Gallium Fluoride Complexes with Acyclic Bispicolinic Ligands as Potential New Fluorine-18 Labelled Imaging Agents

Article abstract of DOI:10.1002/ejic.202000547

The positron-emitting radionuclide, fluorine-18, is used to radiolabel molecules to develop tracers for diagnostic imaging with positron-emission tomography. There is growing interest in the potential of using strong coordinate bonds between electropositive Ga(III) and electronegative fluoride (≈ 557 kJ/mol) to provide new methods of incorporating fluorine-18 into molecules. The potential of gallium(III) complexes with acyclic pentadentate bispicolinic acid containing ligands (H₂L^1–3) to form ternary complexes with fluoride, [GaL^1–3F] was investigated with a view to developing new methods for fluorine-18 radiolabelling. A solid-phase peptide synthesis approach was used to produce a bispicolinic acid chelator with a lysine residue. Characterisation of [GaL¹X] (X = OH, Cl, F) by X-ray crystallography revealed that L¹ acted as dianionic N₂O₂ donor to the Ga(III) with the fifth site occupied by a monodentate anion (OH^–, Cl^– or F^–). Despite its high stability in aqueous mixture and [D₆]DMSO and the straightforward synthesis of [GaL¹F], it was only possible to form the radioactive analogue [¹⁸F][GaL¹F] in low radiochemical yields.

Full text of DOI:10.1002/ejic.202000547

European Journal of Inorganic Chemistry
Accepted Article
Title: Gallium Fluoride Complexes with Acyclic Bispicolinic Ligands as
Potential New Fluorine-18 Labelled Imaging Agents
Authors: HuiJing Koay, Mohammad B. Haskali, Peter D. Roselt,
Jonathan M. White, and Paul Stephen Donnelly
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
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To be cited as: Eur. J. Inorg. Chem. 10.1002/ejic.202000547
Link to VoR: https://doi.org/10.1002/ejic.202000547
0
1/2020

European Journal of Inorganic Chemistry
10.1002/ejic.202000547
FULL PAPER
Gallium Fluoride Complexes with Acyclic Bispicolinic Ligands as
Potential New Fluorine-18 Labelled Imaging Agents
[
a]
[b]
[b]
[a]
HuiJing Koay, Mohammad B. Haskali, Peter D. Roselt, Jonathan M. White, and Paul S.
[
a]
Donnelly*
Abstract: The positron-emitting radionuclide, fluorine-18, is used to
radiolabel molecules to develop tracers for diagnostic imaging with
positron-emission tomography. There is growing interest in the
potential of using strong coordinate bonds between electropositive
Ga(III) and electronegative fluoride (~ 557 kJ/mol) to provide new
methods of incorporating fluorine-18 into molecules. The potential of
gallium(III) complexes with acyclic pentadentate bis-dipicolinic acid
electropositive group 13 elements Al(III) and Ga(III) and
-
electronegative F to develop fluorine-18 labelled PET diagnostic
imaging agents. The principle behind this approach is based on
-
the strength of the bonds between F and Al(III) and Ga(III) cations
(bond dissociation energies of Al-F and Ga-F are 665 and 557
kJ/mol respectively) that are known to be higher than the C-F
bond (536 kJ/mol).[3] In comparison, the bond dissociation
energies of Al-O and Ga-O are 512 and 285 kJ/mol respectively.[3]
The first fluorine-18 labelled peptide using an Al(III) complex was
reported in 2009.[4] Since the initial report, fluorine-18 labelling
using Al(III) complexes has been explored extensively, mainly
focusing on the use of 1,4,7-triazacyclononane-1,4-diacetic acid
(NODA) and 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA)
analogues.[5] A limitation of the Al(III)-F approach is that the
formation of [ F]Al(III)-F- complexes requires heating to a
relatively high temperature typically above 100 °C. This
methodology is only suitable for labelling peptides or molecules
that are stable at high temperature. The use of the group 13
congener, gallium, has been suggested as a viable alternative to
1-3
containing ligands (H
2
L
) to form ternary complexes with fluoride,
1-3
[
GaL F] was investigated with a view to developing new methods for
fluorine-18 radiolabelling. A solid-phase peptide synthesis approach
was used to produce a bis-dipicolinic acid chelator with a lysine
1
residue. Characterisation of [GaL X] (X= OH, Cl, F) by X-ray
1
crystallography revealed that L acted as dianionic N
2
O
2
donor to the
-
-
-
Ga(III) with the fifth site occupied by a monodentate anion (OH , Cl or
-
18
F ). Despite its high stability in aqueous mixture and d
6
-DMSO and the
1
straightforward synthesis of [GaL F], it was only possible to form the
18
1
radioactive analogue [ F][GaL F] in low radiochemical yields.
-
complexes containing an Al(III)-F bond as the incorporation of
Introduction
fluorine-18 into Ga(III) complexes proved to be achievable at
room temperature or 80 °C.[6]
Molecular imaging with positron emission tomography (PET) can
be used to assist clinicians in diagnosis and monitoring of
progression of disease.[1] The technique relies on molecules
radiolabelled with a positron-emitting radionuclide called ‘tracers’
injected into patient at ‘trace’ concentrations. The interaction of
such tracers and the biological system provides quantitative
information regarding the physiological and biochemical
processes based on the three-dimensional images of the
biodistribution of the tracers. Among the favourable properties of
Macrocyclic ligands are often employed to coordinate metal ions
for radiopharmaceutical applications, but a family of acyclic
ligands based on picolinic acid have been identified as being
suitable ligands to coordinate a variety of different radionuclides.
