Site-Selective, Late-Stage C?H 18F-Fluorination on Unprotected Peptides for Positron Emission Tomography Imaging

Article abstract of DOI:10.1002/anie.201806966

Peptides are often ideal ligands for diagnostic molecular imaging due to their ease of synthesis and tuneable targeting properties. However, labelling unmodified peptides with ¹⁸F for positron emission tomography (PET) imaging presents a number of challenges. Here we show the combination of photoactivated sodium decatungstate and [¹⁸F]-N-fluorobenzenesulfonimide effects site-selective ¹⁸F-fluorination at the branched position in leucine residues in unprotected and unaltered peptides. This streamlined process provides a means to directly convert native peptides into PET imaging agents under mild aqueous conditions, enabling rapid discovery and development of peptide-based molecular imaging tools.

Full text of DOI:10.1002/anie.201806966

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
International Edition Chemie
www.angewandte.org
Accepted Article
Title: Site-Selective, Late-Stage C-H 18F-Fluorination on Unprotected
Peptides for Positron Emission Tomography Imaging
Authors: Robert Britton, Zheliang Yuan, Matthew Nodwell, Hua Yang,
Noeen Malik, Helen Merkens, Francois Benard, Rainer
Martin, and Paul Schaffer
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201806966
Angew. Chem. 10.1002/ange.201806966
Link to VoR: http://dx.doi.org/10.1002/anie.201806966
http://dx.doi.org/10.1002/ange.201806966

Angewandte Chemie International Edition
10.1002/anie.201806966
COMMUNICATION
1
8
Site-Selective, Late-Stage C-H F-Fluorination on Unprotected
Peptides for Positron Emission Tomography Imaging
†
†
Zheliang Yuan, Matthew B. Nodwell, Hua Yang, Noeen Malik, Helen Merkens, François Bénard,
Rainer E. Martin, Paul Schaffer,* Robert Britton*
Abstract: Peptides are often ideal ligands for diagnostic molecular
Most commonly, electrophile-containing prosthetic groups such
[
9]
[10]
18
imaging due to their ease of synthesis and tuneable targeting
as Michael acceptors or acylating agents are F-labelled
prior to reaction with a nucleophilic residue on a peptide (e.g.,
1
8
properties. However, labelling unmodified peptides with F for
positron emission tomography (PET) imaging presents a number of
challenges. Here we show the combination of photoactivated sodium
1
8
[10]
[ F]SFB (2),
Figure 1). However, the late-stage, aqueous
labelling of peptide-bound prosthetic groups by isotopic
1
8
18
[11]
18
[12]
decatungstate and [ F]-N-fluorobenzenesulfonimide effects site-
exchange ([ F]AmBF
3
or [ F]SiFA ), formation of a metal-
1
8
18
[13]
[14]
selective F-fluorination at the branched position in leucine residues
in unprotected and unaltered peptides. This streamlined process
provides a means to directly convert native peptides into PET
imaging agents under mild aqueous conditions, enabling rapid dis-
covery and development of peptide-based molecular imaging tools.
fluoride complex ([ F]AlF ) or via S
N
Ar
reactions are also
[
8]
18
viable alternatives. Very recently the F-trifluoromethylation of
[
15a]
19
cysteine residues
and F-trifluoromethylation of tyrosine
[
15b]
18
residues
in unmodified peptides, and F-fluorination of C-H
[
15c]
bonds in (hetero)arenes
have also been reported.
18F-labelled prosthetic group attached to peptide
O
O
Positron emission tomography is a functional imaging
technique whereby a ligand labelled with a positron-emitting
N
O
O
R
O
1
1
18
68
R
radioisotope (e.g., C, F, Ga) is administered to a patient
18F
[18F]SFB (2)
N
Peptide
[
1]
H N
Peptide
2
H
and its biodistribution is then monitored in real time. Thus,
radiotracers that target a specific cellular or metabolic pathway
can non-invasively provide information critical to disease
18F
1
3
1
8
Prosthetic groups for F-labelling of peptides by reaction with fluoride
[
2]
R
F
18F
diagnosis, status and response to therapy.
