Synthesis of a 68Ga-labeled peptoid?peptide hybrid for imaging of neurotensin receptor expression in vivo

Article abstract of DOI:10.1021/ml1000728

The neurotensin receptor subtype 1 (NTS1) represents an attractive molecular target for imaging various tumors. Positron emission tomography (PET) gained widespread importance due to its sensitivity. We combined the design of a metabolically stable neurotensin analogue with a ⁶⁸Ga-radiolabeling approach. The ⁶⁸Ga-labeled peptoid?peptide hybrid [⁶⁸Ga]3 revealed high stability, specific tumor uptake (0.7%ID/g, 65 min p.i.), and advantageous biokinetics in vivo using HT29 tumor-bearing nude mice. Because of the ability to internalize into NTS1-expressing tumor cells, [⁶⁸Ga]3 proved to be highly suitable for a reliable and practical visualization of NTS1-expressing tumors in vivo by small animal PET.

Full text of DOI:10.1021/ml1000728

pubs.acs.org/acsmedchemlett
Synthesis of a 68Ga-Labeled Peptoid-Peptide Hybrid
for Imaging of Neurotensin Receptor Expression in Vivo
†
‡
†
‡
†
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Simone Maschauer, Jurgen Einsiedel, Carsten Hocke, Harald Hubner, Torsten Kuwert,
Peter Gmeiner,‡ and Olaf Prante*,†
†Laboratory of Molecular Imaging, Clinic of Nuclear Medicine, Friedrich-Alexander University, Schwabachanlage 6,
D-91054 Erlangen, Germany and ‡Department of Chemisty and Pharmacy, Emil Fischer Center,
Friedrich-Alexander University, Schuhstrasse 19, D-91052 Erlangen, Germany
ABSTRACT The neurotensin receptor subtype 1 (NTS1) represents an attractive
molecular target for imaging various tumors. Positron emission tomography (PET)
gained widespread importance due to its sensitivity. We combined the design of a
metabolically stable neurotensin analogue with a 68Ga-radiolabeling approach.
The 68Ga-labeled peptoid-peptide hybrid [68Ga]3 revealed high stability, specific
tumor uptake (0.7%ID/g, 65 min p.i.), and advantageous biokinetics in vivo using
HT29 tumor-bearing nude mice. Because of the ability to internalize into NTS1-
expressing tumor cells, [68Ga]3 proved to be highly suitable for a reliable and
practical visualization of NTS1-expressing tumors in vivo by small animal PET.
KEYWORDS Neurotensin, neurotensin receptor, peptide, positron emission tomo-
graphy (PET), gallium-68
ositron emission tomography (PET) has emerged as an
imaging modality with superior sensitivity. It has been
used to study the expression and activity of a variety of
very few radiolabeled peptides suitable for PET imaging
studies have been developed so far.2 Thus, the majority of
peptide receptors that are potential molecular targets for
imaging of, for example, tumor response or tumor progres-
sion, have not yet been addressed by adequate peptide-
based PET imaging probes.
P
molecular targets such as receptors in vivo.1 Bioactive pep-
tides that specifically recognize their corresponding recep-
tors in vivo represent a class of PET tracers with growing
importance for imaging therapy response in the clinical
surrounding.2 To date, the majority of peptide-based radio-
pharmaceuticals are labeled with single photon emitters,
such as technetium-99 m, indium-111, or iodine-123. Pro-
minent examples are a 99mTc-labeled bombesin derivative
([99mTc]Leu13-BN), [111 In]octreotide (OctreoScan), or 123I-
labeled vasoactive intestinal peptide ([123I]VIP).2 Recent
progress has also been achieved with regard to labeling
peptides with the positron emitter 18F (t1/2 = 110 min).2,3
These approaches include rapid, chemoselective ligation
methods with 18F-labeled prosthetic groups.4 One major
obstacle to developing and using PET tracers of peptide
receptors is the limited availability of the radionuclides
suitable for PET imaging. One solution to this problem is
offered by the 68Ge/68Ga generator,5,6 providing frequent
and easy access to the short-lived 68Ga isotope (t1/2=68 min)
multiple times a day within the generator's lifetime of about
1 year. Therefore, the 68Ge/68Ga generator system provides
increased availability of the short-lived 68Ga and significant
cost reduction in comparison with cyclotron-produced positron
emitters, such as 18F. The chemistry of 68Ga relies on the use
of chelators that provide advantages, such as the use of very
low amounts of chelator-linked peptides in aqueous buffer
solution for quantitative radiolabeling reactions. However,
The pivotal role of neurotensin (NT) and its receptors
(NTS1, NTS2, and NTS3) in oncogenesis relies on auto-
crine, paracrine, and endocrine mechanisms. The crucial
importance of the NTS1 expression has been demon-
strated for various types of human tumors, such as breast
cancer, prostate cancer, and colorectal tumors.7 The NT
carboxy terminus NT(8-13) represents the truncated
binding sequence of the natural agonist NT; however,
the versatility of NTS1 imaging agents derived from
NT(8-13) is frequently hampered by the low resistance
of NT(8-13) toward degradation by endogenous pepti-
dases. Avariety of studies addressed this issue by modify-
ing the amino acid sequence of NT(8-13).7 Among these,
radiolabeled peptide candidates for therapy and in vivo
imaging applications by single photon emitter tomogra-
phy (SPECT) have been developed.8-15 However, PET
offers significant advantages over SPECT, such as impro-
ved spatial resolution and sensitivity combined with the
option to quantify tracer concentration in absolute units
in vivo.16
Received Date: April 13, 2010
Accepted Date: May 14, 2010
Published on Web Date: May 21, 2010
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Scheme 1a
Figure 1. Chemical structure of the glycopeptoid [18F]FGlc-NT419
and the DOTA-conjugated derivative [68Ga]3.
