A simple, rapid method for the preparation of [11C]formaldehyde

Article abstract of DOI:10.1002/anie.200800991

A PET project: A powerful reagent for the synthesis of positron-emitting imaging molecules - [¹¹C]formaldehyde - is accessible from [ ¹¹C]methyl iodide and trimethylamine N-oxide (TMAO) in high yields and under mild conditions. Easy access to [¹¹C]formaldehyde expands the scope of the carbon-11 toolbox and will lead to new reaction methodology and imaging compounds. (Chemical Equation Presented).

Full text of DOI:10.1002/anie.200800991

Angewandte
Chemie
DOI: 10.1002/anie.200800991
Isotopically Labeled Formaldehyde
A Simple, Rapid Method for the Preparation of [11C]Formaldehyde**
Jacob M. Hooker,* Matthias Schönberger, Hanno Schieferstein, and Joanna S. Fowler
The incorporation of carbon-11 into small molecules has been
paramount to the success of positron emission tomography
(PET) for in vivo molecular imaging and drug research and
development.[1] However, many of the properties that make
11C an ideal radionuclide for PET have impeded its chemical
development. For instance, the short half-life (t1/2 = 20.4 min),
which allows for repeated studies within a short time span,
necessitates rapid chemical syntheses and purifications.
Moreover, high specific activity, which makes it possible to
image low-concentration receptors and molecular targets,
places the working concentration range of 11C-labeling
reagents in the lownanomolar range. But perhaps the biggest
challenge in the synthesis of 11C-labeled compounds is the
lack of available labeling reagents. Bear in mind, nearly all
carbon-11 syntheses begin with a nuclear reaction [14N-
(p,a)11C] using a cyclotron that produces 11CO2 or 11CH4,
from which labeling reagents must be prepared.
By far the most common, almost canonical method, to
label a molecule with 11C is through methylation, typically
with 11CH3I.[2] While pendant methyl groups appear quite
frequently in relevant compounds and 11C methylation has led
to many successful radiotracers, reliance on methylation
limits the range of potential probes. Consequently, new
reaction development should focus on methods to incorpo-
rate 11C in skeletal positions of target molecules, and several
research groups have developed or adapted synthetic meth-
ods for 11C incorporation into benzene rings, carbocycles, and
heterocycles as well as nonpendant locations.[3] By using
carefully designed organic reactions, each of these has
expanded the types of radiotracers that can be accessed.
[11C]Formaldehyde has shown great promise as a labeling
reagent for the preparation of PET compounds. Owing to its
versatile oxidation state, [11C]formaldehyde has been used in
the syntheses of compounds otherwise unlabelable, through
reductive methylations,[4] ring-closure reactions,[5] and elec-
trophilic aromatic substitutions,[6] among others.[7] However,
the widespread development and use of synthetic methods for
[11C]formaldehyde in the preparation of PET compounds has
been hindered by its limited access. Several methods have
been developed for the synthesis of [11C]formaldehyde from
[11C]methanol beginning in 1972 here at Brookhaven
National Laboratory,[8] improved over time with new cata-
lysts,[9] and quite elegantly synthesized enzymatically.[10]
While each of these methods has found utility, they each
have disadvantages preventing more prevalent use.
Recognizing the power of [11C]formaldehyde as a labeling
reagent, demonstrated in these previous reports, we sought to
develop a very simple and rapid method that would provide
access to [11C]formaldehyde without the need for any new
equipment. To make [11C]formaldehyde instantly available to
all chemists interested in isotopically labeled compounds, we
also constrained our method to rely on only commercially
available starting materials, mild conditions, and short
reaction times. Herein, we report a high-yielding method for
the production of [11C]formaldehyde that meets all of these
criteria.
Previous
methods
for
the
preparation
of
[11C]formaldehyde have relied on the partial reduction of
11CO2 or the complete reduction of 11CO2 to 11CH3OH
followed by oxidation (Scheme 1). We surmised that using
[11C]methyl iodide to access [11C]formaldehyde would be
advantageous to these methods for several reasons. First,
