A fluoride-derived electrophilic late-stage fluorination reagent for PET imaging

Article abstract of DOI:10.1126/science.1212625

The unnatural isotope fluorine-18 (¹⁸F) is used as a positron emitter in molecular imaging. Currently, many potentially useful ¹⁸F-labeled probe molecules are inaccessible for imaging because no fluorination chemistry is available to

Full text of DOI:10.1126/science.1212625

A Fluoride-Derived Electrophilic Late-Stage Fluorination Reagent for
PET Imaging
Eunsung Lee et al.
Science 334, 639 (2011);
DOI: 10.1126/science.1212625
This copy is for your personal, non-commercial use only.
If you wish to distribute this article to others, you can order high-quality copies for your
colleagues, clients, or customers by clicking here.
Permission to republish or repurpose articles or portions of articles can be obtained by
following the guidelines here.
The following resources related to this article are available online at
www.sciencemag.org (this information is current as of November 12, 2012 ):
Updated information and services, including high-resolution figures, can be found in the online
version of this article at:
http://www.sciencemag.org/content/334/6056/639.full.html
Supporting Online Material can be found at:
http://www.sciencemag.org/content/suppl/2011/11/03/334.6056.639.DC1.html
A list of selected additional articles on the Science Web sites related to this article can be
found at:
http://www.sciencemag.org/content/334/6056/639.full.html#related
This article cites 28 articles, 3 of which can be accessed free:
http://www.sciencemag.org/content/334/6056/639.full.html#ref-list-1
This article has been cited by 1 articles hosted by HighWire Press; see:
http://www.sciencemag.org/content/334/6056/639.full.html#related-urls
This article appears in the following subject collections:
Chemistry
http://www.sciencemag.org/cgi/collection/chemistry
Science (print ISSN 0036-8075; online ISSN 1095-9203) is published weekly, except the last week in December, by the
American Association for the Advancement of Science, 1200 New York Avenue NW, Washington, DC 20005. Copyright
2011 by the American Association for the Advancement of Science; all rights reserved. The title Science is a
registered trademark of AAAS.

REPORTS
34. J. P. Collman, N. K. Devaraj, T. P. A. Eberspacher,
C. E. D. Chidsey, Langmuir 22, 2457 (2006).
35. S. Park, K. Kwak, M. D. Fayer, Laser Phys. Lett. 4, 704
(2007).
42. D. L. Huber, D. S. Hamilton, B. Barnett, Phys. Rev. B 16,
4642 (1977).
43. R. B. Williams, R. F. Loring, M. D. Fayer, J. Phys. Chem. B
105, 4068 (2001).
and the Department of Energy under grant DE-FG03-
84ER13251. In addition, B.J.S. and T.D.P.S. thank
the National Institutes of Health (GM50730).
36. K. Kwak, S. Park, I. J. Finkelstein, M. D. Fayer, J. Chem.
44. C. J. Fecko, J. J. Loparo, S. T. Roberts, A. Tokmakoff,
J. Chem. Phys. 122, 054506 (2005).
Supporting Online Material
www.sciencemag.org/cgi/content/full/science.1211350/DC1
Materials and Methods
SOM Text
Figs. S1 to S10
Phys. 127, 124503 (2007).
37. K. Kwak, D. E. Rosenfeld, M. D. Fayer, J. Chem. Phys.
128, 204505 (2008).
Acknowledgments: The authors thank C. Xie and B. Cui for
preparation of the SiO2-coated CaF2 substrates and
D. B. Wong for making the bulk solution orientational
relaxation measurements. D.E.R. acknowledges the
support of the Fannie and John Hertz Foundation, a
National Science Foundation Graduate Research Fellowship,
and a Stanford Graduate Fellowship. This material is
based on work supported by the Air Force Office of
Scientific Research under AFOSR grant F49620-01-1-0018
38. V. M. Kenkre, A. Tokmakoff, M. D. Fayer, J. Chem. Phys.
101, 10618 (1994).
39. R. K. Hocking, T. W. Hambley, Organometallics 26, 2815
(2007).