The 1,2-[[6-carboxy-pyridin-2-yl]-methylamino]ethane (H
ligand and its derivatives feature two picolinic acids joined by a
diamine backbone. The dedpa chelator coordinates to
Ga]Ga(III) at room temperature within minutes to form a six-
2
dedpa)
H
2
[67/68
coordinate complex and is stable for at least 2 h (Figure 1).[7] In
18
-
the positron-emitting isotope fluorine-18 ([ F]F ) are the high
positron decay ratio (97%), low positron energy (635 keV) and the
relatively small size of the radionuclide mean that it can often be
incorporated into organic molecules without significant changes
to biochemical interactions.[2] Conventional approaches to
radiolabelling with fluorine-18 involve the formation of a covalent
this work, we aimed to prepare coordinatively unsaturated Ga(III)
complexes with picolinic acid containing ligands of lower denticity
-
to enable the formation of ternary Ga(III)-F complexes. We
focused on a variation where two picolinic acids are linked at the
6
’ position via two methylene bridges joined through a single
secondary amine dipicolinic acid (dpa). The synthesis of the
dpa ligand and its coordination chemistry with Ga(III) and La(III)
18
C- F bond. There is growing interest in developing alternative
strategies utilising the coordinate bond formation between the
H
2
was published by Orvig et. al.[8]
[
[
a]
b]
Dr. HuiJing Koay, Prof. Jonathan M. White, Prof. Paul S. Donnelly
School of Chemistry and Bio21 Molecular Science and Biotechnology Institute
University of Melbourne
Melbourne, Victoria 3010, Australia
E-mail: pauld@unimelb.edu.au
Dr. Mohammad B. Haskali, Dr. Peter D. Roselt
Centre for Cancer Imaging
Peter MacCallum Cancer Centre
Melbourne, Victoria 3000 Australia
1
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European Journal of Inorganic Chemistry
10.1002/ejic.202000547
FULL PAPER
was functionalised with two dipicolinic acid molecules by the
addition of an excess of methyl 6-(bromomethyl)picolinate in
dichloromethane (DCM) with N,N-Diisopropylethylamine (DIPEA)
(
Scheme 2). The product (7) was cleaved from the resin beads
using an aqueous solution of trifluoroacetic acid (TFA) and
triisopropylsilane (TIPS) to afford compound (8). The methyl ester
protecting groups were removed under acidic conditions to give
H
2
L3·xHCl.
Figure 1. Chemical structures of [18F][AlF(NOTA-Bn-NCS-peptide)],
[18
F][GaF(Bn(CH
O)].
COO)
2 2
-tacn)], [18F][GaF(BnMe -tacn)], [Ga(dedpa)]+ and
2
[
Ga(dpa)(H
2
Results and Discussion
Synthesis and Characterisation. A ‘dpa’ chelator with a benzyl
functional group on the central nitrogen, H
L1 was synthesised by
2
minor modifications of a literature procedure.[9] Esterification of
the carboxylic acid groups of 2,6-pyridinedicarboxylic acid (1)
allowed isolation of dimethyl pyridine-2,6-dicarboxylate (2)
(
Scheme 1). A selective reduction of one methyl ester of (2) with
sodium borohydride in methanol gave methyl 6-
hydroxymethyl)picolinate (3). Treatment of (3) with phosphorus
tribromide in anhydrous dichloromethane yielded methyl 6-
bromomethyl)picolinate (4). Reductive amination reaction
Scheme 2. Synthesis of H
Black circle indicates polymer-bound resin beads.
L3·HCl using the solid-phase peptide synthesis.
2
(
(
2
3
The preparation of L and L demonstrates the capacity of this
family of ligands to be further elaborated to incorporate biological
targeting molecules. Investigations of the coordination chemistry
focused on L1 in this work. The Ga(III) complexes, [GaL (OH)]
and [GaL1-2Cl] were synthesised in anhydrous ethanol at 60 C
under an atmosphere of nitrogen (Scheme 3). Analysis of both
complexes by ESI-MS gave signals at m/z 444.05 and 488.037
for [GaL1]+ and [GaL2]+ respectively with the expected isotope
patterns.
between two equivalents of methyl 6-(bromomethyl)picolinate (4)
and benzylamine in anhydrous acetonitrile followed by hydrolysis
of the methyl ester functional groups with 5 M HCl gave the
1
product
H
2
L1·HCl.
A
bifunctional ligand containing
a free
o
carboxylic acid group,
H
2
L2, was prepared by replacing
benzylamine with aminobenzoic acid, which allowed the isolation
of (6). The compounds were characterised by 1H and 13C{ H}
nuclear magnetic resonance (NMR) spectroscopy and
electrospray ionisation-mass spectrometry (ESI-MS).
1
Scheme 3. Synthesis of [GaL OH)] and [GaL1-2Cl].
1
Scheme 1. Synthesis of H
2 2
L1·HCl and H L2·xHCl.
Upon coordination to Ga(III), there is an upfield shift of the signals
attributed to the methylene protons of H
2 2
L1 and H L2 as well as a
To prepare a versatile ligand that could be inserted at any position
along a peptide sequence, a single amino acid chelate (SAAC)[10]
variant of ‘dpa’ was prepared using solid-phase peptide synthesis
significant change in resonance attributed to the aromatic protons
1
13
1
1
(Figure 2). The H and C{ H} NMR spectra of [GaL (OH)] and
1
6
[GaL Cl] in d -DMSO were identical.