Among the
[18
[18F]AmBF3
R
[18F]SiFA
F]AlF
N
B
t
N
Si( Bu)2
1
8
F
18F
positron-emitting radioisotopes, F is most commonly used in
Al18F]2+
[
+
O
O
R
PET imaging based on favourable decay characteristics (97% β
N
N
R
R
N
N
N
N
H
Peptide
N
H
Peptide
decay), low positron energy (0.64 MeV), and a half-life (t1/2
=
[
3]
S
R
O
N
1
09.8 min) compatible with radiotracer distribution. Owing to
4
5
6
N
H
N
H
Peptide
their ease of synthesis, low immunogenicity, tuneable targeting
properties and favourable pharmacokinetics, peptides often
This work: direct prosthetic-group-free 18F-labeliing of C-H bonds in peptides
[
4,5]
provide ideal leads for PET ligands.
However, there is a
18F
[18
F]NFSI, NaDT
fundamental incompatibility between the hydrophilic and
structurally sensitive nature of peptides and the violent reactivity
O
O
H
N
hν, MeCN, H2O, rt
H
N
Peptide
Peptide
N
H
Peptide
N
H
Peptide
1
8
40 min
of [ F]F
2
gas or the high temperature and anhydrous reaction
R
O
R
O
1
8
[4]
selective and functional group compatible, in water, at room temperature
no protecting groups or derivatization required, mild conditions
requirements typical for [ F]fluoride ion labelling. Thus, recent
1
1
efforts have focused on late-stage C-labelling (t1/2 = 20.4 min)
1
8
1
1
[6]
11
Figure 1. Prosthetic groups commonly used for F-labelling of peptides and a
prosthetic-group-free F-labelling of Leu-containing peptides.
of peptides and include C-acylation of lysine residues or C-
1
8
[
7]
18
cyanation of peptide-bound arylpalladium complexes. For F-
fluorination, multi-step labelling approaches are generally
required that involve the following key transformations executed
While the impact of prosthetic groups on radiopharma-
ceutical discovery has been profound, advanced knowledge of
structure-activity relationships is required to identify a suitable
1
8
in either order: i) incorporation of F onto a prosthetic group;
[
3,8]
and ii) coupling of a prosthetic group to the target peptide.
[
8,16]
site for prosthetic group attachment.
Additionally, this
approach can require complex protecting group strategies, multi-
step syntheses and face challenges with chemoselectivity.
Prosthetic groups also impact peptide structure, and can
negatively affect biological properties that include binding affinity
[∗]
Dr. Z. Yuan, Dr. M. B. Nodwell, Prof. R. Britton
Department of Chemistry, Simon Fraser University
Burnaby, British Columbia, Canada, V5A 1S6
E-mail: rbritton@sfu.ca
[
8,17]
and target specificity, as well as pharmacokinetic behaviour.
Dr. H. Yang, Dr. P. Schaffer
Thus, an ideal scenario would involve the direct and selective
Life Science Division, TRIUMF, Vancouver, BC, Canada, V6T 2A3
E-mail: pschaffer@triumf.ca
18
F-fluorination of a single C-H bond in a native peptide under
rapid, mild, and aqueous conditions. While important
1
8
19
Dr. N. Malik, H. Merkens, Dr. F. Bénard
contributions towards the selective F- and F-fluorination of C-
[
18]
Department of Molecular Oncology, BC Cancer Agency
Vancouver, British Columbia, Canada, V5Z 1L3
H bonds in peptides have been made, amine and carboxylic
acid protecting groups are mandatory. To the best of our
1
8
knowledge the only direct C-H F-fluorination of an unprotected
peptide was carried out on cyclic RGD peptide using
F]AcOF, and the extreme reactivity of this reagent resulted in
Dr. R. E. Martin
Medicinal Chemistry, Roche Pharma Research and Early
Development (pRED), Roche Innovation Center Basel, F. Hoffmann-
La Roche Ltd, Grenzacherstrasse 124, CH-4070 Basel, Switzerland
a
1
8
[
[19]
a mixture of fluorinated products. Here we show that a range
of unprotected and unaltered peptides can be directly labelled
[†]
These authors contributed equally
Supporting information for this article is available on the WWW
under http://
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.201806966
COMMUNICATION
1
8
with F using an inexpensive photocatalyst
and apparatus under mild aqueous reaction
conditions (Figure 1, inset).
