18F-Fluorodeoxyglycosylamines: Maillard reaction of 18F-fluorodeoxyglucose with biological amines

Article abstract of DOI:10.1002/jlcr.3168

The Maillard reaction of sugars and amines resulting in the formation of glycosylamines and Amadori products is of biological significance, for drug delivery, role in central nervous system, and other potential applications. We have examined the interaction of ¹⁸F-fluorodeoxyglucose ( ¹⁸F-FDG) with biological amines to study the formation of ¹⁸F-fluorodeoxyglycosylamines (¹⁸F-FDGly). Respective amines N-allyl-2-aminomethylpyrrolidine (NAP) and 2-(4′-aminophenyl)-6- hydroxybenzothiazole (PIB precursor) were mixed with FDG to provide glycosylamines, FDGNAP and FDGBTA. Radiosynthesis using ¹⁸F-FDG (2-5 mCi) was carried out to provide ¹⁸F-FDGNAP and ¹⁸F-FDGBTA. Binding of FDGBTA and ¹⁸F-FDGBTA was evaluated in human brain sections of Alzheimer's disease (AD) patients and control subjects using autoradiography. Both FDGNAP and FDGBTA were isolated as stable products. Kinetics of ¹⁸F-FDGNAP reaction indicated a significant product at 4 h (63% radiochemical yield). ¹⁸F-FDGBTA was prepared in 57% yield. Preliminary studies of FDGBTA showed displacement of ³H-PIB (reduced by 80%), and ¹⁸F-FDGBTA indicated selective binding to Aβ-amyloid plaques present in postmortem AD human brain, with a gray matter ratio of 3 between the AD patients and control subjects. We have demonstrated that ¹⁸F-FDG couples with amines under mild conditions to form ¹⁸F-FDGly in a manner similar to click chemistry. Although these amine derivatives are stable in vitro, stability in vivo and selective binding is under investigation.

Full text of DOI:10.1002/jlcr.3168

Research Article
Received 6 September 2013,
Revised 3 October 2013,
Accepted 31 October 2013
Published online 11 December 2013 in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.3168
18
F-Fluorodeoxyglycosylamines: Maillard
18
reaction of F-fluorodeoxyglucose with
biological amines
†
*
Aparna Baranwal, Himika H. Patel, and Jogeshwar Mukherjee
The Maillard reaction of sugars and amines resulting in the formation of glycosylamines and Amadori products is of
biological significance, for drug delivery, role in central nervous system, and other potential applications. We have
examined the interaction of 18F-fluorodeoxyglucose (18F-FDG) with biological amines to study the formation of 18F-
fluorodeoxyglycosylamines
(
18F-FDGly). Respective amines N-allyl-2-aminomethylpyrrolidine (NAP) and 2-(4′-
aminophenyl)-6-hydroxybenzothiazole (PIB precursor) were mixed with FDG to provide glycosylamines, FDGNAP and
FDGBTA. Radiosynthesis using 18F-FDG (2–5 mCi) was carried out to provide 18F-FDGNAP and 18F-FDGBTA. Binding of
FDGBTA and 18F-FDGBTA was evaluated in human brain sections of Alzheimer’s disease (AD) patients and control
subjects using autoradiography. Both FDGNAP and FDGBTA were isolated as stable products. Kinetics of 18F-FDGNAP
reaction indicated a significant product at 4 h (63% radiochemical yield). 18F-FDGBTA was prepared in 57% yield.
Preliminary studies of FDGBTA showed displacement of 3H-PIB (reduced by 80%), and 18F-FDGBTA indicated selective
binding to Aβ-amyloid plaques present in postmortem AD human brain, with a gray matter ratio of 3 between the AD
patients and control subjects. We have demonstrated that 18F-FDG couples with amines under mild conditions to form
18F-FDGly in a manner similar to click chemistry. Although these amine derivatives are stable in vitro, stability in vivo
and selective binding is under investigation.