(
SPPS). The x-amine of lysine that had been immobilised on resin
2
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European Journal of Inorganic Chemistry
10.1002/ejic.202000547
FULL PAPER
1
1
1
2
2
Figure 2. Regions of H NMR spectra of H
2
L , [GaL (OH)], H
2
L and [GaL Cl]. Asterisk indicates residual solvent peak.
1
Crystals suitable for single X-ray crystallography of H
2
L1·HCl,
The fluoride-containing complex, [GaL F], was readily obtained
1
1
1
1
1
by treatment of either [GaL (OH)] or [GaL Cl] with potassium
fluoride (Scheme 4). Analysis of [GaL F] by 19F NMR
[GaL (OH)], [GaL Cl] and [GaL F] were grown by evaporation of
1
an aqueous solution of the compounds at room temperature
spectroscopy revealed a single resonance at d
F
= -141 ppm,
(Figure 3). The ‘free’ ligand, H
2
L1·HCl, crystallised with one
-
confirming the formation of a Ga(III)-F bond. In addition, the
molecule of hydrochloric acid with the hydrogen bonding between
1
1
-
resonances in the H NMR spectrum of [GaL F] slightly shifted
Cl and three hydrogen atoms attached to the central nitrogen
1
1
compared to [GaL (OH)] and [GaL Cl].
atom (N(2)) and two oxygen atoms (O(1) and O(3)). For each
1
complex, L acts as a tetradentate dianionic N
2
O
2
donor to the
Ga(III). The tertiary nitrogen atom, N(2), is involved in a close
contact with the Ga(III) (Ga(1)-N(2) ~ 2.440 (2) – 2.471 (2) Å) but
this distance is greater than the sum of the effective ionic radii for
Ga-N (Van der Waals radii of Ga-N ~2.08 Å) so the complexes
are best described as five-coordinate. Calculation of the tau
parameters confirmed the coordination geometries of each
complex as best described as distorted square pyramidal.[11] The
Ga(1)-N(1) and Ga(1)-N(3) bond lengths range from 2.001 Å to
2
.075 Å, and the Ga(1)-O(1) and Ga(1)-O(3) bond lengths range
from 1.981 Å to 2.056 Å (Table 1). In each of the Ga(III)
Scheme 4. Synthesis of [GaL OH)] and [GaL1-2Cl].
1
complexes, the fifth site is occupied by a monodentate anion (OH ,
-
-
-
Cl or F ).
1
1
1
1
Figure 3. ORTEP representations of the X-ray crystal structures (30% ellipsoids) of (a) H
2
L ·HCl, (b) [GaL (OH)]·5H
2
O, (c) [GaL Cl] and (d) [GaL F]·5H
2
O with
solvent and selected hydrogen atoms omitted for clarity.
3
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European Journal of Inorganic Chemistry
10.1002/ejic.202000547
FULL PAPER
Table 1. Selected bond lengths (Å) for the Ga(III) complexes.
distinct peaks corresponding to each Ga(III) complexes (Figure
6c).
Bond length
Å)
[GaL1(OH)]
[GaL1Cl]
[GaL1F]
(
Ga(1)-N(1)
Ga(1)-N(2)
Ga(1)-N(3)
Ga(1)-O(1)
Ga(1)-O(3)
Ga(1)-O(5)
Ga(1)-Cl(1)
Ga(1)-F(1)
2.029(2)
2.471(2)
2.075(2)
2.056(2)
2.006(2)
1.831(2)
2.001(2)
2.442(1)
2.072(2)
2.002(2)
1.981(1)
2.063(2)
2.440(2)
2.012(2)
1.996(2)
2.024(2)
2.2194(6)
1.797(2)
Figure 5. 1H NMR spectrum of [GaL (OH)] and TFA (0.1%) in d
1
-DMSO upon
6
1
The Ga(1)-F(1) bond length of [GaL F] was found to be 1.797(2)
Å, which is relatively short. The ORTEP representation revealed
an extensive hydrogen bonding (F…H-OH) interaction between
F- and the lattice water molecules (Figure 4).
1
L1·HCl (e).
addition (a), at 1 h (b), 3 h (c) and 24 h (d). H NMR spectrum of H
2
Figure 4. ORTEP representation of the X-ray crystal structure (30% ellipsoids)
1
of the hydrogen bonding network of [GaL F]·5H
2
O. Selected hydrogen atoms
and solvent atoms have been omitted for clarity.
Stability of Ga(III) complexes. Acquisition of H and 19F NMR
1
1
spectra of a mixture of [GaL F] in d
6
-DMSO over several weeks
1
revealed no shift changes to the spectra demonstrating [GaL F]
is stable in DMSO for several weeks. As suspected, the Ga(III)
complexes are susceptible to strong acids likely due to
protonation of the carboxylic acid groups. Analysis by 1H NMR
1
1
Figure 6. RP-HPLC chromatogram (UV absorbance at l 254 nm) of (a) [GaL Cl]
spectroscopy of a mixture of [GaL F] in d
6
-DMSO in the presence
1
(
retention time = 9.5 min), (b) [GaL F] (retention time = 10.2 min) and (c)
co-injection of [GaL Cl] (retention time = 9.5 min) with [GaL F] (retention time =
of trifluoroacetic acid (TFA, 0.1%) demonstrated that within one
hour approximately 50% of the complex had dissociated to give
the protonated free ligand (Figure 5). This decomposition was
most likely due to the cleavage of the Ga-O bonds by acid-
catalysed dissociation.