2
0 examples
F
NaDT (2 mol%)
NFSI, MeCN-H2O
O
O
X
L
TFA H2N
OH
TFA H2N
OH
X
fL
N
H
N
H
1
8
hν (365 nm)
Our group has reported the direct F-
R
O
R
O
fluorination of several branched aliphatic
A. Charged side chains
B. Polar side chains
[
20]
amino acids
photoactivated
via
a
reaction involving
decatungstate
H
N
NH
NH2
O
NH2
fL
sodium
NH2
N
O
OH
NH2
HO
(
NaDT) as
a
hydrogen atom abstracting
N
H
HO
O
[
21,22]
agent
in combination with the fluorine
1
8
R
fL
1h: 50% 1h: 19%
h: 79% 6h: 54%
fL
R
K
fL fL
K
H
fL
D
fL
S
fL
T
fL
N
fL
Q
atom donor [ F]-N-fluorobenzenesulfonimide
1
8
[23,24]
1h: 62% 1h: 40%
6h: 82% 6h: 51%
1h: 29%
6h: 70%
1h: 59% 1h: 49%
6h: 85% 6h: 63%
1h: 47%
6h: 25%
1h: 62%
6h: 83%
1h: 56%
6h: 65%
(
[ F]NFSI).
considered the feasibility of using leucine
Leu (L)) as a native fluorination site in
Inspired by this advance, we
6
C. Hydrophobic side chains
(
O
HO
HN
S
peptides. An examination of the literature
revealed that Leu is uniquely susceptible to
NH
HS
H
CH3
fL
*
[
25-27]
C-H abstraction
and most commonly
G
fL
A
V
fL
I
fL
C
fL
M
fL
F
fL
Y
fL
W
fL
P
fL
forms carbon centered radical at the
a
[a]
[a]
[a]
1h: 9%[b] 1h: 21%
6h: 44% 6h: 48%
1
h: 61% 1h: 70% 1h: 57% 1h: 58%
1h: 0%
6h: 0%
1h: 5%
6h: 24%
1h: 0%
6h: 0%
1h: 56%
6h: 87%
[a]
[b]
branched (isopropyl) position. In our hands,
subjecting various amino acids (e.g., Glu (E),
Lys (K), Arg (R), Phe (F)) to NaDT
fluorination returned unreacted amino acid
without degradation. Encouraged by these
6h: 86% 6h: 81% 6h: 80% 6h: 85%
Figure 2. NaDT-promoted fluorination of Leu-containing dipeptides. Conversion at 1h (determined
by analysis of NMR spectra) and reaction yield after 6 h are reported. Product accompanied by
fluorination at a secondary site; accompanied by formation of sulfoxide or sulfonic acid. Note for
proline (P) the * denotes the carbon adjacent to the amide carbonyl. fLR and fLK refer to dipeptides
with Leu at the N-terminus. fL = 4-fluoroleucine.
[a]
[b]
results, we prepared
a series of Leu-
containing dipeptides to test the compatibility
positioning and amino acid compatibility. As indicated, while the
and kinetics of peptide fluorination. As detailed in Figure 2, the
selectivity of this reaction for the branched position of Leu
residues and compatibility with charged, polar and hydrophobic
amino acid residues is striking. For example, the charged amino
acids Arg, Lys, His (H) and Asp (D) all proved to be fully
compatible with both the photocatalyst and NFSI, and the
respective dipeptides underwent rapid and clean fluorination.
