A rapid one-step radiosynthesis of [11C]-d-threo-methylphenidate

Article abstract of DOI:10.1002/jlcr.1824

Carbon-11 labelled d-threo-methylphenidate ([¹¹C]-(1)), a radiopharmaceutical commonly used to image the dopamine transporter, has been labelled in one step using [¹¹C]-methyl triflate. No protection of the nitrogen atom on the piperidine ring of d-threo-ritalinic acid·HCl was required, as O-methylation was favored over N-methylation by performing the methylation in buffered solutions which effectively protonate and protect the amine functionality. The reaction was effectively carried out at room temperature in solution by captive solvent 'LOOP' methods or using conventional glass vials. Copyright

Full text of DOI:10.1002/jlcr.1824

Note
Received 21 May 2010,
Revised 6 July 2010,
Accepted 27 July 2010
Published online 16 September 2010 in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.1824
A rapid one-step radiosynthesis of
[11C]-d-threo-methylphenidate
Matthew D. Moran,a,b Alan A. Wilson,a,b Winston T. Stableford,a Min Wong,a
Ã
Armando Garcia,a Sylvain Houle,a,b and Neil Vasdeva,b
Carbon-11 labelled d-threo-methylphenidate ([11C]-(1)), a radiopharmaceutical commonly used to image the dopamine
transporter, has been labelled in one step using [11C]-methyl triflate. No protection of the nitrogen atom on the piperidine
ring of d-threo-ritalinic acid Á HCl was required, as O-methylation was favored over N-methylation by performing the
methylation in buffered solutions which effectively protonate and protect the amine functionality. The reaction was
effectively carried out at room temperature in solution by captive solvent ‘LOOP’ methods or using conventional glass vials.
Keywords: PET; carbon-11; methyl triflate; methylphenidate
solvents were purchased from commercial sources and were
used without further purification.
Several reaction conditions were explored to produce (1) or
Introduction
d,l-threo-Methylphenidate (RitalinTM) is often prescribed for the
treatment of attention deficit hyperactivity disorder.1 Carbon-11
labelled d-threo-methylphenidate, ((R)-methyl 2-phenyl-2-((R)-
piperidin-2-yl)acetate; [11C]-(1)), is an established radiopharma-
ceutical for imaging the dopamine transporter using positron
emission tomography (PET)2 in both animal and human
subjects.3
[11C]-(1) by methylation of (3) with CH3I, [11C]-CH3I, and [11C]-
CH3OTf. These reactions were performed in DMF or MEK with
bases of various strength (as well as in the absence of base), but
were inferior to those outlined below (Methods D1–D3), as they
gave lower yields and/or more impurities, and were not further
pursued.
The original syntheses of [11C]-(1) utilized the o-nitrophenyl-
sulfenyl group (NPS) to protect the nitrogen atom on the
piperidine ring of d-threo-ritalinic acid, and this precursor (2) was
reacted with [11C]-iodomethane ([11C]-CH3I) in the presence of
base at 801C, followed by deprotection with a mixture of HCl
and mercaptoacetic acid (Scheme 1, Method A).4 Method A has
been modified to employ the sodium salt of N-NPS-ritalinic acid
(Na Á (2)) with a more facile removal of the protecting group
(Scheme 1, Method B) and solid phase extraction for the final
purification.5 Another reported preparation of [11C]-(1) was
accomplished by reacting (2) with [11C]-diazomethane at room
temperature (Scheme 1, Method C).6 However, [11C]-CH2N2 is
not a commonly used [11C]-methylating agent as its present
production is low yielding and cumbersome. In contrast, [11C]-
methyl triflate ([11C]-CH3OTf) is an attractive methylating agent
that is more reactive than [11C]-CH3I, is relatively easy to
prepare,7 and is routinely produced in many laboratories
worldwide. Herein, we report a fast, one-step radiosynthesis of
[11C]-(1) from the acid form of the unprotected precursor, d-
threo-ritalinic acid Á HCl (3) with [11C]-CH3OTf, resulting in good
yields (Scheme 1, Method D).
Radiosynthesis of [11C]-(1) via the ‘LOOP’ method
(Method D1)
Reactions using [11C]-methyl triflate,7 made via [11C]-methyl
iodide,8 were performed inside an HPLC sample loop9 following
a previously described procedure.10 Precursor (3) (0.5 mg) was
dissolved (with vigorous vortexing for ca. 2 min) in a mixture of
72 mL methyl ethyl ketone (MEK) and 8 mL of 0.25 M NaOH/
KH2PO4 phosphate buffer solution (pH = 7.4; referred hitherto
as ‘buffer’), followed by loading onto the HPLC loop. After a
5-minute reaction with [11C]-CH3OTf (reaction time not opti-
mized), the product was purified using a Phemomenex Luna (2)
C18 10 m (250 Â 10 mm) column and a mixture of 20:80 CH3CN/
H2O10.1 N ammonium formate (pH = 4) as the mobile phase
with a flow rate of 7.0 mL/min (l = 254 nm). No radioactivity was
observed after product elution up until 30 min. The purified
[11C]-(1) was formulated as described previously.10 At the end of
aPET Centre, Centre for Addiction and Mental Health, 250 College Street,
Toronto, Ont., Canada M5T 1R8
bDepartment of Psychiatry, University of Toronto, 250 College Street, Toronto,
Ont., Canada M5T 1R8
Experimental
Samples of (1) Á HCl and (3), as well as d,l-threo-methylphenida-
te Á HCl and d,l-erythro/d,l-threo-methylphenidate Á HCl (chiral
HPLC standards), were purchased from JML Biopharm Inc. and
used without further purification. All other reagents and
*Correspondence to: Neil Vasdev, PET Centre, Centre for Addiction and Mental
Health and Department of Psychiatry, University of Toronto, 250 College Street,
Toronto, Ont., Canada M5T 1R8.
E-mail: neil.vasdev@camhpet.ca
J. Label Compd. Radiopharm 2011, 54 168–170
Copyright r 2010 John Wiley & Sons, Ltd.