40. S. Yamamoto, A. Ghosh, H.-K. Nienhuys, M. Bonn,
Phys. Chem. Chem. Phys. 12, 12909 (2010).
41. T. Förster, Radiat. Res. Suppl. 2, 326 (1960).
Tables S1 and S2
References (45–64)
18 July 2011; accepted 14 September 2011
Published online 20 October 2011;
10.1126/science.1211350
Research toward PET tracer development has
focused on the use of [18F]fluoride to make PET
tracers with high specific activity. Incorporation
of 18F still usually relies on simple nucleophilic
substitution reactions, a class of reactions origi-
nally developed more than 100 years ago (7) and
often not suitable to address modern challenges
in imaging. Recent advances in nucleophilic fluo-
rination (8–11) include a palladium-catalyzed fluo-
rination reaction of aryl triflates with anhydrous
cesium fluoride developed by the Buchwald group
in which carbon-fluorine bond formation proceeds
by reductive elimination from palladium(II) aryl
fluoride complexes (12, 13). Challenges associ-
ated with the application of fluorination reactions
A Fluoride-Derived Electrophilic
Late-Stage Fluorination Reagent
for PET Imaging
Eunsung Lee,1* Adam S. Kamlet,1* David C. Powers,1 Constanze N. Neumann,1
Gregory B. Boursalian,1 Takeru Furuya,1 Daniel C. Choi,1 Jacob M. Hooker,2,3† Tobias Ritter,1,3
†
The unnatural isotope fluorine-18 (18F) is used as a positron emitter in molecular imaging.
Currently, many potentially useful 18F-labeled probe molecules are inaccessible for imaging
because no fluorination chemistry is available to make them. The 110-minute half-life of 18F
requires rapid syntheses for which [18F]fluoride is the preferred source of fluorine because of
its practical access and suitable isotope enrichment. However, conventional [18F]fluoride chemistry has to PET include the requirement of short reaction
been limited to nucleophilic fluorination reactions. We report the development of a palladium-based
electrophilic fluorination reagent derived from fluoride and its application to the synthesis of
aromatic 18F-labeled molecules via late-stage fluorination. Late-stage fluorination enables the
times, as well as different reaction conditions for
18F chemistry relative to 19F chemistry. For ex-
ample, extensive drying of fluoride is readily
synthesis of conventionally unavailable positron emission tomography (PET) tracers for anticipated achieved for 19F chemistry but can be impractical
applications in pharmaceutical development as well as preclinical and clinical PET imaging.
for radiochemistry, which is typically executed
on a nanomole scale. When transitioning from
ositron emission tomography (PET) is of the variety of functional groups commonly 19F chemistry to 18F chemistry, the smaller ratio
a noninvasive imaging technology used found in structurally complex molecules (6). For of fluorine to water can be problematic because
to observe and probe biological processes PET applications, chemical challenges are ex- hydrated fluoride has diminished nucleophilicity.
P
in vivo (1, 2). Although several positron- acerbated by the short half-life of 18F (110 min), As a consequence, even promising modern fluo-
emitting isotopes can be used for PET imaging, which dictates that carbon-fluorine bond forma- rination reactions developed for 19F chemistry are
fluorine-18 (18F) is the most clinically relevant tion occur at a late stage in the synthesis to avoid often not translated to radiochemistry.
radioisotope (3, 4). For example, the radiotracer unproductive radioactive decay before injection
Electrophilic and nucleophilic fluorination re-
actions allow access to complementary sets of
[18F]fluorodeoxyglucose ([18F]FDG) has revo- in vivo.