Likewise, dipeptides containing the amino acids Ser (S), Thr (T),
Asn (N) and Gln (Q) fluorinated cleanly, though the Thr-
containing dipeptide partially degraded after extended (6 h)
reaction times. Among the hydrophobic amino acids, dipeptides
incorporating Gly, Ala, Val (V), Ile (I), Pro (P) and Phe were all
compatible. Notably, the branched position in Val and Ile also
eventually underwent fluorination, however, in both cases the
amount of difluorinated peptide was only ~5% after 30 min. In
the case of the Tyr (Y)-containing dipeptide, the fluorination
proceeded smoothly, albeit at a decreased rate, while Trp (W)
proved to be incompatible. Reaction of a Met (M)-containing
dipeptide resulted in coincident oxidation at sulfur by NFSI and
afforded the corresponding sulfoxide fluorinated on the Leu
residue, while fluorination of a Cys (C)-containing dipeptide led
to a mixture of oxidation products. Considering, however, that
Cys, Met, and Trp are the rarest amino acids, their
incompatibility should not significantly impact the utility of this
peptide labelling strategy.
N-terminal Leu isomer LAEF underwent clean fluorination,
production of AEfLF (14) and EfLAF (15) were accompanied by
degradation. Established pathways for peptide hydrolysis by
[
28]
polyoxometalates notwithstanding, we speculated that here C-
H abstraction on Leu could be followed by intramolecular
abstraction of a benzylic hydrogen atom on a proximal Phe
residue and subsequent fragmentation; a process known to
[
29]
occur between Leu residues in short peptides. Notably, when
Phe was replaced with Gly (i.e., AELG), the resulting
tetrapeptide fluorinated in much improved yield (18: 41% yield
after 2 h). Two additional isomeric tetrapeptides consisting of
ARLF or LRAF were also fluorinated and again degradation was
only observed when Leu and Phe residues were proximal
(
ARLF) and not when separated (LRAF). We also examined
fluorination of the hexapeptide FALGEA-NH , a ligand for the
and were pleased to see
2
[
30]
cancer-specific receptor EGFRvIII,
that fluorination occurred cleanly on the Leu residue. Likewise,
fluorination of the pseudopeptide matrix metalloproteinase
[
31]
inhibitor marimastat,
the inhibitor of NAAG peptidase ZJ-43
21), as well as two structural analogues of ZJ-43 (22 and 23)
occurred on the Leu residue.
[
32]
(
1
8
Prior to examining the direct F-labelling of peptides, we
explored the use of three unique 365 nm photochemical reactor
[
33]
configurations
mm diameter) immersed in a custom photochemical reactor (8 x
W UV curing lamps), ii) a narrow bore PTFE tube wrapped
that comprised i) a borosilicate glass tube (5
To further examine the scope of this process, several
tetrapeptides containing Leu residues at various positions were
prepared and their fluorination examined. As highlighted in
Figure 3, Leu residues in GLKA, EKLA and GKLK, and C-
terminal Leu residues in KSGL, PAKL and AEFL were all
fluorinated selectively in yields varying from ~10-30% after 2 h.
Considering the decreased yield for AEFfL (12) (12% after 2 h),
we examined fluorination of positional isomers of this
tetrapeptide in an effort to deconvolute the influence of Leu
9
around a BLB lamp, and iii) a microreactor glass chip placed on
a transilluminator (see Supplementary Figures 1-3 for details).