Keywords: 18F-FDG; Maillard reaction; quasi-Amadori product
Because [18F]FDG contains the aldehyde group, but lacks the
Introduction
hydroxyl group at the 2′-position, it is potentially capable of
The Maillard reaction of sugars and amines results in the formation
undergoing the Maillard reaction with amines to form the
of glycosylamines and Amadori products.1 These are of great
biological significance, for drug delivery as prodrugs, role in central
nervous system, and other potential applications.2,3 The formation
of Amadori product occurs by the reaction of the amine with
the aldehyde at the 1-position of glucose to form a Schiff base 3
(Figure 1), followed by dehydration and rearrangement of
the hydroxyl at the 2-position to form a ketone 5 (Figure 1).4,5 It
has been shown that glucose reacts with serotonin to undergo
the Maillard reaction and produce an Amadori product, 6
desoxyfructoserotonin.6 This Amadori product has been used to
elevate brain serotonin levels in mice studies.3 Maillard reaction
products have been observed and assessed in aging, diabetes,
and Alzheimer’s disease (AD) pathologies..7,8
Glycosylamines are significant in various aspects of human
physiology. Involved in the characterization of glycoprotein
and glycopeptides, glycosylamines have become an area of
interest because of their involvement in metabolic pathways.
An Amadori product obtained from the Maillard reaction is
fructoselysine 7 (Figure 1) that is present in tissue proteins.7
2-18F-Fluorodeoxyglucose 8 ([18F]FDG; Figure 2), a 2-deoxy
analog of glucose is used clinically in various studies for evaluating
alterations in glucose metabolic rates using positron emission
tomography.9,10 [18F] FDG is phosphorylated by hexokinase and
is trapped in the cell in the form of [18F]FDG-6-phosphate because
of the absence of the hydroxyl group at the 2′ position of glucose.
Schiff base 10 ([18F]FDGly, a quasi-Amadori product; Figure 2)
without progressing to the classical Amadori product as shown
in Figure 1.4
Our goal here was to examine if fluorodeoxyglucose (FDG)
reacts with simple amines to form the Maillard reaction products.
In this paper, we have investigated the following: (1) the formation
of fluorodeoxyglycosylamines (FDGly) as shown in Figure 2 using
the model amine N-allyl-2-aminomethylpyrrolidine (NAP) to
generate fluorodeoxyglycosyl-N-allyl-2-aminomethylpyrrolidine
(FDGNAP), 11 (Figure 2). This methodology was then extended to
biological amines of interest that may interact with Aβ-amyloid
plaque, 2-(4′-aminophenyl)-6-hydroxybenzothiazole (BTA) to
form fluorodeoxyglycosyl-2-(4′-aminophenyl)-6-hydroxybenzothiazole
(FDGBTA), 12 (Figure 2); (2) radiosynthesis of 18F-FDGNAP and
18F-FDGBTA; and (3) biological evaluation of FDGBTA and 18F-FDGBTA.
Preclinical Imaging, Department of Radiological Sciences, University of
California – Irvine, Irvine, CA 92697, USA
*Correspondence to: Jogesh Mukherjee, B138 Medical Sciences, Department of
Radiological Sciences, University of California – Irvine, Irvine, CA 92697-5000, USA.
E-mail: j.mukherjee@uci.edu
† Presented at the Annual Meeting of the Society of Nuclear Medicine, Vancouver,
Canada, June 8–12, 2013.
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Copyright © 2013 John Wiley & Sons, Ltd.

A. Baranwal et al.
Figure 1. (A) Reaction scheme showing Maillard reaction of glucose (1) and substituted amine resulting in the formation of Schiff base (3) and subsequent isomerization
to the Amadori product (5). (B) Example of Amadori products, desoxyfructoseserotonin (6), and fructoselysine (7).
Figure 2. (A) Generic synthesis scheme of 18F-FDG (8) with amines leading to the 18F-FDGly (10), quasi-Amadori product. This is expected from reaction of 18F-FDG with
amines. (B) Two synthesized FDGly products are reported here: FDGNAP (11) and FDGBTA (12).
solution. Fluorine-18 radioactivity was counted in a Capintec dose
calibrator while low level counting was carried out in a well-counter
(Cobra quantum, Packard Instruments Co., Boston, MA, USA).
Materials and methods
General methods
Radioactive thin layer chromatographs were obtained by scanning
in a Bioscan system 200 Imaging scanner (Bioscan, Inc., Washington,
DC, USA). Human postmortem brain slices were obtained on a (Leica
Microsystems Inc., Deerfield, IL USA) 1850 cryotome. Fluorine-18
All chemicals and solvents were of analytical or HPLC grade from
(Aldrich Chemical Co., Milwaukee, WI USA) and (Fisher Scientific, Inc.,
Pittsburgh, PA USA). 2-(4′-Aminophenyl)-6-hydroxybenzothiazole
(also referred as 6-OH-BTA-0) was purchased from ABX Chemicals,
autoradiographic studies were carried out by exposing tissue
Radeberg, Germany. Electrospray mass spectra were obtained on a
samples on storage phosphor screens. The apposed phosphor
Model 7250 mass spectrometer (Micromass LCT, Waters, Milford,
screens were read and analyzed by (OptiQuant, Perkinelmer.