On the basis of our studies on the influence of peptide
backbone modifications and ligand conformation on affinity
changes for a series of NT(8-13) analogues,17,18 we recently
discovered a metabolically stabilized amino acid sequence
by alteration of three amino acids in the sequence of NT-
(8-13), most importantly including the replacement of the
N-terminal Arg-Arg by the peptoid-like residue N-(4-amino-
butyl)Gly-Lys (NLys-Lys).17,19 These studies led to the char-
acterization of the first metabolically stable 18F-labeled NTS1
imaging probe for PET ([18F]FGlc-NT4; see Figure 1) whenwe
applied the strategy of an efficient click chemistry-based 18F-
labeling and glycosylation method20 to a NT(8-13) related
amino acid sequence. The 18F-glycopeptide mimetic [18F]-
FGlc-NT4 displayed a Ki value of 16 nM for hNTS1 and was
successfully applied to small-animal PET (μPET) studies for
imaging hNTS1 expression in vivo.19 However, [18F]FGlc-
NT4 showed high kidney uptake in vivo and suffered from
insufficient clearance properties. Because elongation of the
N-terminal ending of NT(8-13) is generally well-tolerated
with respect to NTS recognition, we aimed at the synthesis of
an N-terminal chelator-linked peptoid-peptide hybrid, which
could provide both the opportunity for simple 68Ga-radiolabel-
ing by the formation of stable complexes with 68Ga and impro-
ved biokinetic properties of the resulting 68Ga-labeled peptide
mimetic [68Ga]3 (Figure 1).
a Reagents and conditions: (a) (1) Piperidine/DMF (1:4), μ∼:5 ꢀ 5s, 100 W,
5ꢀ cooling to -10 °C; (2) Fmoc-tLeu-OH, PyBOP, DIPEA, HOBt, DMF, μ∼:
15 ꢀ10s, 50 W, 15ꢀ cooling to -10 °C. (b) (1) Fmoc deprotection (see a);
(2) Fmoc-Tyr(OtBu)-OH, HATU, DIPEA, DMF, μ∼-assisted coupling (see a).
(c) (1) Fmoc deprotection (see a); (2) Fmoc-Pro-OH (for coupling condi-
tions, see a), successively repeated with Fmoc-Lys(Boc)-OH, N-Fmoc-
N-(4-Boc-aminobutyl)-Gly-OH, DOTA-trit-Bu-ester. (d) (1) H2SO4/dioxan
(1:9), 8 °C, 2 h; (2) 30% v/v DIPEA in CH2Cl2; (3) TFA, phenol, H2O,
triisopropylsilane 88:5:5:2, 2 h, followed by RP-HPLC. (e) 1.2 equiv of
Ga(NO3)3 ꢀ H2O, sodium acetate buffer, pH 4.5, 90 °C, 15 min, followed
by the addition of 0.2 equiv of Ga(NO3)3 ꢀ H2O, 90 °C, 3 min, followed by
RP-HPLC. (f) [68Ga]GaCl3 (200 MBq, 400 μL), 2 (20 nmol), acetate buffer,
pH 4.5, 95 °C, 10 min, >98% (RCY).