lutionized clinical diagnosis in oncology. Despite
The unnatural isotope 18F is generated using molecules (6), yet all electrophilic 18F-fluorination
the success of PET and decades of research, a cyclotron, either as nucleophilic [18F]fluoride reactions developed to date use electrophilic flu-
there remains a major deficiency in the ability to or as electrophilic [18F]fluorine gas ([18F]F2). orination reagents that ultimately originate from
synthesize complex PET tracers; in fact, no gen- [18F]Fluoride, formed from proton bombardment [18F]F2. In 1997, Solin developed a method to
eral method is available to radiolabel structurally of oxygen-18–enriched water, is easier to make generate [18F]F2 with higher specific activity
complex molecules with 18F. In organic molecules, and handle than [18F]F2. Moreover, [18F]F2 gas than is common for [18F]F2, by minimizing the
fluorine atoms are typically attached by carbon- is liberated from the cyclotron with [19F]F2; 19
F
amount of [19F]F2 used (14). By using [18F]F2
fluorine bonds (5), yet carbon-fluorine bond for- is the natural, PET-inactive isotope of fluorine. made via the Solin method, Gouverneur suc-
mation is challenging, especially in the presence As a result, the 18F/19F ratio, quantified as spe- ceeded in synthesizing [18F]N-chloromethyl-N-
cific activity, is substantially lower when [18F]F2 fluorotriethylenediammonium bis(tetrafluoroborate)
is used than when [18F]fluoride is used. High ([18F]F-TEDA), an electrophilic 18F-fluorination
1Department of Chemistry and Chemical Biology, Harvard
specific activity is often critical to PET imaging. reagent more useful and selective than [18F]F2 (15).
University, Cambridge, MA 02138, USA. 2Athinoula A. Martinos
If a biological target of a radiotracer is saturated However, nucleophilic [18F]fluoride is currently
Center for Biomedical Imaging, Massachusetts General Hos-
with the non–positron-emitting 19F-isotopolog the only practical and generally available source
pital and Harvard Medical School, Charlestown, MA 02129, USA.
3Division of Nuclear Medicine and Molecular Imaging, Depart-
of the tracer, a meaningful PET image cannot of fluorine to prepare PET tracers with high spe-
be obtained. PET tracers of low specific activity cific activity (3). If an electrophilic fluorination
cannot be used to visualize biological targets that reagent were to be made from fluoride (16, 17)
are of low concentration. For example, imaging without the need for F2, electrophilic fluorination
ment of Radiology, Massachusetts General Hospital, Boston, MA
02114, USA.
*These authors contributed equally to this work.
†To whom correspondence should be addressed. E-mail:
hooker@nmr.mgh.harvard.edu (J.M.H.); ritter@chemistry.
harvard.edu (T.R.)
neurotransmitter receptors in the brain typically could become a general and widely used meth-
necessitates tracers of high specific activity (3).
od to prepare PET tracers that are currently
www.sciencemag.org SCIENCE VOL 334 4 NOVEMBER 2011
639

REPORTS
inaccessible via conventional nucleophilic fluo- substituents to prevent nucleophilic attack on the ophilic attack of the dz2 -based orbital on palladi-
rination chemistry. carbon and nitrogen atoms coordinated to palla- um of 3 (fig. S17) on the s*Pd–F-based orbital of
Previously, we reported the fluorination of pal- dium. Complex 2 was devised to act as an elec- the LUMO of 2, or via electron transfer (23, 24)
ladium aryl complexes with the electrophilic fluo- trophilic fluorination reagent through nucleophilic from 3 to 2 with interposed or subsequent flu-
rination reagent F-TEDA (Fig. 1) (18). F-TEDA attack at the antibonding palladium-fluorine– orine transfer. Currently available data cannot
can oxidize palladium(II) aryl complexes, which based orbital (s*Pd–F) at fluorine in an SN2 reac- distinguish between these mechanisms. In ad-
subsequently afford aryl fluorides by carbon- tion. In such a putative SN2 reaction, palladium dition, other pathways that intercept interme-
fluorine reductive elimination from palladium(IV) would function as a leaving group, with concom- diates such as 5 could potentially be used for
aryl fluoride complexes (19, 20). Replacement of itant reduction to the oxidation state +II [Pd(II)]. carbon-fluorine bond formation. Palladium com-
F-TEDA by a fluorination reagent that mimics Nucleophilic attack would occur at the lowest plex 2 is both an oxidant and a fluoride donor.