MA USA). Proton NMR spectra were recorded on a (Bruker Biospin
Walthman, MA USA) acquisition and analysis program of the
Corporation, Billerica, MA USA) OMEGA 500 MHz spectrometer.
Cyclone Storage Phosphor System (Packard Instruments Co.).
Analytical thin layer chromatography (TLC) was carried out on silica
coated plates (Baker-Flex, Phillipsburg, NJ, USA). Chromatographic
Synthesis
separations were carried out on preparative TLC (silica gel GF
20 × 20 cm, 2000 μm thick; Alltech Assoc. Inc., Deerfield, IL, USA) or
silica gel flash columns or semi-preparative reverse-phase columns
FDGNAP
using the (Gilson, Inc., Middleton, WI USA) HPLC systems. 18F-FDG To synthesize FDGNAP, 7 μl (5.50 × 10À5 mol) of NAP and 5.0 mg
was obtained from (PETNET, Culver City, CA USA) in sterile saline (2.75 × 10À5 mol) of FDG were dissolved in 0.2 ml acetate buffer
J. Label Compd. Radiopharm 2014, 57 86–91
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A. Baranwal et al.
(0.1 M sodium acetate-acetic acid, pH4.2) and 5 μl aniline as a 18F-FDGBTA). The purified 18F-FDGBTA (18) was obtained in 57%
catalyst. The solution was left at room temperature for 4 h. radiochemical yield with specific activities of approximately
Preparatory TLC was performed using 9:1 dichloromethane/ 1000 Ci/mmol (Figure 4). This was used for biological studies.
methanol to provide FDGNAP in 31% yield. Mass Spectrometry
(MS): m/z 305 [M + H]+. Aniline used as a catalyst also showed small
In vitro studies
amounts (approximately 20–30%) of the FDG adduct (MS: m/z 280
3H-PIB binding
[M + Na]+).
Human hippocampus sections (7 μm thick) were preincubated in
FDGBTA
10% alcohol Phosphate Buffered Saline (PBS) buffer for 10 min.
For the synthesis of FDGBTA, 2.0 mg (3.29 × 10À5 mol) of BTA and
The brain sections were placed in a glass chamber and incubated
1.5 mg (1.65 × 10À5 mol) of FDG were dissolved in 0.25 ml EtOH.
3
with H-PIB (2 μCi/cc) in 10% alcohol PBS buffer, pH 7.4 at 37 °C
The solution was heated for 1 h at 99 °C. Retention time of BTA
was 11.3 min while that of FDGBTA was 7.5 min (reverse-phase
10 μm C-18 HPLC column, 10 × 250 mm, 40% 0.1% triethylamine
in water:60% acetonitrile, flow rate 1.5 ml/min). Preparatory TLC
was performed using 9:1 dichloromethane/methanol solvent to
extract FDGBTA in 58% yield. MS: m/z 429 [M + Na]+(Figure 3).
for 1 h. The slices were then washed with cold 10% alcohol PBS
buffer (2 × 3 min) and cold deionized water for 1 min. The brain
sections were air dried, exposed overnight on a phosphor film,
and then placed on the Phosphor Autoradiographic Imaging
System/Cyclone Storage Phosphor System (Packard Instruments
Co.). Regions of interest (ROIs) were drawn on the slices, and the
3
extent of binding of H-PIB was measured with DLU/mm2 using
Radiosynthesis
the OptiQuant acquisition and analysis program (Packard
Instruments Co.).
11C-PIB binding
18F-FDGNAP
To synthesize 18F-FDGNAP (15), 9 μl aniline catalyst and 5 μl NAP
(13) were dissolved in 0.1 ml acetate buffer, and 0.1 ml of 1 mCi
18F-FDG (8, in 0.9% sterile saline) was added to this mixture.
The reaction was monitored by radio-TLC at 0.17, 1, 2, 3, and 4 h
using the Optiquant software, and the product was confirmed by
coelution of reference standard.
