB
 New methodology and targets in progress
 Precursor production:
- automation, robust/reproducible, high purity, QC
- GMP grade material
Next steps
 ABT Biomarker Generator, carbon-11 and other radioisotopes
 Clincial production – MHRA Specials Licence
 Expand the range of pre-clinical imaging agents – single kit design
New castle - Chem istry
L. M. Kamara
J. Woodcraft
S.-L. Tang
Dr S. Jiang
Dr G. Smith
Dr R. Yan
Dr L. Dixon
E. Fisher
P. D. Hancock
P. K. D. Dawson
Dr S. Hobson
Dr G. Launay
C. Reed
M. Charlton
C. McCardle
S. Bhatt
I m perial College
Dr. D. A. Widdowson
Dr. E. Wilson
Dr H. S. Rzepa
Dr S. Martin-Santamaria
W BI C, Cam bridge
Dr. F. I. Aigbirhio
Dr. D. Soloviev
Dr L. Brichard
New castle - I m aging
Prof. H. Newell, Dr R. Maxwell
Dr I. Wilson, Dr S. Gartside
NI M H, USA
Prof. V. W. Pike
Ham m ersm ith I m anet
Dr S. Luthra, Dr F. Brady,
Dr F. Shah, G. Brown
Funding
Newcastle University
(NICR, IoN, IAH)
ONE North East
Cancer Research UK
EPSRC, MRC, NHS
Royal Society
Hammersmith Imanet
GE-Healthcare
‘I+PET’ Technology
 Improved preparation of known targets
35-45 min
1 min
[18F]SFB
‘I+PET’
current route
 Access to ‘impossible’ targets
3-[18F]pyridine
63%
‘I+PET’
Unique understanding/skills in the preparation
and purification of ‘I+PET’ reagents
4-[18F]SFB: Iodonium Approach
O
O
O
O
COOH
O
I
N
O
O
I
N
O
Bu3Sn
O
O
CF3COO
O
N
O
I
S
Newcastle – Fine Chemical Production
‘on-demand’ synthesis of organics
 Multi-step synthesis of both precursors and imaging agents
- reduce synthetic steps (pre- and post-labelling)
- enhanced purity requirements cf. APIs
- uses many metal catalysed steps
(key: selectivity, rate, mild conditions)
(reagents with low reactivity e.g. [11C]CH4, [11C]CO, [11C]CO2)
- rapid optimisation required (automated process)
- flow and batch processes (micro and meso)
- scale range (mgs – 100gs – kgs)
- translate rapidly to GMP
- specific Newcastle technology NOT restricted to fluorination
PET: Applications/Potential
 Almost any biological process may be studied
 Range of half-lives and elements available
 Low dose – typically ng or pg required (limits toxicity)
 Label species of interest
 Diagnostic – response to treatment
 Biological data
- Combination with other techniques – MRI, CT
 Real-time monitoring
- improved data handling/processing
 in vivo data
 whole body: off-target activity, non-specific binding
 Early in the drug development process
Fluorine-18 Automation
 Batch (Eckert & Zeigler Modular Lab)
- [18F]FEC
 Microwave
- [18F]MPPF
cps
34.67% radiochemical
incorporation
35000.0
30000.0
25000.0
O
20000.0
15000.0
18F
10000.0
5000.0
0.0
0:00
m AU
5:00
15:00
10:00
m m :s s
O
300.0
250.0
NO2
200.0
O
150.0
100.0
50.0
18F
0.0
0:00
5:00
10:00
15:00
m m :s s
Synthetic
Radiochemistry
 Microfluidic production
- Advion NanoTek LF
- Multi-step,
flexible system
Fluorine-18 Automation
 Microfluidic (Advion NanoTek)





Variation of multiple reaction parameters
Rapid optimisation of protocols (>30 runs per batch of [18F]fluoride)
Robust performance
Introduction of Et4N.HCO3 as a new phase transfer reagent
ALL reaction types now achieved
Analytical/QC
Radiochemistry
 Radioanalytical Systems
- radioHPLC (Agilent1200)
- radioGC (Agilent 6890)
- radioTLC (Bioscan AR2000)
Summary
 Very flexible radiosynthetic & analytical facility
 Batch and microfluidic production
 Range of [18F]fluoride chemistries possible
 Small molecule and biomacromolecule targets
Integrated Chemistry and QC
Lead Shield
Reagent Metering Kit
HPLC Column
Chemistry Card
UV Detector
Syringe Pump
Radiation
Detector
Probe
RI Detector
Isocratic Pump
Gas Manifold
NI RIO Chassis
Power Supply
(24 vdc)
Degasser
Waste container
mounted on side
Radiochemistry Facility