The peptide coupling of Fmoc-Tyr(tBu)-OH to the sterically
demanding t-leucyl residue was achieved by activation with
HATU. The attachment of the chelator 1,4,7,10-tetraazacy-
clododecane-1,4,7,10-tetraacetic acid (DOTA) was performed
employing the commercially available tri-t-butyl ester deriva-
tive. Microwave acceleration proved to be advantageous for
both Fmoc deprotection of the resin and acylation to afford
1 (Scheme 1). The direct cleavage of the peptide from the
resin with TFA resulted in the formation of hardly separable
t-butylated byproducts. This obstacle was overcome by
following a previously reported protocol using 10% sulfuric
acid in dioxan at 8 °C, which allowed us to safely remove the
t-butyl-based protective groups while preventing liberation
of the peptide from the solid support.21 Thereafter, TFA-mediated
We here report the first 68Ga-labeled NTsurrogate suitable
for imaging of NT receptor expression in vivo by PET. After
demonstration of binding affinity to hNTS1, radiolabeling
with 68Ga, and investigation of metabolic stability in vitro,
[
68Ga]3 was successfully applied to biodistribution and μPET
studies using a HT29 xenograft nude mice model.
Our plan of synthesis was based on our previous publica-
tions on metabolically stabilized NT(8-13) derivatives
(Scheme 1).17,19 In detail, we applied solid-phase methods
with repetitive cycles of Fmoc deprotection with piperid-
ine and acylation with the Fmoc-protected amino acids in
the presence of PyBOP/HOBt, thus allowing us to incorpo-
rate t-leucine, proline, lysine, and N-(4-aminobutyl)-glycine.
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Table 1. Receptor Binding Data of NT Analogues in Comparison
with the Reference NT(8-13) as Determined by Displacement of
[3H]NT Using hNTS1-Expressing CHO Cellsa
Figure 2. Time dependency of internalization of [68Ga]3 in HT29
cells. Data are expressed as mean values ( SDs from two inde-
pendent experiments, each performed in quadruplicate.
(20 nmol, acetate buffer, pH 4.5) at 95 °C (Scheme 1). The
68Ga-labeled peptide complex [68Ga]3 was obtained in a
radiochemical yield (RCY) and purity of >98% (radio-
HPLC) within a total synthesis time of only 16 min. Because
of the low amount of the peptide precursor (2, 20 nmol)
that was needed for the labeling reaction and the low NTS1
affinity of 2, we could omit a time-consuming subsequent
HPLC separation of 2 and [68Ga]3. The use of aqueous
buffer allowed an easy formulation of [68Ga]3 by pH
adjustment of the final product solution and a sufficient
radioactivity concentration for further experimental use.
The specific activity of [68Ga]3 was about 10 GBq/μmol at
the end of radiosynthesis, rendering [68Ga]3 suitable for
PET imaging of apparently high NT receptor densities on
tumors grown as subcutaneous xenografts.
a Ki values are based on the means of 2-7 individual experiments,
each done in triplicate. b Ki ( SEM (nM). c Values are from ref 19. d Ki (
SD (nM).
cleavage furnished the DOTAderivative 2 sufficiently pure to
allow successful high-performance liquid chromatography
(HPLC) purification.
The synthesis of the Ga complex 3 was accomplished by
stirring 2 with an excess of Ga(NO3)3 (1.4 equiv) in acetate
buffer (pH 4) at 90 °C, followed by RP-HPLC purification
(Scheme 1). Electrospray ionization-mass spectrometry re-
vealed the [M]þ peak of 3, confirming previous studies on
DOTA-conjugated peptides with one free deprotonated carbox-
ylate group at physiological pH that does not participate with
the pseudo-octahedral geometry of the Ga-DOTA complex.
After confirmation of the high purity of 3 (>99%) by liquid
chromatography-mass spectrometry (LC-MS), we proceeded
with NT receptor binding studies using a Chinese hamster
ovary (CHO) cell line, stably expressing the human NTS1 as
described previously.19 The Ga-DOTA conjugate 3 turned out
to be significantly less potent in comparison with NT(8-13)
and the previouslydescribed fluoroglycosyl-conjugated peptide
mimetic FGlc-NT4 (Table 1). Notably, the DOTA-linked precur-
sor 2 displayed a 13-fold lower NTS1 affinity when compared
with the Ga-DOTAcomplex 3. Thus, small amounts of 2 within
the radiolabeled product solution of [68Ga]3 could be tolerated
without significantly suppressing the specific binding of [68Ga]3
in vivo. The Ki values of 3 and FGlc-NT4 differed by a factor of
10. This effect could be due to the sterically demanding
Ga-DOTA moiety directly linked to the pharmacophoric resi-
due 8 of the parent peptide.14 On the other hand, the ability of
agonist ligands to internalize into tumor cells via NTS1 could
provide sufficient tumor labeling in vivo, even for ligands with
lower affinities. Thus, we continued our efforts on the develop-
ment of the 68Ga-labeled analogue.