11CH3I is routinely produced at virtually every location where
11C-labeled compounds are synthesized. Second, we antici-
pated we could capitalize on the incredible amount of effort
that has gone into the development of methods and equip-
ment (nowcommercially available) for the gas-phase syn-
thesis for high-specific-activity 11CH3I. Each of the existing
methods for [11C]formaldehyde relies on a reduction step that
occurs in solution, typically with lithium aluminum hydride,
which often causes a reduction in specific activity avoided by
gas-phase production of 11CH3I.[2] Thus, our efforts began with
[*] Dr. J. M. Hooker, Prof. Dr. J. S. Fowler
Medical Department
Brookhaven National Laboratory, Upton, NY 11973-5000 (USA)
Fax: (+1)631-344-5815
E-mail: hooker@bnl.gov
M. Schönberger, H. Schieferstein
Johannes-Gutenberg-Universität Mainz (Germany)
Prof. Dr. J. S. Fowler
State Universityof New York at StonyBrook (USA)
Prof. Dr. J. S. Fowler
Mount Sinai School of Medicine, New York (USA)
[**] This work was carried out at Brookhaven National Laboratory
(contract DE-AC02-98CH10886 with the U.S. Department of Energy
and supported byits Office of Biological and Environmental
Research). J.M.H. was supported bythe NIH (1F32EB008320-01)
and a Goldhaber Fellowship at BNL. M.S. and H.S. were supported
byDeutscher Akademischer Austauschdienst (DAAD) and BNL.
Scheme 1. Methods for the production of [11C]formaldehyde: a) by
partial reduction of 11CO2; b) byreduction of 11CO2 and subsequent
oxidation; c) from [11C]methyl iodide (reported here).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200800991.
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the premise of
(Scheme 1c).
a
mechanistically simple oxidation
TMAO, 4 underwent elimination to form formaldehyde at
room temperature. This process occurred quantitatively at
slightly elevated temperatures. Triethylamine N-oxide and
N-methylmorpholine N-oxide were also effective but neces-
sitated longer reaction times, whereas pyridine N-oxide was
ineffective under all condition screened. Upon formation,
formaldehyde oligomerized in the presence of TMAO giving
rise to multiple methylene resonances at 4.3–4.8 ppm (as is
the case in the presence of water).[14] We used 13CH3I to
determine if the use of TMAO introduced any isotopic
dilution during course of the reaction and to assign all
resonances resulting from methyliodide (Figure 1. We found
that the ratio of 12C/13C remained 1:100 throughout the
reaction, suggesting that the methyl groups of TMAO would
not impact the specific activity of reactions performed with
11CH3I.
Using 1H NMR spectrometry, we screened the reaction of
substoichiometric amounts of methyl iodide with a number of
oxygen nucleophiles containing a pendant leaving group
(LG). Many inorganic compounds were effective but led to
over oxidation. Our first lead resulting exclusively in form-
aldehyde was found by comparing the reaction of o-iodoxy-
benzoic acid (IBX, 1) with methanol and methyl iodide
(Scheme 2). The common intermediate 2 was observed, which
converted to formaldehyde over the course of several days.[11]
It was evident from this study that oxidation rather than
methylation was rate limiting. To improve the reaction rate,
we turned to trialkylamine N-oxides, which we predicted
would provide a better leaving group.
To test the viability of this method for the preparation of
[11C]formaldehyde, we assayed the effect of solvent, TMAO
concentration, and reaction time and temperature with the
dimedone precipitation method used in previous
[11C]formaldehyde reports, (see Table 1). Briefly, an aliquot
of the 11C reaction mixture was added to carrier formalde-
hyde, which was subsequently precipitated as a dimedone
adduct. The precipitate was separated by filtration or
centrifugation, and the percentage of radioactivity in the
precipitate was determined. As a control, we omitted TMAO
from the reaction and performed the formaldehyde analysis
(for example, see Table 1, entry 5) and found < 5% of the
radioactivity was associated with the precipitate, which could
be removed with washing. We found that DMF was an
excellent solvent for the transformation, providing high yields
of [11C]formaldehyde in under 2 min at only 708C.
Scheme 2. Oxidation of methanol and methyl iodide with IBX (1).
By reacting trimethylamine N-oxide (TMAO, 3) with