the function of F-TEDA but is made from fluo- unoccupied molecular orbital (LUMO) of 2. The oxidation equivalents are inherent in the
ride has the potential for use in the synthesis of The calculated LUMO of 2 (Fig. 2B) shows that transition metal oxidation state, and the fluo-
18F radiotracers with high specific activity. Here, only the lobe on fluorine points into unoccupied rine substituent is negatively polarized, because
we report the design and synthesis of an organo- space; no other LUMO lobe is available for nu- fluorine is the most electronegative element.
metallic complex made from fluoride (1 → 2, cleophilic attack because the aromatic ligands But oxidation of 3 with an external oxidant fol-
Fig. 1) that behaves as an electrophilic fluorina- block the trajectories.
tion reagent, and the use of the reagent for the Treatment of the palladium complex 1 with oride source could also provide 5. In such a
synthesis of 18F-labeled small molecules via late- nucleophilic fluoride (KF) afforded the palladium stepwise approach, potential side reactions of
stage fluorination. fluoride complex 2 within 5 min at 90% yield putative intermediates, such as undesired reduc-
lowed by a reaction with an independent flu-
Palladium complex 2 was envisioned to ac- (Fig. 2A). The ability of 2 to function as an tive elimination reactions, must be prevented.
complish oxidative fluorine transfer by serving as electrophilic fluorination reagent was confirmed Conceptually, several combinations of an oxidant
an electrophile in SN2 reactions with nucleophilic by fluorination of Pd(II) aryl complex 3 (Fig. 2C). and a fluoride source are conceivable for suc-
attack occurring at the fluorine substituent. The Fluorine transfer from 2 to 3 results in oxidation cessful oxidative fluorination.
complexes 1 and 2 were designed according to of 3 to form Pd(IV) aryl fluoride intermediate
The fluorination reagent 2 was subsequently
the following five considerations (Fig. 2): (i) The 5, assigned by 1H and 19F nuclear magnetic res- evaluated for late-stage fluorination. Fluorination
palladium center in 1 carries three formal positive onance (NMR). Carbon-fluorine reductive elim- of the Pd(II) aryl complexes 8 to 11 with 2 af-
charges (countercharges to two triflate anions and ination from reactive intermediate 5 occurs at a forded aryl fluorides 12 to 15 at 67 to 93% yield
one negatively charged borate ligand) and should rate comparable to oxidation of 3 with 2. Oxi- (Fig. 3). We propose that Pd(IV) fluoride com-
therefore capture negatively charged fluoride from dation of 3 with the electrophilic fluorination plex 2 oxidizes the Pd(II) aryl complexes by flu-
solution. High fluorophilicity of the palladium reagent F-TEDA afforded 5 at a faster rate than orine transfer to form high-valent Pd(IV) aryl
complex 1 is required for radiochemistry appli- oxidation with 2, which allowed independent fluoride complexes, analogous to 5, from which
cations because of the low effective concentra- synthesis and identification of 5 (fig. S2). Re- carbon-fluorine reductive elimination can occur
tion of fluoride in solution (roughly 10−4 M). (ii) duction of palladium from Pd(IV) in oxidant 2 to form aryl fluoride products 12 to 15. The aryl
The palladium centers in 1 and 2 are in the oxi- to Pd(II) was established by isolation of Pd(II) fluoride molecules shown in Fig. 3 were selected
dation state +IV [Pd(IV)], a high oxidation state complex 4.
on the basis of their structure and exhibition of a
for palladium. Late transition metals such as Oxidative fluorine transfer from 2 to 3 could variety of functional groups, akin to potential small-
palladium, when in a high oxidation state, can proceed by SN2 reaction as designed, with nucle- molecule PET tracers (25, 26). The molecules
function as an oxidant and transfer a ligand to a
nucleophile while being reduced to a lower oxi-
dation state (21). The palladium in 2 can function
as an electron acceptor, which rationalizes the
reactivity of 2 as an oxidant. (iii) The supporting
benzo[h]quinolyl and tetrapyrazole borate (Tp)
ligands are multidentate ligands that were se-
lected to impart stability on both 1 and 2 toward
undesired reductive processes such as carbon-
fluorine reductive elimination. Reductive elimi-
nation from 2 would likely require dissociation of
one ligand to form a pentacoordinate palladium
complex (19, 20), and multidentate ligands such
as Tp are less likely to dissociate and hence re-
duce the rate of potential reductive elimination.