Human hippocampus sections (7 μm thick) were preincubated
(40% EtOH:60% deionized water) for 10 min. The brain sections
were placed in a glass chamber and incubated with 11C-PIB
(20 μCi/cc) in 40% EtOH:60% deionized water at 37 °C for 1 h.
The slices were then washed with cold millipore water, 70%–
90% EtOH, for 2, 1, 1, 1, and 1 min. The brain sections were air
dried, exposed overnight on a phosphor film, and then placed
18F-FDGBTA
For the synthesis of 18F-FDGBTA (18), 1 mg (4.13 × 10À6 mol) BTA on the Phosphor Autoradiographic Imaging System/Cyclone
(16) was dissolved in 0.2 ml EtOH and 0.1 ml of 2 to 5 mCi. 18F-FDG Storage Phosphor System (Packard Instruments Co.). ROIs were
(8, in 0.9% sterile saline) was dissolved in the solution. The solution drawn on the slices, and the extent of binding of 11C-PIB was
was heated for 2 h at 99 °C. Preparatory TLC (9:1 dichloromethane/ measured with DLU/mm2 using the OptiQuant acquisition and
methanol) was used to isolate and purify 18F-FDGBTA (rf = 0.3 for analysis program (Packard Instruments Co.).
Figure 3. (A) Radiosynthesis of 18F-FDGNAP (15) showing reaction of 18F-FDG (8) with NAP (13) and subsequent dehydration of intermediate 14. (B) Kinetics of 18F-
FDGNAP reaction from 0.17 to 4 h showing progressive increase in radiochemical yield of 15. (C) Radio-TLC of 18F-FDGNAP reaction mixture at 10 min of reaction time,
showing the presence of product along with some 18F-FDG, and (D) Radio-TLC at 4h of reaction time showing significant increase in product.
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A. Baranwal et al.
18F-FDGBTA binding
with NAP and BTA. The reaction kinetics of 18F-FDG with NAP
at room temperature was monitored by radio-TLC at 0.17, 1, 2,
3, and 4 h (Figure 3C and D). Over time, the 18F-FDGNAP product
increased and the 18F-FDG decreased (Figure 3B). The amount
of 18F-FDG aniline was consistently around 25–30% in solution
and served as an intermediate product for the formation of
18F-FDGNAP. 18F-FDGNAP increased over time from 21% to
63% while 18F-FDG decreased to 10% in 4 h (Figure 3B).
The reaction of BTA with 18F-FDG was carried out in ethanol
without the catalyst, aniline, and thus required heating. The
radioactive product 18F-FDG BTA was purified by radio-TLC in
57% yield, and few significant side products were observed
(Figure 4B).
Human hippocampus sections (7 μm thick) were preincubated in
10% alcohol PBS buffer for 10 min. The brain sections were
placed in a glass chamber and incubated with 18F-FDGBTA
(2 μCi/cc) in 10% alcohol PBS buffer, pH 7.4 at 37 °C for 1 h. The
slices were then washed with cold 10% alcohol PBS buffer
(2 × 3 min) and cold deionized water for 1 min. The brain sections
were air dried, exposed overnight on a phosphor film, and then
placed on the Phosphor Autoradiographic Imaging System/
Cyclone Storage Phosphor System (Packard Instruments Co.).
ROIs were drawn on the slices, and the extent of binding of
18F-FDGBTA was measured with DLU/mm2 using the OptiQuant
acquisition and analysis program (Packard Instruments Co.).
The synthesis and radiosynthesis of FDGly occurred at room
temperature by the addition of the substituted amines to FDG
and may thus be akin to click chemistry.12 Thus, this synthetic
approach may be considered similar to click chemistry using
FDG. This method may be applied generally to various amines
using the simple reaction conditions described here, similar to
click chemistry approaches with other substrates.13 It may
therefore be used for rapid radiosynthesis using 18F-FDG as
exemplified in the preparation of 18F-FDGNAP and 18F-FDGBTA.
Results and discussion
Fluoro-2-deoxyglucose reacted with both the primary aliphatic
amine (NAP) and the substituted aniline derivative (BTA) to
provide stable products, 11 and 12 (Figure 2). A classical
Amadori product, similar to that found with glucose 5 (Figure 1),
is not expected because of the fluorine at the 2-position in FDG.
