A new multi-gram synthetic route to labeling precursors for the D2/3 PET agent 18F-fallypride

Article abstract of DOI:10.1016/j.bmcl.2008.07.065

This Letter describes a new multi-gram synthetic protocol for the preparation of the classic tosylate labeling precursor for the D_2/3 PET agent [¹⁸F]fallypride. In the course of our studies, we also discovered two novel labeling prec

Full text of DOI:10.1016/j.bmcl.2008.07.065

Bioorganic & Medicinal Chemistry Letters 18 (2008) 4467–4469
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
A new multi-gram synthetic route to labeling precursors for the D2/3 PET agent
18F-fallypride
*
Kwangho Kim, Nicole R. Miller, Gary A. Sulikowski, Craig W. Lindsley
Department of Chemistry and Pharmacology, Institute of Chemical Biology, Vanderbilt University, 802 Robinson Research Building, Nashville, TN 37235–1822, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
This Letter describes a new multi-gram synthetic protocol for the preparation of the classic tosylate label-
ing precursor for the D2/3 PET agent [18F]fallypride. In the course of our studies, we also discovered two
novel labeling precusors, the previously undescribed mesylate and chloro congeners of fallypride.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 21 June 2008
Revised 15 July 2008
Accepted 16 July 2008
Available online 20 July 2008
Keywords:
PET
D2 antagonist
Imaging agent
Fallypride
Dysfunction in dopaminergic neurotransmission has been
implicated in a number of neuropsychiatric disorders including
Parkinson’s disease, Alzheimer’s disease, schizophrenia, and
Huntington’s disease.1–4 The discovery and development of small
molecule ligands that can selectively target dopamine receptors
(D1–D4), transport, and synthesis is central to the development of
therapeutic agents for the treatment of these complex diseases.1–4
The D2 receptor antagonists fallypride (FP) 1 and desmethoxy
fallypride (DFP) 2 stand out due to their selectivity, affinity, and
reversibility (Fig. 1).5,6
anhydride coupling between the corresponding substituted
benzoic acid 5 and proline-derived amine 6 to afford 7 in an
unspecified yield (Scheme 2).16 Earlier de Paulis reported hydrob-
The corresponding [18F] and [11C]-labeled analogs of 1 have
found utility as positron emission tomography (PET) agents.7–13
In particular, [18F]FP has been employed to study D2/3 receptor
occupancy and density in neuropsychiatric disorders and aging in
both preclinical species and in humans.7–15
The Vanderbilt Institute of Chemical Biology (VICB) established
a Synthesis Core to provide synthetic and medicinal chemistry re-
sources to the biomedical research community across the Vander-
bilt campus, including the Vanderbilt Imaging Center. On one
occasion, a request was made for a multi-gram synthesis of a label-
ing precursor for [18F]fallypride 4, classically accessed by 18F dis-
placement of the corresponding tosylate 3 (Scheme 1).7–15 Upon
examination of the literature, we were dismayed to see that the
classical published synthetic routes to 3 were performed on milli-
gram quantities of material, employed preparative TLC for purifica-
tion and afforded 30–50% yields for every step.8,9 In 2007, Rosch
and co-workers reported a large-scale synthesis utilizing a mixed
Figure 1. Structures of the D2/3 antagonists fallypride (FP), 1, and desmethoxy
fallypride (DFP), 2.
* Corresponding author. Tel.: +1 615 322 8700; fax: +1 615 343 6532.
E-mail address: craig.lindsley@vanderbilt.edu (C.W. Lindsley).
Scheme 1. Synthesis of [18F]fallypride 4. Reagents: (a) 18F, Kryptofix, K2CO3, CH3CN.
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.07.065