(iv) An octahedral Pd(IV) complex was chosen
to avoid undesired nucleophilic attack at the tran-
sition metal. The palladium-fluorine bond is po-
larized toward fluorine, with partial negative charge
on fluorine and positive charge on palladium.
Solely on the basis of coulombic interactions, nu-
cleophilic attack is expected at palladium rather
than fluorine. However, the orbitals available
for nucleophilic attack on octahedral (t2g)6(eg)0
Pd(IV) complexes, the dx2−y2 and dz2 orbitals, are
high in energy, and nucleophilic attack on high-
energy orbitals is disfavored (22). (v) The multi-
dentate supporting ligands in 2 feature aromatic fluoride (F⊝). Ar, aryl; Me, methyl; Tf, trifluoromethanesulfonyl.
Fig. 1. Electrophilic fluorination of palladium aryl complexes to afford aryl fluorides. Top: With the
electrophilic fluorination reagent F-TEDA. Bottom: With the Pd(IV) fluoride complex 2, made from
640
4 NOVEMBER 2011 VOL 334 SCIENCE www.sciencemag.org

REPORTS
are electron-rich arenes, which would be diffi- in medical imaging. Organometallic synthesis in for 24 hours at 100°C), and water (no observed
cult to prepare by conventional fluorination a hospital setting would be impractical. However, decomposition in 10% aqueous acetonitrile solu-
reactions with [18F]fluoride.
the palladium complexes discussed here can be tion after 3 hours at 23°C). Thermal stability and
The transition from 19F chemistry to 18F chem- prepared conveniently on scale, stored, and sub- tolerance toward water are beneficial for prac-
istry is challenging because the concentration sequently transported to imaging sites when tical PET applications, because reaction mixtures
of the limiting reagent (fluoride) changes from needed. The palladium(II) aryl complexes such are often heated to increase reaction rates and
millimolar to micromolar, and because synthe- as 8 to 11 can be purified by chromatography or [18F]fluoride is made from oxygen-18–enriched
ses must be performed in the presence of ionizing recrystallization and can be stored and transported water.
radiation and under a time constraint due to the in air at ambient temperature. Palladium complex
The synthesis of 18F-radiolabeled molecules
110-min half-life of 18F. Therefore, reaction chem- 1 is stable at room temperature and can be ma- using such a fluoride-derived reagent is opera-
istry applicable to 18F chemistry must be robust nipulated briefly in air. Palladium complex 2 is tionally simple. Pd(IV) complex 1 reacts with con-
and as simple as possible for broad applications stable toward heat (no observed decomposition ventionally prepared solutions of [18F]fluoride
Fig. 2. Reactivity and structure of 1 and 2. (A) Nucleophilic fluoride capture by Fluorination of Pd(II) aryl complex 3 by reagent 2 to form Pd(IV) aryl fluoride
Pd(IV) complex 1 to form electrophilic fluorination reagent 2. (B) X-ray structure of complex 5, followed by C–F reductive elimination from 5. Reductive elimination
2 (ORTEP drawing at 50% probability; hydrogen atoms and counteranion omitted from reactive intermediate 5 to 6 proceeds at 23°C; the highest yield of 6 (80%)
for clarity) and calculated lowest unoccupied molecular orbital (LUMO) of 2. (C) was obtained upon heating 2 and 3 at 85°C. 18-cr-6, 18-crown-6; iPr, isopropyl.