After the successful radiosynthesis of [68Ga]3, we turned
our attention to the stability of the 68Ga-labeled NTanalogue
toward degradation by peptidases present in serum. The
stability of [68Ga]3 was investigated in human serum at 37 °C.
The HPLC data indicated high metabolic stability of 96% after
an incubation time of 60 min (see the Supporting Information).
Moreover, the lipophilicity (logD7.4) of [68Ga]3 was determined
to be -4.35 ( 0.26 (n =6), and internalization studies with
[68Ga]3 were performed in vitro using HT29 cells. The HT29 cell
line is a human colon cancer cell line that expresses the hNTS1
similarly to cells from normal intestinal mucosa.22 The inter-
nalization rate of the [68Ga]3/NTS1 complex into HT29 cells was
approximately 70% as determined by the acid wash pro-
cedure19,23 after incubation with the tracer for 30 min at room
temperature (Figure 2). The ability of [68Ga]3 to internalize
in vitro suggested enhanced retention of this tracer in NTS1-
expressing tumors in vivo, thus prompting us to perform
biodistribution studies.
We investigated the biodistribution of [68Ga]3 in HT29
xenografted nude mice at 10, 30, and 65 min postinjection
(p.i.; Figure 3). [68Ga]3 demonstrated metabolic stability in
vivo (90% intact tracer in blood, 10 min p.i.; see the
Supporting Information), fast blood clearance, high uptake
in the kidneys, and low uptake in the liver, suggesting that
hepatobiliary clearance of [68Ga]3 did not play a role. The
markedly dominating excretion kinetics of [68Ga]3 occurred
via fast renal clearance (Figure 3a). This notion is consistent
with various other studies on DOTA-conjugated peptides,23,24
reflecting the effect of the free carboxylate group of the DOTA
The radiosynthesis of [68Ga]3 was performed by the addition
of an aliquot of the [68Ga]GaCl3 eluate, freshly obtained from
the 68Ge/68Ga generator, to an aqueous-buffered solution of 2
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Figure 4. Static μPET images (transaxial and coronal projections)
of HT29 tumor-bearing nude mice at 45-65 min postinjection of
[
68Ga]3 with (right) and without (left) coinjection of NT4 (100 μg/
mouse) (a) (white arrows indicate the tumor). Statistical analysis of
the animal group injected with the tracer alone ([68Ga]3, n = 3)
and the coinjected animals ([68Ga]3 þ NT4, n = 4) (b). Maximum
standard uptake values (SUV) were determined by μPET data
analysis of the tumor region in each animal using the software
ASI Pro. Data are expressed as mean values ( SDs from all animals
in each group.
Figure 3. Biodistribution of [68Ga]3 in nude mice bearing HT29
xenografts (a) and tumor/blood ratio (b). Data are expressed as mean
values ( standard deviations (SDs) from 3 to 4 animals [*P <
0.05, 65 min p.i.: 0.72 ( 0.18% ID/g (n = 3) vs 0.34 ( 0.17% ID/g
(n = 4)].
subcutaneous xenografts, when 20 min static PET images were
acquired at 45 min after injection. For each PETscan, regions of
interest were drawn around the tumor and analyzed on decay-
corrected whole-body coronal images. The statistical analysis of
the animal group injected with the tracer alone (n=3) and the
coinjected animals (n=4) confirmed the results obtained by the
dissection analysis and revealed a significantly reduced stan-
dard uptake value (SUV) for the tumor region in coinjected
animals (Figure 4b). These results provide evidence for the
specificity of [68Ga]3 for imaging NTS1 expression in vivo.
In conclusion, we successfully developed [68Ga]3 as the
first 68Ga-labeled tracer for imaging NTS1 expression in vivo
by PET. Our data confirmed that the in vitro binding affinity
of a radiotracer candidate is not the only parameter that
determines its suitability for in vivo imaging applications.
