.
Angewandte
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are not commercially available and not trivial to prepare by evaporate the solution of [18F]KF/K222 in acetonitrile. Evap-
non-chemist professionals performing (pre)clinical PET stud- oration under N2 led to decreased RCYs and encouraged the
ies. These characteristics, coupled with the necessity to formation of 1,1’-biphenyl, an observation indicating that the
develop automated procedures in compliance with good presence of O2 is beneficial for the reaction. Consequently,
manufacturing practice (GMP) requirements, encourage the the reaction vial was purged with air after drying [18F]fluoride.
development of simpler and readily applicable solutions for These modifications led to the formation of [18F]2a in up to
the direct nucleophilic 18F fluorination of (hetero)arenes from 43% RCY ([1a] 0.26m in DMF). We then focused on the
easy to prepare, shelf-stable materials. Herein, we report the nature of the copper complex itself and the effect of any
unprecedented nucleophilic 18F fluorination of a broad range ligand on reaction efficiency. All ligands tested had a detri-
of pinacol-derived aryl boronate esters with [18F]KF/K222 in mental effect on the RCY with the exception of pyridine.[20]
the presence of the commercially available copper complex These experiments prompted the use of the pyridine copper
[Cu(OTf)2(py)4] (OTf = trifluoromethanesulfonate, py = pyr- complex [Cu(OTf)2(py)4] for further optimization. To our
idine). This transformative method is characterized by its delight, this complex proved optimal, affording [18F]2a in
broad substrate scope and its direct application to the 73% RCY. When samples of [Cu(OTf)2(py)4] were left open
synthesis of radiotracers currently prepared in the clinic to air for two weeks and subsequently employed in radio-
from [18F]F+ sources (Scheme 1).
fluorination, no adverse effect on RCY was observed. The
We have recently exploited the value of copper complexes screening of various additives did not lead to further
for 18F-labeling with the [18F]trifluoromethylation of improvements in RCY, so the reaction requires only the
(hetero)aryl iodides from [18F]CuCF3.[16] Our next objective copper complex, in addition to the substrate and [18F]KF/K222
.
was the development of a copper-mediated nucleophilic Applying the optimized reaction conditions, [18F]4-fluoro-
18F fluorination of readily available and stable precursors 1,1’-biphenyl (2a) was obtained in 74% RCY (n = 4, number
with the aim to provide a general and direct method to access of repeats).
18F-labeled arenes. The remarkable scope of the copper(II)-
To evaluate the utility of the Cu-mediated 18F fluorina-
promoted Chan–Lam coupling reaction of boronic acids and tion, a series of pinacol-derived (hetero)aryl boronic esters
derivatives with heteronucleophiles provided a focus,[17] and was tested (Scheme 2). Numerous functional groups, such as
the ability of aryltrifluoroborates and arylboronate esters to alkyl, aryl, aldehyde, ketone, nitro, cyano, amido, sulfonami-
undergo fluorination with KF and Cu(OTf)2 served as do, ether, ester, alkene, alkyne, bromo, piperidino, morpho-
a
starting point for 18F-radiochemical development.[18] lino, Boc-protected amines (Boc = tert-butoxycarbonyl), and
Translation to no-carrier-added 18F radiochemistry presents alcohols, are compatible with this new 18F fluorination with
distinctive challenges since only minute quantities of 18F are RCYs reaching up to 83%. Precursors with unprotected
available for labeling (10À7–10À9 m), and complications could alcohol or amine functionalities give only trace amounts of
arise from sequestration of [18F]fluoride onto the boron- the desired 18F-product (RCY< 10%), a result possibly owing
containing substrates which are used in excess.[19] We dis- to competitive C O or C N coupling. The reaction of
carded aryltrifluoroborates for 18F-labeling as these substrates arylBPin with ortho-, para-, and meta-positioned electron-
could undergo 19F/18F isotopic exchange, a process resulting in withdrawing groups proceeds efficiently, and the presence of
[17]
À
À
decreased specific activity (SA).
electron-donating groups on the arylBPin precursor is very
2-([1,1’-Biphenyl]-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxa-
well tolerated. Ortho-substituted [18F]fluoroarenes are also
borolane (1a) served as the model substrate for validation accessible by application of our standard method. [18F]6-
and optimization studies.[20] All reactions were conducted Fluoroquinoline and [18F]5-fluoro-1-tosyl-1H-indole were
without deliberate addition of 19F-fluoride (no-carrier added). obtained in 50% and 19% RCY, respectively. The reaction
When the reaction was performed in acetonitrile at 608C for can also be extended to an alkenylBpin precursor as
20 minutes using [18F]KF/K222 with a 1a:[Cu(OTf)2] ratio of demonstrated by the preparation of the [18F]fluoroalkene
1:4, the formation of compound 4-[18F]fluoro-1,1’-biphenyl derived from (E)-4,4,5,5-tetramethyl-2-styryl-1,3,2-dioxabor-
[18F]2a was not detected. This result prompted an explora- olane. The successful application of our method to electron-
tion of key parameters to induce 18F incorporation. rich arenes such as phenol, aniline, and veratrole derivatives
18F Fluorination of 1a was observed at 1508C using [18F]KF/ offers tantalizing opportunities in PET ligands and radio-
K222 in dimethylformamide (DMF) or in N-methylpyrroli- pharmaceuticals development. Ultimately, a major benefit of
done affording [18F]2a in low radiochemical yield (RCY< our method is its amenability to late-stage 18F fluorination of
5%); higher RCYs averaging 15% were obtained in DMF at radiotracers notoriously difficult to access from [18F]fluoride.
1108C. The RCYs were affected by the 1a:[Cu(OTf)2] ratio. Our methodology provided easy access to known radiotracers
The best results were obtained by reducing the amount of Cu without the need for further optimization. The translocator
complex relative to 1a (ratio 1a:[Cu(OTf)2] = 10:1). During protein (TSPO) PET ligand [18F]DAA1106 was readily
the optimization studies, we observed the formation of 1,1’- labeled in 59% RCY by applying our method.[21] TSPO is
biphenyl and (1,1’-biphenyl)-4-ol, resulting from competitive up-regulated in activated microglia and can serve as a bio-
protodeboronation and oxidation, respectively. These prod- marker for many applications, for example, in the early stages
ucts are not 18F-labeled contaminants but the similar polar- of neuroinflammation associated with brain tumors. 6-
ities of 1,1’-biphenyl and 4-[18F]fluoro-1,1’-biphenyl cause [18F]Fluoro-l-tyrosine[22] could be prepared from the N,N-
complications with purification. Both 18F fluorination and diBoc-protected arylBPin precursor. The 18F fluorination step
protodeboronation were affected by the procedure applied to delivered protected 6-[18F]fluoro-m-d,l-tyrosine in 58%
2
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!