methyl iodide, we observed methylation (!4) and subse-
quent formaldehyde formation immediately (as determined
by the presence of a 1H NMR resonance at ca. 9.5 ppm).[12] In
fact, the decomposition of solid 4 to formaldehyde at high
temperatures was reported nearly a century ago when the
structure of TMAO was under debate.[13] Given excess
Figure 1. a) The reaction between TMAO and MeI. b–e) 1H NMR spectra (400 MHz, CD3CN): b,c) When excess MeI was used, intermediate 4 was
observed. d,e) In the presence of excess TMAO, an equilibrium mixture of formaldehyde and its oligomers 5 was observed. Full 1H NMR spectra
as well as 13C NMR spectra are available in the Supporting Information.
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Chemie
Table 1: Optimization of [11C]formaldehyde yield.[a]
tive-scale conditions. In the first, we omitted MeI and found
no product formation occurred. In the second, TMAO was
EntrySolvent
t [s]
TMAO [mg]
T [8C]
Yield [%][b]
omitted, and no [11C]-7 was observed.
1
MeCN
120
120
120
120
120
120
30
60
120
120
4.0
25.0
4.0
4.0
–
1.0
4.0
4.0
4.0
4.0
70
70
70
70
70
70
70
70
70
20
27 ꢁ 7
58 ꢁ 8
23 ꢁ 7
26 ꢁ 4
3 ꢁ 2[c]
80 ꢁ 2
72 ꢁ 5
86 ꢁ 4
89 ꢁ 4
38 ꢁ 6
In summary, we have developed a simple and accessible
method for production of isotopically labelled formaldehyde.
We demonstrated that commercially available, inexpensive
trimethylamine N-oxide is highly effective at converting
[11C]methyl iodide to [11C]formaldehyde under mild condi-
tions with no erosion of specific activity. We anticipate easy
access to [11C]formaldehyde will result in the increased use
and scope of reactions such as electrophilic aromatic sub-
stitution, Mannich-type condensations, and cyclization reac-
tions for the preparation of [11C]-labeled compounds. Current
studies are underway to expand the scope and utility of
[11C]formaldehyde as a labeling reagent for the synthesis of
PET radiotracers.
2
3
4
MeCN
DMSO
THF
5
6
7
DMF
DMF
DMF
DMF
DMF
DMF
8
9[d]
10
[a] Reactions were performed in 300 mL of solvent with ca. 1 mCi 11CH3I.
[b] Average ꢁ standard deviation (n=3) based on dimedone precip-
itation method. [c] Radioactivitylost from precipitate through exhaustive
washing. [d] Recommended conditions (n=12).
We found that the reaction was reproducible and robust. Experimental Section
General procedure for the conversion of 11CH3I to 11CH2O: A mixture
The reaction was not sensitive to small amounts of water (up
to 10 mL), and the dihydrate form of TMAO, which is less
expensive, was an equally effective reagent. Added base was
tolerated as long as it did not competitively methylate.
However, the addition of acid lowered reaction yields or
prevented [11C]formaldehyde formation altogether. Higher
temperatures were equally effective with no overoxidation
observed.
of trimethylamine N-oxide or its hydrate (4 mg) and DMF (300 mL)
cooled to ꢀ408C was used to capture 11CH3I produced using
PETtrace MeI Microlab (GE Medical Systems, Milwaukee, WI,
USA). The sealed vessel was heated to 708C for 2 min and then
cooled in an ice bath.
Received: February 29, 2008
Published online: July 4, 2008
In 12C test experiments with nonlabeled compounds, we
successfully used the formaldehyde–oligomer mixture 5 in a
variety of reaction scenarios including reductive amination of
anilines, oxime and hydrazone formation, and cyclization
reactions. To highlight the efficacy of this mixture as no
carrier added [11C]formaldehyde and to determine specific
activity, we performed a Pictet–Spengler condensation with
tryptamine (Scheme 3). The reaction of tryptamine with 6
occurred readily under acidic conditions affording [11C]-
2,3,4,9-tetrahydro-1H-b-carboline (7) in excellent radiochem-
ical yield. The product was isolated by semipreparative HPLC
using a C18 column, and the mass was determined by
absorbance at 254 nm. Using a portion of [11C]MeI from a
clinical production run, we determined 7 had a specific
activity of 3.0 Cimmolꢀ1 (as compared to 4.5 Cimmolꢀ1 for the
clinical product).[15]
Keywords: formaldehyde · isotopic labeling · N-oxides ·
oxidation · positron emission tomography
.
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Ts =toluenesulfonyl.
Angew. Chem. Int. Ed. 2008, 47, 5989 –5992
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5991

Communications
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