As summarized in Figure
3 (inset), fluorination of the
tetrapeptide AELG was significantly improved in both the PTFE
tube reactor and microreactor. In fact, after one hour this
reaction was near complete in the microreactor (86%
conversion). Likewise, fluorination of the dipeptides HL and DL
reached 82% and 98% conversion, respectively, after 1 h in the
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Angewandte Chemie International Edition
10.1002/anie.201806966
COMMUNICATION
microrector. Here,
a combination of
Leucine with charged amino acids (yield after 2 h)
increased surface area and light
NH2
O
NH2
O
NH2
F
intensity
clearly
benefits
Leu
[
33]
O
O
O
O
fluorination.
H
N
H
H
H2N
OH H N
N
OH H N
N
OH
2
2
N
N
N
N
H
N
N
H
1
8
H
H
H
H
To explore the F-fluorination of
unprotected peptides we further
optimized the synthesis of [ F]NFSI
O
O
O
O
O
O
F
F
GfLKA (7: 29%)
NH2
EKfLA (8: 16%)
GKfLK (9: 17%)
1
8
HO
O
[
23]
Leucine at C-terminus (different AA cohort, yield after 2 h)
reported by Luthra and Gouverneur,
O
OH
1
8
F
F
F
and ultimately, [ F]NFSI was produced
as solution in MeCN with
OH
O
OH
N
O
O
O
O
O
H
N
H
N
H
N
a
a
H2N
OH
OH H N
OH
2
N
H
N
H
N
H
N
H
N
H
radiochemical purity >90%. An aqueous
mixture of the peptide and NaDT
catalyst were then added to an MeCN
O
O
O
O
O
O
NH2
KSGfL (10: 20%)
PAKfL (11: 33%)
NH2
AEFfL (12: 12%)
1
8
Leucine at N-terminus or internal positions (same AA cohort, yield after 2 h)
solution of [ F]NFSI (no azeotropic
drying required) and the solution was
irradiated for 40 min in a narrow-bore
PTFE tube or in a microreactor. As
summarized in Figure 4, we observed
O
OH
F
O
O
O
O
O
O
H
N
H
N
H
N
H2N
OH H2N
OH H2N
OH
N
H
N
H
N
H
N
H
N
H
N
H
O
O
O
O
O
O
excellent
radiochemical
conversion
F
F
fLAEF (13: 33%)
AEfLF (14, 20%)
12% degradation
EfLAF (15: 41%)
9% degradation
1
8
O
OH
O
OH
(
RCC) in the
F-fluorination of
1
8
Probing the degradation of Leu-Phe containing peptides (yield after 2 h)
dipeptides, producing the
F-labelled
H
H
dipeptides 24 – 27 with no detectable
epimerization or fluorination at other
sites. The radiochemical yield (RCY,
H2N
O
N
H2N
O
N
O
OH
NH
NH
O
O
O
O
H
H
H
H2N
N
OH
H2N
N
OH
H2N
N
OH
1
8
N
H
N
H
N
H
N
H
N
H
N
H
decay corrected from [ F]NFSI) for
these processes were comparable or
better than those reported previously by
us for the radiofluorination of branched
O
O
O
O
O
O
ARfLF (16: 14%)
0% degradation
F
F
fLRAF (17: 15%)
<1% degradation
AEfLG (18: 41%)
<1% degradation
F
1
reactor
surface/volume conv.
Bioactive molecules (yield after 2 h)
2
configuration ratio (cm /mL) at 1 h
[
20]
O
O
O
F
aliphatic amino acids.