Structures 11 and 12 are Schiff bases and may be considered as
quasi-Amadori products resulting from the Maillard reaction as
shown in Figure 1. The fluorine present at the 2-position traps
the Schiff base as a quasi-Amadori product. Reactions were
carried out under aqueous and nonaqueous conditions with
little effect on yields. Addition of aniline as a catalyst increased
the yields as reported previously.11
Based on our findings with unlabeled FDG, an 18F-FDGly quasi-
Amadori product was expected from the reaction of 18F-FDG
Figure 5. (A) Human postmortem brain autoradiographs showing 3H-PIB binding to
AD brain slices. Total binding (left), competition with 10μM FDGBTA (middle) and
nonspecific binding, 10 μM PIB (right). (B) Location of gray matter and white matter
on the scanned brain slices of (A). (C) Graph showing the relative displacement of
3H-PIB by FDGBTA based on autoradiographs in the gray and white matter.
Figure 4. (A) Radiosynthesis of 18F-FDGBTA (18) showing reaction of 18F-FDG (8)
with BTA (16) and subsequent dehydration of intermediate 17. (B) Radio-TLC of
18F-FDGBTA (18) reaction mixture, showing the presence of product.
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A. Baranwal et al.
Figure 6. (A) Structure of 11C-PIB. (B) Binding of 11C-PIB on control versus AD brain. (C) Graph shows the relative binding of 11C-PIB on control versus AD brain slices based
on autoradiographs. (D) Structure of 18F-FDGBTA. (E) Binding of 18F-FDGBTA on control versus AD brain. (F) Graph shows the relative binding of 18F-FDGBTA on control
versus AD brain slices based on autoradiographs.
Because FDGBTA is an analog of PIB, which is known to bind to in vivo relevance of the formation of 18F-FDGly during 18F-FDG
human Aβ-amyloid plaques, we tested the competition of both studies has yet to be determined.
PIB and FDGBTA with postmortem human brain Aβ-amyloid sites
labeled with 3H-PIB (Figure 5A). Preliminary studies indicated
Conclusions
that at 10 μM concentration, 3H-PIB was displaced from the
Fluorodeoxyglucose couples with amines under mild conditions
to form FDGly, which are stable, isolated quasi-Amadori
products. We have demonstrated that 18F-FDG couples with
amines under appropriate conditions to form 18F-FDGly. Although
these amine derivatives are stable in vitro and exhibit biological
properties, stability in vivo is under investigation. Additionally,
reductive amination to produce reduced FDGly is underway in
order to enhance in vivo stability.
Aβ-plaque binding sites by FDGBTA and PIB, and the reduction
in the gray matter areas was >80% (Figure 5C). A more detailed
dose–response study is planned in order to obtain the binding
affinity of FDGBTA for these sites.
Radiolabeled 18F-FDGBTA (Figure 6D) was evaluated and
compared with 11C-PIB (Figure 6A) for binding to postmortem
human brain Aβ-amyloid sites. As expected 11C-PIB exhibited
significant binding to AD brain gray matter as shown previously
(Figure 6B), whereas binding of 18F-FDGBTA was found to be
nonuniform but exhibited regions of high binding (Figure 6E).14
Ratio of AD brain versus control subjects was 6 for 11C-PIB, while
that for 18F-FDGBTA was 3. In contrast, 18F-FDG did not exhibit any
binding to the gray matter areas of AD subjects. These findings
suggest that 18F-FDGBTA is stable in vitro and exhibits biological
properties similar to 11C-PIB with lower ratios, suggesting that
either the affinity of FDGBTA may be lower than PIB or there may
be additional sites of binding due to a significant difference in
the size of the substituent (11C-methyl in PIB versus 18F-FDG in
FDGBTA).
Acknowledgements
Research support was provided by NIH AG029479 and DK092917.
We like to thank Christopher Liang for technical assistance. We
would like to thank Mr. Said Shokair at the Undergraduate Research
Opportunities Program (UROP) of the University of California-Irvine
for summer support (AB and HHP) through the ID-SURE program.
Conflict of Interest
The authors did not report any conflict of interest.
Our preliminary studies suggest that 18F-FDGly are stable
in vitro and exhibit biological properties. Presence of glucose-
derived Amadori products have been reported in vivo and their
use suggested as prodrugs (e.g., for the timed-release of
serotonin).15 However, there have been no in vivo studies on
the Maillard reactions of deoxyglucose or FDG with various
biological amines (proteins, lipids, or small molecules). Therefore,
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