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V. J. Majo et al. / Bioorg. Med. Chem. Lett. 23 (2013) 4191–4194
to human study is not practical as the imaging probe requires days
for equilibration, and offer poor target/nontarget contrast due to
the expression of IGF-1R in normal tissues. There have been unsuc-
cessful attempts to image IGF-1R antibodies with quantum dots
using fluorescent techniques.23,34,35 IGF-1R based PNA has been re-
cently radiolabeled with 64Cu and 99mTc and tested in IGF-1R over-
exchange reaction with cold BMS-754807 under microwave condi-
tions using [18F]KF/K222. However, the bromo precursor 1a did not
undergo radiofluorination using [18F]KF/K222 under thermal or
microwave conditions (Scheme 1). However, the radioproduct
was obtained in 8% yield by treating bromo precursor 1a with
[
18F]TBAF in DMSO at 170 °C in high radiochemical purity (>95%)
expressing breast cancer xenografts in mice.36,37
A
few
and specific activity (1–2 Ci/
fluorination via the displacement of 2-bromo pyridyl system with-
out using catalyst is widely reported in literature.47 18F]TBAF was
l
mol).49 Nucleophilic aromatic radio-
radioligands based on IGF-1R selected antibody have been labeled
with 111In and show modest tumor uptake and tumor to blood ra-
tio.38 Recently, [18F]FDG and [18F]FLT have been employed to ac-
cess response to IGF-1R inhibitors in preclinical and human
subjects.39–41
[
in situ generated from freshly prepared tetrabutylammonium
bicarbonate by azeotropic distillation with [18F]fluoride. Tetrabu-
tylammonium bicarbonate in turn was freshly prepared by bub-
bling carbon dioxide from dry ice into tetrabutylammonium
hydroxide (4 mL, 13% by weight in water, 0.5 M) for 4 h at room
temperature. The radioproduct was stable in 10% ethanol–saline
solution for over 6 h. The experimental partition coefficient (logP)
of [18F]1 was measured as 2.8, indicating that the radioligand has
adequate lipophilicity for brain imaging.50
Some of the ligands listed above show promise for imaging IGF-
1R, but do not cross the blood brain barrier (BBB) and hence are
limited to use in imaging studies outside the brain. To quantify
binding to IGF-1R in brain requires development of selective non-
peptide PET ligands. High affinity, lipophilic TKRIs of IGF-1R are po-
tential candidates for developing such imaging agents. We have
screened a large number of TKRIs for this purpose and identified
BMS-754807 as a small molecule dual inhibitor of IGF-1R/insulin
receptor (IR), that has been clinical evaluation, as a lead ligand
for imaging using PET.42–44 BMS-754807 (1) is an orally bioavail-
able, potent and reversible small molecule inhibitor of the IGF-
1R/IR family kinases (Ki <2 nmol/L), which is currently in phase II
clinical trial for the treatment of a variety of human cancers.42–46
The selectivity of compound 1 over other kinases, presence of met-
abolically stable fluorine in the 2-substituted pyridine ring, which
is amenable for radiolabeling using nucleophilic displacement with
After optimizing the synthesize of [18F]1, the proof of concept of
IGF-1R imaging with the radiotracer was performed in surgically
removed and pathologically identified grade IV-glioblastoma,
breast cancer and pancreatic tumor using phosphor imager autora-
diography (Fig. 1).51–53 Pathologically identified frozen sections of
glioblastoma IV, pancreatic tumor and breast cancer were used
for phosphor image studies. The slide mounted tumor sections
were brought to room temperature and incubated with [18F]1
(0.1 nM) for 1 h.54 The adjacent sections were incubated with
1 lM of GSK1838705A, a specific IGF-1R ligand to determine non-
[
18F]fluoride47 and a calculated lipophilicity (clogP) 3.5, prompted
specific binding. After incubation, sections were washed, dried and
exposed to phosphor imaging screen. As evident from Figure 1,
there is specific binding of [18F]1 in the three tumor/cancer tissues
tested. Grade IV gliobalstoma shows higher tracer uptake and spe-
cific binding in comparison to pancreatic tumor and breast cancer
tissues. The binding rations of total verses nonspecific binding ob-
tained are 5.25 (N = 9), 1.92 (N = 4) and 1.7 (N = 4) for grade IV glio-
blastoma, pancreatic tumor and breast cancer, respectively.
In summary, we successfully synthesized [18F]1, a potential
imaging agent for IFG-1R. The total time required for radiosynthe-
sis was 60 min from EOS in 8% yield with excellent chemical and
radiochemical purities and specific activity. Autoradiography stud-
ies by phosphor imaging indicate that [18F]1 binds to IGF-1R of
us to choose it as a candidate radiotracer for imaging IGF-1R with
PET.
BMS-754807 (1) and the corresponding bromo precursor (1a)
for radiosynthesis, were prepared based on modification of a pub-
lished procedure.45 Preferential displacement of the C-4 chloride in
compound 4 with 5-cyclopropyl-1H-pyrazol-3-amine (5) followed
by displacement at C-2 position with (S)-2-methylpyrrolidine-
2-carboxylic acid gave the corresponding carboxylic acid 7 in two
steps with 65% yield. The carboxylic acid was then condensed with
6-bromopyridin-3-amine or 6-fluoropyridin-3-amine to yield the
precursor 1a or the standard 1 in 78–70% yield (Scheme 1).48
Radiosynthesis of [18F]BMS-754807 was initially optimized by
H
O
N
N
Cl
H
OH
N
N
HN
N
H
N
+
DIPEA
N
H2N
N
N
Cl
2-propanol, rt
NMP, KOtBu, 180 ºC
N
N
Cl
4
5
6
H
N
H
N
N
N
N
HN
HN
1. SOCl2, DMF
N
X
HO
O
N
O
2.
N
H
N
X
N
N
N
N
N
N
1 X = F
H2N
7
1a X= Br
H
N
N
18F]TBAF
DMSO, 170 o
[
18F]F-, MW
or Heat
HN
[
N
18F
O
1
1a
N
C
N
H
N
N
N
[
18F]BMS754807 ([18F]1)
Scheme 1. Synthesis and radiosynthesis of BMS-754807 and [18F]BMS-754807.
Majo, Vattoly J.