A
B
Fig. 3. Synthesis and fluorination of palladium aryl complexes. (A)
Representative synthesis of a palladium aryl complex from palladium
acetate complex 7. (B) Fluorination of palladium aryl complexes 8 to
11 with electrophilic fluorination reagent 2. [Pd], as shown for complex
7; Ac, acetate; Bn, benzyl; Boc, tert-butoxycarbonyl; MOM, methoxy-
methyl; DAM, di-(p-anisyl)methyl.
www.sciencemag.org SCIENCE VOL 334 4 NOVEMBER 2011
641

REPORTS
3. S. M. Ametamey, M. Honer, P. A. Schubiger, Chem. Rev.
108, 1501 (2008).
4. P. W. Miller, N. J. Long, R. Vilar, A. D. Gee, Angew. Chem.
Int. Ed. 47, 8998 (2008).
5. D. O’Hagan, Chem. Soc. Rev. 37, 308 (2008).
6. T. Furuya, A. S. Kamlet, T. Ritter, Nature 473, 470 (2011).
7. S. Young, J. Chem. Soc. Trans. 39, 489 (1881).
8. V. W. Pike, F. I. Aigbirhio, J. Chem. Soc. Chem. Commun.
1995, 2215 (1995).
9. H. Sun, S. G. DiMagno, Angew. Chem. Int. Ed. 45, 2720
(2006).
10. M. H. Katcher, A. G. Doyle, J. Am. Chem. Soc. 132,
17402 (2010).
11. C. Hollingworth et al., Angew. Chem. Int. Ed. 50, 2613
(2011).
12. D. A. Watson et al., Science 325, 1661 (2009);
10.1126/science.1178239.
13. T. Noël, T. J. Maimone, S. L. Buchwald, Angew. Chem.
Int. Ed. 10.1002/anie.201104652 (2011).
14. J. Bergman, O. Solin, Nucl. Med. Biol. 24, 677 (1997).
15. H. Teare et al., Angew. Chem. Int. Ed. 49, 6821 (2010).
16. B. Brauner, Z. Anorg. Chem 7, 1 (1894).
17. K. O. Christe, Inorg. Chem. 25, 3721 (1986).
18. T. Furuya, H. M. Kaiser, T. Ritter, Angew. Chem. Int. Ed.
47, 5993 (2008).
19. T. Furuya, T. Ritter, J. Am. Chem. Soc. 130, 10060
(2008).
20. T. Furuya et al., J. Am. Chem. Soc. 132, 3793 (2010).
21. S. S. Stahl, J. A. Labinger, J. E. Bercaw, Angew. Chem. Int. Ed.
37, 2180 (1998).
22. F. A. Cotton, Chemical Applications of Group Theory
(Wiley, New York, ed. 3, 1990), chap. 9.
23. H. Taube, H. Myers, J. Am. Chem. Soc. 76, 2103 (1954).
24. A. Haim, Prog. Inorg. Chem. 30, 273 (1983).
25. V. Pomel et al., J. Med. Chem. 49, 3857 (2006).
26. A. P. Kozikowski et al., ChemMedChem 5, 1221
(2010).
27. F. T. Chin et al., Mol. Imaging Biol. 10, 82 (2008).
28. J. Toyohara et al., Ann. Nucl. Med. 23, 301 (2009).
29. U.S. Department of Health and Human Services,
Food and Drug Administration, www.fda.gov/downloads/
Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/ucm078933.pdf.
Fig. 4. Late-stage fluorination to form 18F-labeled aryl fluorides. [18F]Fluoride capture by Pd(IV) com-
plex 1 to form electrophilic fluorination reagent [18F]2 and subsequent fluorination of palladium
aryl complexes 9 to 11. Reported radiochemical yields (RCYs) are averaged over n experiments at a
500-mCi scale.