1
1
10.2 min).
Radiolabelling of [GaL1]+ with fluorine-18. The ease of
1
synthesis [GaL F] in aqueous solutions at room temperature and
Analysis of Ga(III) complexes by RP-HPLC. The Ga(III)
the stability of the complex in aqueous mixtures encouraged the
investigation of the preparation of the complex with radioactive
fluorine-18 in relatively challenging aqueous conditions. A mixture
1
1
complexes, [GaL Cl] and [GaL F] were characterised by
analytical RP-HPLC with an elution gradient of 0-95%
acetonitrile) in A (Milli-Q H O) over 15 min, 1 mL/min (Figure 6).
B
18
-
O was obtained from a 18O(p,n) F nuclear reaction
18
(
2
of [ F]F /H
(98% 18O isotopic enrichment) on a 16.5 MeV cyclotron (~1,000-
2
1
The elution profile of [GaL F] detected at UV absorbance l 254
18
1
nm (retention time = 10.2 min, Figure 6a) is different to that of
1,500 MBq/mL). Formation of [ F][GaL F] was attempted by
1
1
1
18
-
[
GaL Cl], which elutes at 9.5 min (Figure 6b) under the same
adding either [GaL (OH)] or [GaL Cl] to a mixture of [ F]F /H
2
O
1
1
conditions. Co-injection of [GaL Cl] with [GaL F] showed two
(500 MBq, ~ 25 nM) in sodium acetate buffer (pH 4.0) at room
4
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European Journal of Inorganic Chemistry
10.1002/ejic.202000547
FULL PAPER
o
-
temperature and 80 C (method A). Despite the relatively
to prepare Ga(III)-F complexes in an aqueous mixture. The
1
1
1
1
straightforward preparation of the non-radioactive [GaL F], the
structures of [GaL (OH)], [GaL Cl] and [GaL F] were determined
18
1
1
radioactive analogue, [ F][GaL F], could only be synthesised in
by X-ray crystallography revealed that in each case L acted as
very low radiochemical yield. This was presumably due to the
tetradentate dianion ligand with an additional weaker interaction
to the tertiary nitrogen atom N(2). Although the close contact
between Ga(III) and N(2) could not considered a bond it was
hoped that it might confer some enhanced resistance to the
substitution of the coordinated fluoride by disfavouring associative
(A) ligand exchange processes with competing nucleophiles.
18
-
incompatibility of the nanomolar concentration of [ F]F in the
1
-
diluted buffer solution at pH 4. The instability of [GaL X] (X = OH ,
-
-
Cl , F ) in low pH (<3) precluded the possibility of attempting the
18
1
radiolabelling at lower pH. Preparation of [ F][GaL F] was then
18
-
attempted using a source of [ F]F that was azeotropically dried,
adsorbed on a QMA cartridge and then eluted with potassium
1
[GaL F] is stable for at least several weeks in aqueous mixture
1
carbonate and [2,2,2]Kryptofix mixture (~1% H
2
O in acetonitrile).
and d
6
-DMSO. Despite the facile synthesis of [GaL F] in aqueous
18
-
1
This [ F]F mixture was reacted with [GaL Cl] (method B). The
solutions by the simple addition of potassium fluoride to either
18
-
1
1
18
1
incorporation of [ F]F was determined from the chromatogram of
an RP-HPLC equipped with a radiation detector of the crude
[GaL (OH)] or [GaL Cl], we were unable to prepare [ F][GaL F]
18
-
in significant quantities using aqueous sources of [ F]F . The
18
1
18
reaction mixture, where [ F][GaL F] (retention time = 12.6 min)
inability to form [ F]Ga-F complexes using nanomolar
1
8
-
elutes with a similar retention time to the non-radioactive
concentrations of [ F]F , in aqueous buffer at pH 4, may reflect
the strength of hydrogen bonds in HF and bifluoride (HF
-) under
2
these conditions. The bond dissociation energy of HF is 184 kJ
1
analogue, [GaL F] detected at l 254 nm (retention time = 12.7
2
18
1
-
min) (Figure 7). [ F][GaL F] was prepared in a radiochemical
yield of ~ 2%, estimated from the integration of the peak
corresponding to the radioactive species in the HPLC
-
1 [12]
mol . Considering these limitations, the Ga(III) complexes with
the acyclic ‘dpa’ chelator presented in this work do not offer any
18
-
18
chromatogram. Unreacted [ F]F elutes with the solvent front at 2
min (recovered percentage ~ 96%). The non-radioactive elution
profile (blue trace) detected by UV absorbance at l 254 nm shows
advantages when compared to the cyclic [ F][AlF(NOTA-Bn-
18
NCS)] and [ F][GaF(Bn(CH
previously.[4, 6b]
2 2
COO) -tacn)] systems presented
a second peak at retention time = 12.3 min that corresponds to
1
[
GaL Cl], which is consistent with the order of elution of the Ga(III)
complexes in Figure 6c. The addition of an excess of ‘carrier-
Experimental Section
18
-
19
added’ [ F]F , [ F]KF may improve the synthetic yield of
[18
F][GaL F] in acetonitrile as was demonstrated in the synthesis
(BzMe
-tacn)].[6a] Considering that a goal of this research
1
General procedures: All standard reagents and solvents were obtained
from commercial suppliers and were used as received. Nuclear magnetic
resonance (NMR) spectra were acquired on a Varian FT-NMR 500
spectrometer or a Varian FT-NMR 400 spectrometer. 1H NMR spectra
of [GaF
3
2
was to prepare an alternative facile approach to incorporate
fluorine-18 into molecules in aqueous mixtures, this was not
pursued further.
were acquired at 400 or 500 MHz, 13C{ H} NMR spectra were acquired at
1
25.7 MHz and referenced to an internal solvent residue. 19F{ H} NMR
1
1
spectra were acquired at 470.4 MHz. All spectra were recorded at 297 K.