demonstrated the radiofluorination on a
small series of Leu-containing
tetrapeptides, and in each case the
We next
H
N
H
N
OH
NMR tube
H2N
NH2
O
N
(1400 µW cm-1)
9.4
36%
N
H
N
H
N
H
H
N
O
O
O
N
H
O
PTFE tube
(1500 µW cm-1)
57.8
28.8
67%
86%
F
O
OH
microreactor
O
OH
(>6000 µW cm-1)
marimastat (matrix
metalloproteinase inhibitor)
1
8
RCC was >25% and
F-labelled
For images and full description of each
reactor see Supplementary Information
ligand for cancer-specific receptor EGFRvIII
[a]
[a]
1
9 (25%
)
20 (14% )
tetrapeptides 28–30 were isolated in
RCYs ranging from 16 to 35%. The
EGFRvIII-targeting peptide FALGEA-
NH2
O
O
OH
O
O
OH
O
O
OH
F
F
F
HO
O
[
30]
NH
providing [ F]FAfLGEA-NH
10%) after ~80 min total radiosynthesis
2
was also directly radiofluorinated
H
N
H
N
HO
OH
OH
1
8
N
H
N
H
OH
N
H
N
H
2
(31) (RCC
N
H
N
H
O
O
O
O
O
O
~
HO
O
HO
O
NAAG peptidase inhibitor
fluoro-ZJ-43)
22 (35%[c]
)
23 (69%[c]
)
time. This last result compares well to
previous labelling studies of FALGEA-
(
fluorinated anlogues of NAAG peptidase inhibitor ZJ-43
[a,b]
21 (16%
)
NH
2
that involved coupling with the
Figure 3. Fluorination of Leu-containing tetrapeptides. Yields were determined using the ERETIC
1
8
18
[38]
[
F]fluorobenzoic
acid
([ F]FBA)
method
after 2 hours of irradiation in a borosilicate glass NMR tube immersed in a custom
photochemical reactor (Supplementary Figure 1). Degradation refers to the formation of other
prosthetic group and proceeded with
RCYs ranging from of 2.6-9.8% (decay
[a]
fluoroleucine-containing products. Reaction in a PTFE tube reactor system (Supplementary Figure 2);
[b]
[c]
1
reaction time = 3 h; Yield determined by analysis of H NMR spectra with internal standard after 6 h.
[
34]
corrected) after a 3 h radiosynthesis.
Finally, the NAAG peptidase inhibitor ZJ-43
fluorinated to provide 32, and fluorination of a homologated
−
1
[
32]
1.3–5.3 MBq µmol , significant improvements in SA can be
was directly
1
8
2
achieved by lengthening the proton irradiation time on [ O]O .
1
8
−1
1
8
2
Moroever, [ F]F with SAs up to 55 GBq µmol can be
analogue afforded the F-labelled peptide 33. We note that
[
36]
1
8
prepared using a process described by Bergman and Solin,
these are the only examples of prostethic group free F-
fluorination within this important family of prostate cancer
1
8
and [ F]NFSI produced via this method has a SA of 10.3 GBq
−
1 [37]
[
35]
µmol .
imaging agents. Importantly, analysis of the biodistribution of
1
8
[
F]ZJ-43 (32) in healthy mice showed low bone accumulation
In summary, we have developed a versatile and direct,
1
8
(
1.7% ID/g) suggesting that the peptidic [ F]fluoroleucine
aqueous approach for radiofluorination of unprotected Leu-
containing peptides that does not rely on prosthetic groups. This
unique approach, successfully demonstrated on 10 peptides, is
amenable to radiopharmaceutical production with mild reaction
conditions, a simple fluid path and column-based purification.
fragment is not susceptible to the same degradation pathways of
1
8
[
F]fluoroleucine itself, which displays significant bone
[
20]
accumulation (11.9% ID/g). While the specific activitiy (SA) of
1
8
F-labelled peptides 24–33 produced in this study ranged from
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Angewandte Chemie International Edition
10.1002/anie.201806966
COMMUNICATION
18F
18F
18F
18F
[10] G. Vaidyanthan, M. R. Zalutsky, Nat. Protoc. 2006, 1,
1655.
O
O
O
O
H
2
N
OH
H
O
N
OH
H N
OH
H N
OH
2
2
2
[11] D. M. Perrin, Acc. Chem. Res. 2016, 49, 1333.
[12] C. Wängler, S. Niedermoser, J. Chin, K. Orchowski, E.
Schirrmacher, K. Jurkschat, L. Iovkova-Berends, A. P.