4468
K. Kim et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4467–4469
To this end, alcohol 5 was derived from commercially available
methyl benzoate 10 in three steps starting with O-methylation to
afford benzoate 11 in 95% yield (Scheme 3). Hydroboration of 11
followed by treatment with basic peroxide then gave alcohol 12.
Following ester hydrolysis (92%), benzoic acid 5 was treated with
TBSCl and imidazole in DMF to provide TBS protected alcohol 13
in good overall yield. Next, the coupling of 13 with amine 6 (de-
rived in two-steps from L-prolineamide) was examined. Optimal
conditions employed EDCI in combination with HOBt and i-Pr2NEt
as base to provide 14. Under these conditions, the coupled product
was obtained in yields ranging from 45% to 64%. Finally, removal of
the TBS group with TBAF delivered alcohol 7. Standard conditions
then provided the tosylate 15, the immediate precursor to
[
18F]fallypride 4 in seven steps with an overall yield of 11%.18
Importantly, all the steps leading to 14 were conducted on multi-
gram scales with standard column chromatographic purification,
while the final deprotection and tosylation steps were run on 1–
2 gram scales (See Supporting Information).
The silyl protection of 5 and subsequent deprotection steps
were a necessity for the multi-gram synthesis of 15. All attempts
to perform the amide coupling of 5 and 6, with multiple peptide
coupling reagents (EDCI, HATU, TFFH, etc) afforded poor results
(yields less than 20%) and isolation of the extremely polar 7 proved
difficult. Standard normal phase chromatography was insufficient
on large scale to deliver pure 7 for the tosylation step. Thus, we
were required to pursue preparative reverse phase chromatogra-
phy with multiple injections, resulting in large volumes of
CH3CN/H2O/TFA solutions to dry down with longer turn-around.
While the protection/deprotection sequence adds two chemical
steps, the overall yields and efficiency to access pure 15 are mark-
edly improved.
Scheme 2. Existing routes to alcohol 7. Reagents: (a) ClCO2Et, Et3N; 9-BBN, H2O2,
NaOH; (c) TFA, DCM; (d) allyl bromide, K2CO3, DMF.
oration–oxidation of allyl benzamide 8 to give alcohol 9 and fol-
lowing deprotection and N-allylation provide alcohol 7.17 In exam-
ining these synthetic routes, we became concerned with functional
group compatibility under these reaction conditions and therefore
turned our attention to developing a new synthetic route employ-
ing a protected derivative of benzoic acid 5 as a coupling partner.
The major problematic step in the synthesis was the amide cou-
pling between the electron-rich, hindered benzoic acid 13 and
Scheme 3. Improved synthetic route to 15. Reagents: (a) MeI, K2CO3, Me2CO, 95%; (b) i—9-BBN, THF, ii—NaOH, H2O2, 92%; (c) NaOH, THF (aq.), 92%; (d) TBSCl, ImH, DMF, 75%;
(e) 6, EDCI, HOBt, i-Pr2NEt, 45–64%; (f) TBAF, THF, 71%; (g) TsCl, DCM, pyridine, 44%.

K. Kim et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4467–4469
4469
Scheme 4. Synthesis of a novel labeling precursor ClFP 16 and fallypride 1. Reagents: (a) i—SOCl2, toluene, cat. DMF, ii—6, 31%; (b) TBAF, THF, reflux, 55%.
Scheme 5. Synthesis of a novel labeling precursor MsFP 17 and fallypride 1. Reagents: (a) i—MsCl, DCM, Et3N; (b) TBAF, t-BuOH, reflux, 40% over two steps.
amine 6—a historically problematic reaction. We evaluated a num-
ber of coupling reagents (PyBop, BOP, TFFH), but none afforded
advantages over EDCI. One attempted coupling that led to a new
entity involved the treatment of benzoic acid 13 with thionyl chlo-
ride (Scheme 4). Reaction of the intermediate acid chloride with
amine 6 led to the isolation of previously unknown chloride 16,
the result of substitution of the TBS ether for a chloro group, a var-
iation of the Silyl-Durst chlorination.18,19 This new entity 16 (ClFP)
was evaluated as a D2 antagonist, and afforded an IC50 of 17.1 nM.
With 16 in hand, we then evaluated its ability to serve as a labeling
precursor in route to [18F]fallypride 4. Exposure of 16 to TBAF in
THF provided a 55% yield of 1, indicating that this new ClFP conge-
ner 16 is a viable labeling precursor for [18F]fallypride 4. Activity at
the D2 receptor was also confirmed for our synthetic 1 with an IC50
of 5.0 nM, a value in agreement with literature reports.
Supplementary data
Experimental procedures and analytical data for compounds 1,
11-17 are provided. This material is available free of charge via
the Internet at http://www.sciencedirect.com/science/journal/
0960894X. Supplementary data associated with this article can
be found, in the online version, at doi:10.1016/j.bmcl.2008.07.065.
References and notes
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Based on these results, we examined the literature further, and
were surprised to find that the corresponding mesylate analog 17
(MsFP) had never been prepared. To evaluate this potential label-
ing precursor, we intercepted alcohol 7 from the deprotection of
14 and treated it with MsCl in DCM and generated 17 (MsFP); how-
ever, this material was labile and proved difficult to isolate. There-
fore, we generated 17 (MsFP) in situ and immediately treated the
reaction mixture with TBAF in t-BuOH at 85 °C to afford a 40% yield
of 1 (Scheme 5), suggesting that 17 (MsFP) could also serve as a
viable labeling precursor for the preparation of [18F]fallypride 4.18
In summary, we have developed an improved, high yielding,
and scalable synthetic route to the classical labeling precursor 15
for [18F]fallypride 4. During the course of this work, we discovered
16 (ClFP), a novel D2 antagonist and viable labeling precursor for
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[
18F]fallypride 4. This work also prepared and evaluated the previ-
ously unknown mesylate congener, 17 (MsFP), as a labeling precur-
sor, and found that it too was viable. Further studies in this arena
are in progress and will be reported in due course.
Acknowledgments
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The authors thank the Vanderbilt Institute of Chemical Biology,
the Vanderbilt Imaging Center (Dr. Ron Baldwin), and the Vander-
bilt Department of Pharmacology for support of this research.