in acetone and forms the 18F reagent [18F]2 with- for pharmaceuticals because pharmacological ef-
in 10 min (Fig. 4). Subsequent filtration over a fects are not sought (29), and purification is often
polymer-supported resin and addition of the straightforward because of the small amount of
Pd(II) aryl complexes 9 to 11 yielded, upon heat- tracer to be purified. For example, inductively cou-
ing for 10 min, the 18F-labeled aryl fluorides pled plasma mass spectrometry (ICP-MS) analysis
[18F]13 to [18F]15, respectively. Azeotropic dry- of [18F]13 (Fig. 4), purified by conventional HPLC
ing of aqueous [18F]fluoride, the two-step reac- technique (20 min), afforded material with 5 parts
tion sequence (fluoride capture (1 → [18F]2) per billion (ppb) palladium residue, commensu-
followed by fluorine transfer (e.g., 9 → [18F]13), rate with international recommendations on the
and subsequent purification of the 18F-labeled palladium impurity profile for samples injected
molecules by high-performance liquid chromatog- into humans, which demand less than 1000 ppb
raphy (HPLC) results in an overall synthesis palladium (30). Similarly, the synthesis cost for
time of less than 60 min. Automated syntheses the palladium complexes is small relative to the
with up to 1 Ci of radioactivity have been ac- cost of 18F-isotope infrastructure and the cost as-
complished. The efficiency of radiochemical syn- sociated with clinical imaging (31).
30. European Medicines Agency, www.ema.europa.eu/docs/
en_GB/document_library/Scientific_guideline/2009/09/
WC500003587.pdf.
31. A. K. Buck et al., J. Nucl. Med. 51, 401 (2010).
Acknowledgments: Supported by National Institute of
General Medical Sciences grant GM088237, National
Institute of Biomedical Imaging and Bioengineering
grant EB013042, National Center for Research Resources
grant 1S10RR017208-01A1, National Institute on Drug
Abuse grant 5P30DA028800-02, the Richard and Susan
Smith Family Foundation, the Massachusetts Life Science
Center, the Harvard Catalyst, NSF Graduate Research
Fellowship Program grant DGE0644491, and the Harvard
Accelerator Fund. T.R. was also supported by a Sloan
Research Fellowship, grants from Eli Lilly and Co. and
AstraZeneca, a Camille Dreyfus Teacher-Scholar Award,
and an Amgen Young Investigators Award. We thank
S.-L. Zheng for x-ray crystallographic analysis. DFT
computation was performed using the computer facilities
at the Odyssey cluster at Harvard University. Metrical
parameters for the crystal structures of compounds 1, 2,
3, 8, and S10 are available free of charge from the
Cambridge Crystallographic Data Centre under reference
nos. CCDC 829427, 829428, 840744, 829429, and
839058, respectively. A patent application has been filed
through Harvard on methods and reagents presented in
this manuscript.
thesis is given in radiochemical yield, which is
We have shown that a late-stage fluorina-
based on decay-corrected radioactivity rather than tion reaction can access 18F-labeled function-
on mass of isolated material (4). Radiochemical alized molecules, which would be particularly
yields (RCYs) as high as possible are desired, but difficult to prepare with conventional fluorina-
RCYs as low as 5% can provide meaningful PET tion reactions. The availability of a fluorination
imaging (27). The 18F-fluorination method de- reagent with high specific activity that functions
scribed here has afforded RCYs higher than 30%. as an electrophile may find applications in 18F
Stoichiometric amounts of precious transition fluorination of pharmaceutical candidates for
metals such as palladium are typically avoided evaluation of their biodistribution to accelerate
in syntheses of health care products because of drug development, as well as in the development
toxicity and cost considerations. However, such of previously unavailable 18F-PET tracers for
considerations are different for the synthesis of clinical care.
Supporting Online Material
www.sciencemag.org/cgi/content/full/334/6056/639/DC1
Materials and Methods
Figs. S1 to S17
Tables S1 to S16
PET tracers because of the small amount that is
References (32–61)
required (28). PET tracers with high specific
activity are administered at a dose at least 2
orders of magnitude smaller than is common
References and Notes
1. M. E. Phelps, Proc. Natl. Acad. Sci. U.S.A. 97, 9226 (2000).
2. J. S. Fowler, A. P. Wolf, Acc. Chem. Res. 30, 181 (1997).
15 August 2011; accepted 13 September 2011
10.1126/science.1212625
642
4 NOVEMBER 2011 VOL 334 SCIENCE www.sciencemag.org