Kostikov, R. Schirrmacher, B. Wängler, Nat. Protoc. 2012,
N
N
N
H
N
H
H
H
O
O
O
O
NH
2
NH
2
PTFE tube
4: RCC = 35% ±4%
RCY = 24% ±3% (n = 4) RCY = 40% ±4% (n = 4) RCY = 37% ±1% (n = 3)
PTFE tube
microreactor (15 min)
26: RCC = 54% ±6%
microreactor (15 min)
27: RCC = 55% ±5%
RCY = 27% ±7% (n = 3)
2
25: RCC = 51% ±5%
7
, 1946.
[
13] W. J. McBride, R. M. Sharkey, H. Karacay, C. A.
O
OH
18F
18F
D’Souza, E. A. Rossi, P. Laverman, C.-H. Chang, O. C.
Boerman, D. M. Goldenberg, J. Nuc. Med. 2009, 50, 991.
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P. A. Schubiger, S. M. Ametamey, K. Graham, T. Stellfeld,
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Srinivasan, R. Smits, B. Koksch, Bioconjugate Chem.
2009, 20, 2254.
O
O
O
O
H
N
H
N
O
O
H
OH
2
N
OH
OH
H
N
N
H
N
H
N
H
N
H
H
N
2
N
H
N
H
O
O
NH
2
O
O
O
O
NH
2
18F
microreactor
8: RCC = 26 % ±2%
microreactor
29: RCC = 45 ±4%
O
OH
microreactor
2
30: RCC = 35 ±1%
RCY = 26% ±1% (n = 3)
RCY = 16% ±2% (n = 3)
RCY = 35% ±1% (n = 3)
O
O
OH
[
15] a) S. Verhoog, C. Wee Kee, Y. Wang, T.
18F
NAAG peptidase inhibitor:
Khotavivattana, T. C. Wilson, V. Kersemans, S. Smart, M.
18
[
F]ZJ-43 microreactor
O
O
O
Tredwell, B. G. Davis, V. Gouverneur, J. Am. Chem. Soc.
H
H
N
HO
OH
3
2: RCC = 17% ±2%
H
2
N
N
NH
2
N
H
N
H
2
018, 140, 1572; b) N. Ichiishi, J. P. Caldwell, M. Lin, W.
N
N
N
RCY = 14% ±2% (n = 3)
H
H
O
O
O
O
O
Zhong, X. Zhu, E. Streckfuss, H.-Y. Kim, C. A. Parish, S.
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NH
2
18F
O
O
OH
O
OH
18F
ligand for cancer-specific receptor
analogue of [18F]ZJ-43
PTFE tube
F
1
8
EGFRvIII: [ F]FAfLGEA-NH
microreactor
2
H
N
OH
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Imaging 2012, 39, S11.
3
3: RCC = 27% ±4%
N
H
N
H
3
1: RCC = 10 ±2%
RCY = 8% ±1% (n = 3)
RCY = 24% ±4% (n = 5)
O
O
HO
O
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18
Figure 4. Direct site-selective F-fluorination of unprotected peptides. Reaction conditions:
18
peptide·TFA, NaDT (2 mol%),
2
[ F]NFSI, MeCN-H O, hν (365 nm), 40 min. See
Supplementary Information for full experimental details.
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This work was supported by an NSERC Discovery Grant (R.B.), a
MSFHR Career Investigator Award (R.B.), a MSFHR I2I Grant (R.B.),
a Hoffmann-La Roche Fellowship (M.B.N.) and a CCSRI Innovation
Grant (PS). The authors thank the TRIUMF TR13 cyclotron team, in
particular David Prevost, Linda Graham and Samuel Varah. TRIUMF
receives federal funding via a contribution agreement with the
National Research Council of Canada.
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Keywords: F-fluorination, peptides, PET imaging, photocatalysis,
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COMMUNICATION
This article is protected by copyright. All rights reserved.