Spectra were analysed on MestReNova software (MestreLab Research).
High-resolution ESI-QTOF mass spectra were recorded on an Exactive
Plus Orbitrap Infusion mass spectrometer (Exactive Series, 2.8 Build
2
68801, Thermo Fisher Scientific). The analysis was performed using
Xcalibur 4.0.27.10 (Thermo Fisher Scientific). Elemental analysis for C, H
and N was carried out by The Campbell Microanalytical Laboratory, The
University of Otago, Dunedin, New Zealand. UV-Visible spectra were
acquired on a Shimadzu UV-1650 PC UV-Visible spectrophotometer
(
Shimadzu, Kyoto, Japan) from 800 nm to 250 nm. Analytical RP-HPLC
traces were acquired using an Agilent (Santa Clara, CA) 1100 Series
HPLC system with an SGE Analytical Science (Ringwood, VIC) ProteCol
C18 HPH 125 column (4.6 x 150 mm, 5 µm, 120 A) and were monitored at
l = 220, 254 and 280 nm. Agilent 1200 HPLC system equipped with an
Alltech Hypersil BDS C18 analytical HPLC column (4.6 x 150 mm, 5 µm,
1
20 A) with a flow rate of 1 mL/min and were monitored at l = 220, 254
and 280 nm. Retention times were recorded using a gradient elution of 5-
100% B (0.1% TFA in acetonitrile) in A (0.1% TFA in Milli-Q water) over 30
min. [18F]/H2O was obtained from Cyclotek Melbourne Pty Ltd, prepared
using a PETtrace 16.5 MeV cyclotron incorporating a high-pressure
Figure 7. Radio- HPLC trace (red = radiation detection, blue = non-radioactive
analogue at l 254 nm) of the reaction mixture of [GaL Cl] and [18F]/H
1
2
O in
acetonitrile.
niobium target by proton bombardment [18O(p,n)18F] of 98% 18O enriched
[18
O]H2O (GE healthcare). For method B, drying of [18F]F was performed
-
Conclusion
on an iPHASE Flexlab radiochemistry module purchased from iPHASE
Technologies Pty. Ltd. Fluorine-18 was trapped on a QMA strong anion
exchange cartridge (Waters) preconditioned with potassium bicarbonate,
A series of picolinic acid derived acyclic chelators H
L3 were prepared. The SPPS approach employed to
L1, H L2 and
2 2
H
2
[2,2,2]Kryptofix (0.5 mL, 0.05 M solution) and water (5 mL). The
azeotropically dried 18F[F ] was eluted and removed from the module and
then dissolved in acetonitrile and a minimal amount of water to be used for
the synthesis. Radio-RP-HPLC traces were acquired using a Shimadzu
SPD-10ATvP HPLC system equipped with a Waters C column (4.6 x 150
mm, 5 µm) with a 1 mL/min flow rate. Chromatograms were recorded with
a scintillation detector and a UV-vis detector (254 nm and 280 nm).
-
functionalise the chelator with a single lysine residue has an
advantage of simplifying the purification process and could be
useful to incorporate other amino acids for other picolinic acid
derived ligands. The SAAC system can also be incorporated
within any peptide sequence of interest. The new ligands formed
complexes with Ga(III) and encouragingly it was straightforward
5
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European Journal of Inorganic Chemistry
10.1002/ejic.202000547
FULL PAPER
Retention times were recorded using a gradient elution of 0-95% B
(s, 6H; CH3), 3.93 (s, 4H; CH2), 3.70 ppm (s, 2H; CH2). HR-MS(ESI/O-
+
(
acetonitrile) in A (Milli-Q water) over 15 min.
TOF): [C23H23N3O4+H] m/z 406.177 (experimental), 406.177 (calculated).
1
General method 1: Cleavage from the 2-chlorotrityl polymer-bound resin
beads. Cleavage was performed using TFA in the presence of
triisopropylsilane (TIPS) as scavengers. A 1 mL solution containing H2O
H2L ·HCl: Dimethyl 6,6’-(benzylazanediyl)bis(methylene))dipicolinate (1.4
g, 3.4 mmol) was dissolved in HCl (5 M) and heated at reflux for 18 h. A
white solid that formed was collected by filtration and washed with cold
water to give H2L1 as the HCl salt (0.98 g, 70%). 1H NMR (500 MHz,
(
(
50 µL), TIPS (25 µL) and TFA (925 µL) was mixed with the resin beads
o
25 mg). The resin was filtered, and the filtrate was concentrated under
DMSO-d6, 25 C): d = 7.97 (d, 4H, J = 4.3 Hz; PyrH), 7.82 (d, 2H, J = 4.0
nitrogen. The product was precipitated using diethyl ether, centrifuged,
collected, redissolved in water: acetonitrile (50:50) and freeze-dried.