Other factors such as the ability to internalize into cells or its
lipophilicity also contribute to the in vivo binding potential of
a suitable peptide radiopharmaceutical. Using [68Ga]3 as
a lead compound, work is in progress toward the develop-
ment of analogues with high NTS1 binding affinity to facili-
tate PET imaging of low receptor densities in vivo. We
anticipate that [68Ga]3 and derivatives thereof have the
potential to become valuable imaging agents for the ex-
ploration of NTS1 expression in various tumor types by
experimental small animal PET and potentially in human
PET imaging studies.
chelator that is unprotonated under physiological conditions.
Most importantly, [68Ga]3 showed significantly lower kidney
uptake and an improved kidneyclearance[14.1% ID/g (10 min
p.i.); 8.1% ID/g (65 min p.i.); Figure 3a] when compared to the
previously described [18F]FGlc-NT4 [data from ref 19: 57.1%
ID/g (10 min p.i.); 50.0% ID/g (65 min p.i.)]. The uptake of
[68Ga]3 in HT29 tumors was similar (1.2% ID/g at 30 min p.i.;
0.7% ID/g at 65 min p.i.) to our 18F-labeled glycopeptide
mimetic,19 with tumor/blood ratios rapidly increasing from
1.1 to 5.4 (10-65 min p.i.; Figure 3b). This indicates a suitable
signal/noise ratio for in vivo imaging applications at early time
points after injection. The in vivo specificity of NTS1-mediated
uptake of [68Ga]3was proven by the analysis of tumor uptake in
animals that were coinjected with [68Ga]3 and the high affinity
NTS1 ligand NT419 (Table 1; 100 μg/animal). The coinjected
animals revealed a significantly reduced tumor uptake in the
biodistribution studies at 65 min p.i. (P < 0.05; Figure 3a).
Using a μPETscanner and HT29 tumor-bearing nude mice,
we also demonstrated the specific visualization of NTS1 expres-
sion in vivo by [68Ga]3 (Figure 4). One day after administration
of [68Ga]3 in a first PETscan, the experiment was repeated with
the same animal coinjected with [68Ga]3 and an excess of NT4.
A representative set of PET images including transaxial and
coronal image projections is shown in Figure 4a, clearly indicat-
ing specific binding of [68Ga]3 in HT29 tumors grown as
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SUPPORTING INFORMATION AVAILABLE Complete ex-
perimental procedures and characterization data for compounds
1-3 and [68Ga]3. This material is available free of charge via the
Internet at http://pubs.acs.org.
(11) Nock, B. A.; Nikolopoulou, A.; Reubi, J. C.; Maes, V.; Conrath,
ꢀ
P.; Tourwe, D.; Maina, T. Toward stable N4-modified neuro-
tensins for NTS1-receptor-targeted tumor imaging with
99mTc. J. Med. Chem. 2006, 49, 4767–4776.
(12) Zhang, K.; An, R.; Gao, Z.; Zhang, Y.; Aruva, M. R. Radio-
nuclide imaging of small-cell lung cancer (SCLC) using 99mTc-
labeled neurotensin peptide 8-13. Nucl. Med. Biol. 2006, 33,
505–512.
(13) Maina, T.; Nikolopoulou, A.; Stathopoulou, E.; Galanis, A. S.;
Cordopatis, P.; Nock, B. A. [99mTc]Demotensin 5 and 6 in the
NTS1-R-targeted imaging of tumours: Synthesis and precli-
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AUTHOR INFORMATION
Corresponding Author: *To whom correspondence should
be addressed. Tel: þ49 9131 8544440. E-mail: olaf.prante@
uk-erlangen.de.
Funding Sources: This work was supported by the Deutsche
Forschungsgemeinschaft (DFG, MA 4295/1-2) and the BMBF
(01EZ0808).
(14) Alshoukr, F.; Rosant, C.; Maes, V.; Abdelhak, J.; Raguin, O.;
ꢀ
Burg, S.; Sarda, L.; Barbet, J.; Tourwe, D.; Pelaprat, D.; Gruaz-
Guyon, A. Novel Neurotensin Analogues for Radioisotope
Targeting to Neurotensin Receptor-Positive Tumors. Biocon-
jugate Chem. 2009, 20, 1602–1610.
ACKNOWLEDGMENT We thank Bianca Weigel, I. Torres-
Berger, Michaela Kettler, Michael Betz, Michael Echtler, and Stefan
Huber for technical assistance.
(15) Garcia-Garayoa, E.; Blauenstein, P.; Blanc, A.; Maes, V.;
ꢀ
Tourwe, D.; Schubiger, P. A. A stable neurotensin-based radio-
pharmaceutical for targeted imaging and therapy of neuro-
tensin receptor-positive tumours. Eur. J. Nucl. Med. Mol.
Imaging 2009, 36, 37–47.
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