DOI: 10.1002/cplu.201200022
[18F]Si-RiboRGD: From Design and Synthesis to the Imaging of
avb3 Integrins in Melanoma Tumors
Eric Amigues,[a] Jꢀrgen Schulz,[b] Magali Szlosek-Pinaud,*[a] Philippe Fernandez,[b] Sandrine Silvente-Poirot,[c]
Sꢁverine Brillouet,[c] Frꢁdꢁric Courbon,[c] and Eric Fouquet*[a]
Angiogenesis is involved in a variety of pathological processes,
for example rheumatoid arthritis,[1] psoriasis,[2] as well as tumor
growth.[3] Thus, the field of angiogenesis research has evolved
to become one of the most rapidly growing biomedical disci-
plines. The fundamental angiogenesis research is sparked by
the translational therapeutic potential aimed at developing an-
tiangiogenesis drugs as novel therapeutics for tumors and
a number of nononcological diseases. Thus noninvasive moni-
toring of molecular processes in the angiogenic cascade is of
major interest for basic science, as well as clinical settings
where it could help in planning and controlling corresponding
antiangiogenic therapies. One major class of receptors in-
volved in the angiogenic process are the integrins which are
hetero dimeric glycoproteins consisting of a and b subunits.
One of the most prominent members of this receptor class is
the avb3 integrin and great efforts are made to develop
avb3 antagonists for several therapeutic approaches based on
cyclic pentapeptides containing the tripeptide sequence argi-
nine–glycine–aspartic acid (RGD). Indeed, this is a recognition
pattern used by several extracellular matrix proteins to bind
a variety of integrins including avb3. Among the diagnostic
tools in modern medicine, positron emission tomography (PET)
allows high-resolution quantitative imaging of biochemical
processes in vivo by detecting the distribution of labeled bio-
markers over time.[4] Therefore, a variety of different radiola-
beled RGD peptides has been introduced,[5] most efforts being
carried out using [18F]galacto-RGD,[6] a glycosylated cyclic pen-
tapeptide with the sequence cyclo(-Arg-Gly-Asp-dPhe-Lys-
(SAA)-; SAA=sugar amino acid). It has been demonstrated in
murine tumor models,[7] as well as in patients,[8] that this com-
pound allows noninvasive determination of avb3 expression.
Indeed, avb3 expression has been imaged in variety of malig-
nant tumors including melanomas, sarcomas, and head and
neck cancer using this peptide.[9,10] Other 18F-labeled RGD pep-
tides in clinical trials such as [18F]AH111585 and [18F]RGD-
K5,[11,12] have shown that PET with radiolabeled RGD peptides
can be used to detect avb3-expressing tumors in patients and
to quantitatively evaluate the expression levels of
avb3 integrins. However, the synthesis of these 18F-labeled pep-
tides remained highly complex and time consuming, thus
making the development of a remote-controlled synthesis haz-
ardous. Particularly the radiolabeling step in the case of
[18F]galacto-RGD, remains problematic as it involves a multistep
reaction sequence, thus making large-scale clinical studies
challenging. As a consequence, the development of the clinical
use of RGD peptides clearly needs new probes that are less
complex to radiolabel. Such an alternative has been recently
reported, involving the replacement of 18F with 68Ga or 64Cu,
thus leading to the corresponding derivatives of the
[18F]galacto-RGD.[13,14] However [18F]galacto-RGD remains, in
most cases, superior for imaging avb3 expression. The other
way to circumvent this short coming is to keep 18F-labeling
and the major advantages of the original galacto-RGD, but re-
thinking the initial synthesis by using a particularly efficient,
one-step method for a site specific 18F-labeling under mild con-
ditions. Recently, new strategies for direct one-step 18F-labeling
18
of peptides have been reported through a CÀ F bond forma-
tion.[15] Besides this, few research groups have reported the in-
terest of phosphorous-,[16] boron-,[17] 18F-aluminum-chelate,[18]
19
and 18F-silicon radiochemistry by using either 18FÀ F isotope
exchange (SiFA strategy),[19] or silicon-based building blocks.[20]
This last procedure is based on the high SiÀF bond energy
(135 KcalmolÀ1 vs. 116 kcalmolÀ1 for CÀF) and enabling of fluo-
ride substitution at silicon,[21] for the 18F-labeling of biomole-
cules, in a last single step. Having already successfully applied
this methodology to the fluorination of sensitive molecules
such as fully deprotected oligonucleotides,[22] we decided to
apply it for the fluorination of our target RGD derivative.
Beside the radiosynthesis, we also thought to improve the
synthesis of the precursor (RÀSiH), especially by using Huisgen
1,3-dipolar cycloaddition as the coupling reaction between the
different building blocks of 12. Indeed, this reaction proceeds
under mild conditions in aqueous media and requires virtually
no protection of other functional groups allowing its use for
the preparation of 18F-fluoropeptides.[23] Herein, we describe
a convergent and efficient synthesis of a 18F-labeled RGD deri-
vative using advantages of both “click chemistry” and the one-
step labeling protocol applying the silicon-based building
blocks strategy. Thus, our target molecule could be divided in
three different building blocks: a cyclo-RGD (recognition part)
for the selectivity toward avb3 integrin, a silicon moiety (detec-
tion part) for the selective fluorination at the last step of the
synthesis, and finally, between the two first parts, a sugar
[a] Dr. E. Amigues,+ Dr. M. Szlosek-Pinaud,+ Prof. E. Fouquet+
ISM, UMR5255, Synthesis–Bioactive Molecules Group
Universitꢀ de Bordeaux
351, Cours de la Liberation, 33405 Talence (France)
Fax: (+33)0540006386
[b] Dr. J. Schulz,+ Prof. P. Fernandez+
INCIA, UMR5287, Universitꢀ de Bordeaux
146, Rue Leo Saignat, 33076 Bordeaux (France)
[c] Dr. S. Silvente-Poirot, Dr. S. Brillouet, Prof. F. Courbon
CRCT, UMR1037, Insitut Claudius Regaud
20/24 Rue du Pont Saint-Pierre, 31052 Toulouse (France)
[+] Core members of the TRAIL Labex.
Supporting information for this article is available on the WWW under
ChemPlusChem 2012, 77, 345 – 349
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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