Hz; ArH), 7.77 (t, 2H, J = 4.3 Hz; PyrH), 7.38 (d, 3H, J = 4.2 Hz; ArH), 4.67
(s, 2H; CH2), 4.61 ppm (s, 4H; CH2). 13C{ H} NMR (126 MHz, DMSO-d6,
1
2
5 oC): d = 165.4 (C=O), 151.1 (C=O), 147.3, 138.8 (PyrC), 132.0 (ArC),
1
29.6 (ArC), 128.6 (ArC), 128.2 (PyrC), 124.3 (PyrC), 57.6 (CH2), 56.0
Synthetic Procedures
ppm (CH2). HR-MS(ESI/O-TOF): [C21H19N3O4+H]+ m/z 378.145
1
(
experimental), 378.145 (calculated). Crystals of H2L ·HCl suitable for
Dimethyl pyridine-2,6-dicarboxylate (2): Dimethyl 2,6-pyridine-2,6-
dicarboxylate was synthesised using an adapted literature protocol.[9]
Pyridine-2,6-dicarboxylic acid (10.4 g, 62.0 mmol) and sulfuric acid (2 mL)
were heated at reflux in methanol (50 mL) for 18 h. The solid that formed
was collected by filtration then dissolved in dichloromethane and washed
with saturated NaHCO3 and water. The combined organic layers were
dried over Na2SO4, and the solvent was removed under reduced pressure
analysis by X-ray crystallography were grown from a solution of the
compound dissolved in water [CCDC: 2004698].
1
1
[
GaL (OH)]: To a solution of H2L ·HCl (0.51 g, 1.2 mmol) in anhydrous
ethanol (50 mL) was added Ga(NO3)3·9H2O (0.60 g, 1.4 mmol, 1.2 eq) in
o
dry ethanol (6 mL). The reaction mixture was stirred for 2 h at 60 C under
nitrogen. The precipitate was collected by filtration, washed with cold
to give dimethyl pyridine-2,6-dicarboxylate as a colourless solid (9.12 g,
1
1
ethanol and dried in vacuo to give [GaL (OH)] as a colourless solid (0.45
7
5%). H NMR (400 MHz CDCl3): dH (ppm) 8.30 (d, 2H, PyrH), 8.02 (t, 1H,
1
o
PyrH), 4.02 (s, 6H, CH3). 13C{ H} NMR (126 MHz, CDCl3): dC (ppm) = 165.1
1
g, 82%). H NMR (500 MHz, DMSO-d6, 25 C): d = 8.27 (t, 2H, J = 7.7 Hz;
PyrH), 8.06 (d, 2H, J = 7.2 Hz; PyrH), 7.76 (d, 2H, J = 7.7 Hz; PyrH), 7.31
(dd, 2H, J = 6.4, 2.9 Hz; ArH), 7.08 (m, 3H; ArH), 4.18 (s, 4H; CH2), 3.99
ppm (s, 2H; CH2). 13C{ H} NMR (126 MHz, DMSO-d6, 25 oC): d = 163.0
(
C=O), 148.2 (PyrC), 138.4 (PyrC), 128.1 (PyrC), 53.2 (CH3). HR-
MS(ESI/O-TOF): [C9H9NO4+H]+ m/z 196.061 (experimental), 196.061
1
(
calculated).
(
C=O), 154.2 (C=O), 146.6, 143.7 (PyrC), 134.2, 130.5 (ArC), 128.1 (ArC),
27.8 (PyrC), 127.5 (PyrC), 122.2 (PyrC), 58.6 (CH2), 54.7 ppm (CH2).
HR-MS(ESI/O-TOF): [C21H17GaN3O4]+ m/z 444.047 (experimental),
1
Methyl 6-(hydroxymethyl)picolinate (3): Methyl 6-(hydroxymethyl)
picolinate was synthesised using an adapted literature protocol.[9] To
4
4
44.047 (calculated). Anal. Calcd for C21H18GaN3O5·1.5H2O: C, 51.6; H,
dimethyl 2,6-pyridine-2,6-dicarboxylate (5.1 g, 26 mmol) in dry methanol
.3; N, 8.6. Found: C, 51.6; H, 3.3; N, 8.6. RP-HPLC: Rt = 9.5 min. Crystals
(
100 mL) at 0 oC under nitrogen, was added sodium borohydride (1.8 g,
1
of [GaL (OH).5H2O] suitable for analysis by X-ray crystallography were
4
8 mmol). The reaction mixture was stirred for 4 h under nitrogen. The
grown from a solution of the complex dissolved in water [CCDC: 2004697].
solution was diluted using dichloromethane (200 mL) and quenched using
saturated NaHCO3 (200 mL). The aqueous and organic layers were
separated. The aqueous layer was extracted with chloroform (2 x 200 mL).
The combined organic layers were dried over MgSO4, filtered, and the
solvents were removed under reduced pressure. The methyl
1
1
[
GaL Cl]: To a solution of H2L ·HCl (0.20 g, 0.48 mmol) in dry ethanol (100
mL) was added GaCl3 in pentane (1.9 mL, 0.96 mmol, 0.5 M). The reaction
o
mixture was stirred for 2 h at 60 C under nitrogen. A precipitate formed
and was collected by filtration, washed with cold ethanol and dried in vacuo
6
-(hydroxymethyl)picolinate was purified by column chromatography
1
1
1
to give [GaL Cl] as a colourless solid (0.072 g, 31%). H NMR (500 MHz,
DMSO-d6, 25 oC): d = 8.26 (t, 2H; PyrH), 8.05 (d, 2H; PyrH), 7.77 (d, 2H;
PyrH), 7.32 (dd, 2H; ArH), 7.07 (m, 3H; ArH), 4.19 (s, 4H; CH2), 4.00 ppm
(
100% ethyl acetate) to give a colourless solid (1.89 g, 44%). H NMR (400
MHz, CDCl3, 25 oC) : d = 8.03 (d, 1H; PyrH), 7.85 (t, 1H; PyrH), 7.52 (d,
1
H; PyrH), 4.86 (s, 2H; CH2), 4.00 ppm (s, 3H; CH3). HR-MS(ESI/O-TOF):
(s, 2H; CH2). 13C{ H} NMR (126 MHz, DMSO-d6, 25 C): d = 162.6 (C=O),
1
o
+
[
C8H9NO3+H] m/z 168.066 (experimental), 168.066 (calculated).