M. D. Moran et al.
Scheme 1. Radiosynthesis of [11C]-(1) by four different methods (Methods A–D).
synthesis (28 min) the final bottle had 2.770.4 GBq were equivalent to those used for the ‘LOOP’ method (Method
(73711 mCi). The radiochemical purity was determined by D1; vide supra) with similar synthesis times.
analytical HPLC using a Phemomenex Prodigy ODS-Prep 10 m
(250 Â 4.6 mm) column using a flow rate of 3.0 mL/min using Radiosynthesis of [11C]-(1) in a glass V-vial (Method D3)
two mobile phases and wavelengths: (1) 20:80 CH3CN/H2O1
[11C]-Methyl triflate was bubbled (N2 sweep flow of 18 mL/min)
0.1 N ammonium formate, l = 254 nm; (2) 30:70 CH3CN/H2O1
into a solution of (3) (0.5 mg in 72 mL MEK/8 mL 0.25 M buffer at
0.05N ammonium chloride, l = 215 nm. Furthermore, co-injec-
201C) in a 1 mL septum-sealed glass V-vial (vigorously vortexed
for 2 min), fitted with a venting needle piercing the septum.
After 30–45 s, the reaction mixture was quenched with HPLC
buffer (0.6 mL) and purified by semi-preparative HPLC, as
described in Method D1. The overall synthesis time was ca.
30 min.
tions of [11C]-(1) with authentic (1) were performed under
several other HPLC conditions (columns, wavelengths, mobile
phases) to confirm that the N-methylated product was not
obtained. Enantiomeric purity of [11C]-(1) was determined by
chiral HPLC using a Chiralcel OD 10 m (250 Â 4.6 mm) column
(mobile phase: 96:1.95:1.95:0.1 hexanes/MeOH/EtOH/TFA; flow
rate: 1.0 mL/min; l = 254 nm) as previously described.11
Results and discussion
Radiosynthesis of [11C]-(1) in a ‘LOOP’ using an automated
radiofluorination unit (Method D2)
Clinically useful quantities of [11C]-(1) were efficiently and
routinely achieved by reactions of (3) with [11C]-CH3OTf
(Scheme 1, Method D) in MEK/buffer solutions via ‘LOOP’
methods (Methods D1 and D2) or in a glass vial (Method D3).
Radiochemical yields were found to be highest using the ‘LOOP’
method (Method D1). After purification by semi-preparative
Captive solvent [11C]-methylations were also automated using a
GE TRACERlabTM FXFN radiosynthesis module with minor
modifications as described by our laboratory.12 The reaction
and separation conditions for the radiosynthesis of [11C]-(1)
J. Label Compd. Radiopharm 2011, 54 168–170
Copyright r 2010 John Wiley & Sons, Ltd.
www.jlcr.org

M. D. Moran et al.
activity (118763 GBq/mmol; 3.271.7 Ci/mmol), purities, and
synthesis time to that of the ‘LOOP’ methods (Methods D1
and D2).
The original preparation of [11C]-(1) using [11C]-CH3I em-
ployed a suitable N-protected precursor (2),4 leading to a two-
step radiosynthesis: [11C]-methylation (carried out at 801C in the
presence of base), followed by acid deprotection. While
alternative syntheses have been reported,5,6 prior to the present
study no attempt has been made to perform the reaction with
an unprotected precursor in a single step. We postulate herein
that the nitrogen atom in the zwitterionic form of (3) is
effectively protected, by protonation, via judicious control of the
pH of the solution. The use of buffers in radiochemical reactions
has been explored.13,14 Although the pH of mixed solvent/buffer
systems cannot be directly measured,15 reactions of (3) with
[11C]-CH3OTf were performed in several mixtures of MEK or DMF
with different concentrations of phosphate buffer (0.05–1.0 M,
pH = 7.4). In this way, the best condition in our hands (0.5 mg of
(3), 72 mL MEK, and 8 mL of 0.25 M NaOH/KH2PO4 phosphate
buffer solution) resulted in clinically useful quantities of [11C]-(1),
and eliminated the need for elevated temperatures or the use of
a protected precursor.
Figure 1. HPLC chromatogram of the purification of [11C]-(1), prepared via the
‘LOOP’ method (Method D1): (a)
(l = 254 nm).
g trace (tR = 10.2 min), and (b) UV trace
In conclusion, (3), and likely several other related compounds,
can be directly and efficiently O-11CH3 labelled at a carboxylic
acid moiety using [11C]-CH3OTf in appropriately buffered
solutions, thereby eliminating the necessity for protecting
groups on amine functionalities.
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