1
53.9, 145.8, 143.9, 133.7, 130.7, 128.0, 127.4, 122.2, 58.6 (CH2), 54.5
ppm (CH2). HR-MS(ESI/O-TOF): [C21H17GaN3O4]+ m/z 444.047
Methyl 6-(bromomethyl)picolinate (4): Methyl 6-(bromomethyl)
picolinate was synthesised using an adapted literature protocol.[9] To
(experimental), 444.047 (calculated), 480.02 (experimental), 480.02416
(
calculated). Anal. Calcd for C21H17ClGaN3O4·C2H5OH: C, 52.46; H, 4.40;
methyl 6-(hydroxymethyl)picolinate (1.9 g, 11 mmol) in dry
dichloromethane (80 mL) at 0 oC under nitrogen, was added phosphorus
N, 7.98. Found: C, 52.46; H, 3.68; N, 7.86. RP-HPLC: Rt = 9.5 min.
1
tribromide (1.2 mL, 14 mmol) dropwise. The reaction was stirred at 0 o
Crystals of [GaL Cl] suitable for analysis by X-ray crystallography were
C
grown from a solution of the complex dissolved in water [CCDC: 2004695].
under nitrogen for 4 h. The reaction mixture was quenched using Na2CO3
in water (50 mL) and extracted using dichloromethane (2 x 100 mL). The
combined organic layers were dried over MgSO4, filtered and the solvent
1
1
[
GaL F]: Method 1: To a solution of [GaL (OH)] (0.10 g, 0.19 mmol) in
water/acetonitrile mixture (10 mL, 1:1) was added dropwise aqueous
potassium fluoride (0.012 g, 0.21 mmol, 60 µL). The reaction was stirred
at room temperature for 2 h. A colourless precipitate formed that was
was removed under reduced pressure to give methyl 6-
1
(
bromomethyl)picolinate as a colourless solid (2.32 g, 89%). H NMR (400
o
MHz, CDCl3, 25 C): d = 8.05 (d, 1H; PyrH), 7.87 (t, 1H; PyrH), 7.68 (d, 1H;
1
collected by filtration and washed with cold water (5 mL) to give [GaL F]
PyrH), 4.64 (s, 2H; CH2), 4.01 ppm (s, 3H; CH3). HR-MS(ESI/O-TOF):
1
+
as a colourless crystal (0.053 g, 52%). Method 2: A mixture of [GaL Cl]
[
C8H8BrNO2+H] m/z 229.982 (experimental), 229.982 (calculated).
(
0.047 g, 98 µmol), potassium fluoride (0.018 g, 0.31 mmol) and 18-crown-
(0.026 g, 98 µmol) in acetonitrile was heated to reflux for 3 h. The solution
6
Dimethyl 6,6’-(benzylazanediyl)bis(methylene))dipicolinate (5): To a
was allowed to cool to room temperature and the solvent was removed
solution of methyl 6-(bromomethyl)picolinate (1.98 g, 8.61 mmol) in dry
under reduced pressure. The residue was washed with cold acetonitrile
o
acetonitrile (50 mL) at 60 C under nitrogen, was added benzylamine (0.44
1
1
and diethyl ether to afford [GaL F] as a colourless solid (0.019 g, 42%). H
mL, 4.0 mmol) and K2CO3 (1.9 g, 13 mmol). The solution was stirred for
o
NMR (500 MHz, DMSO-d6, 25 C): d = 8.18 (t, 2H, J = 7.5 Hz; PyrH), 8.12
1
8 h. K2CO3 was removed by filtration and washed with acetonitrile. The
(
d, 2H, J = 7.3 Hz; PyrH), 7.65 (d, 2H, J = 7.4 Hz; PyrH), 7.41 (m, 2H, J =
filtrate was collected and solvent was removed under reduced pressure to
and was purified by column chromatography (100% dichloromethane to
7
2
1
.3 Hz; ArH),7.34 (m, 3H, J = 7.2 Hz; ArH), 3.98 (s, 4H; CH2), 3.61 ppm (s,
H; CH2). 13C{ H} NMR (126 MHz, DMSO-d6, 25 oC): d = 163.0 (C=O),
54.3 (C=O), 146.6, 143.7 (PyrC), 134.2, 130.5 (ArC), 128.1 (ArC), 127.8
1
3
6
9
4
%
methanol
in
dichloromethane)
to
afford
dimethyl
,6’-(benzylazanediyl)bis(methylene))dipicolinate as a yellow oil (1.5 g,
(PyrC), 127.4 (PyrC), 122.2 (PyrC), 59.6 (CH2), 54.7 ppm (CH2). 19F NMR
1
o
1%). H NMR (400 MHz, CDCl3, 25 C): d = 7.88 (m, 2H; PyrH), 7.82 (m,
H; PyrH), 7.38 (m, 2H; ArH), 7.30 (m, 2H; ArH), 7.22 (m, 1H; ArH), 3.98
(
470 MHz, DMSO-d6, 25 oC): d = -141.2 ppm. HR-MS(ESI/O-TOF):
6
This article is protected by copyright. All rights reserved.

European Journal of Inorganic Chemistry
10.1002/ejic.202000547
FULL PAPER
[
C21H17GaN3O4]+ m/z 444.047 (experimental), 444.047 (calculated). Anal.
Attempted radiolabelling. [18F][GaL F]. Method A: To a solution of
1
1
Calcd for C21H17FGaN3O4·5H2O: C, 45.51; H, 4.91; N, 7.58. Found: C,
[GaL Cl] (1.0 mg, 2.1 µmol) in sodium acetate buffer (1 mM, pH 4.0, 600
1
µL) was added a solution of 18F[F ] (500 MBq, ~ 25 nM) in water. The
-
4
5.66; H, 4.89; N, 7.59. RP-HPLC: Rt = 10.2 min. Crystals of [GaL F.5H2O]
o
suitable for analysis by X-ray crystallography were grown from a solution
of the complex dissolved in water [CCDC: 2004696].
reaction was incubated for 30 min at 80 C. The radiolabelled complex was
analysed by RP-HPLC (elution gradient 0-95% B (acetonitrile) in A (Milli-
Q H2O) over 15 min, 1 mL/min). Method B: 18F[F ] (~ 500 MBq) trapped on
the QMA cartridge was eluted with potassium bicarbonate (2.0 mg, 20
-
2
H2L ·xHCl: To a solution of methyl 6-(bromomethyl)picolinate (0.70 g, 3.0
mmol) in anhydrous acetonitrile (50 mL) at 60 oC under nitrogen, was
µmol) and [2,2,2]Kryptofix (6.3 mg, 16 µmol) in water:acetonitrile (1 mL,
:4). The azeotropically dried 18F[F ] was removed from the iPHASE
-
1
added 4-(aminomethyl)benzoic acid (0.19 g, 1.3 mmol) and K2CO3 (1.4 g,
Flexlab module and was then dissolved in acetonitrile (400 mL) and a
1
0 mmol). The solution was stirred for 18 h. K2CO3 was removed by
1
minimal amount of water (50 mL). To this was added [GaL Cl] (1.7 mg, 3.5
filtration and washed with acetonitrile. The solvent was removed under
reduced pressure to give a yellow oil. The yellow oil was dissolved in HCl
µmol, 200 mL in acetonitrile) and the reaction was incubated for 30 min at
8
0 oC. An aliquot of the diluted reaction mixture (100 µL, 2.08 MBq) was
(
5 M) and heated at reflux for 18 h. The colourless solid was collected by
analysed by RP-HPLC (elution gradient 0-95% B (acetonitrile) in A (Milli-
Q H2O) over 15 min, 1 mL/min). [18F][GaL F] Rt = 12.6 min (2%); unreacted
[18F]F Rt = 2.0 min (recovered 2.00 MBq, ~ 96%).
filtration and washed with cold water. Purification by semi-prep RP-HPLC
1
2
1
yielded H2L ·xHCl as a colourless solid (0.43 g, 81%). H NMR (500 MHz,
-
o
DMSO-d6, 25 C): d = 8.04-7.96 (m, 4H; ArH), 7.92 (d, J = 8.1 Hz, 2H; ArH),
1
7
.78 (dt, J = 8.6, 4.5 Hz, 4H; ArH), 4.24 ppm (s, 6H; CH2). 13C{ H} NMR
o
(
126 MHz, DMSO-d6, 25 C): d = 166.9 (C=O), 165.6 (C=O), 147.5 (PyrC),
X-ray Crystallography
1
38.7 (PyrC), 131.5 (PyrC), 129.3 (ArC), 127.7 (ArC), 124.1 (PyrC), 56.9
CH2), 56.7 ppm (CH2). HR-MS(ESI/O-TOF): [C22H19N3O6+H]+ m/z
22.135 (experimental), 422.135 (calculated).
(
Crystals were mounted in low-temperature oil and then flash-cooled.
Intensity data were collected at 130 K or 100 K on an X-ray diffractometer
with a CCD detector using Cu Kα (λ = 1.54184 Å) or Mo Kα (λ = 0.71073
Å) radiation. The structures were solved by methods using SHELXT[13] and
refined using SHELXL[14] employing full-matrix least-squares on F2 using
the OLEX2 software package.[15] Thermal ellipsoid plots were generated
using ORTEP integrated within OLEX2 program.
4
2
2
[
GaL Cl]: To a solution of H2L ·xHCl (53 mg, 0.13 mmol) in anhydrous
ethanol (50 mL) was added GaCl3 in pentane (0.50 mL, 0.25 mmol, 0.5 M).
The reaction mixture was stirred for 2 h at 60 oC under nitrogen. The
precipitate was collected by filtration, washed with cold ethanol and dried
2
1
in vacuo to give [GaL Cl] as a colourless solid (32 mg, 49%). H NMR (500
o
MHz, DMSO-d6, 25 C): d = 8.28 (t, 2H, J = 7.0 Hz; PyrH), 8.07 (d, 2H, J =
1
3
Crystal Data for H2L ·HCl: C21H20ClN3O4, 0.551 x 0.205 x 0.123 mm ,
6
7
.9 Hz; PyrH), 7.79 (d, 2H, J = 7.1 Hz; PyrH), 7.65 (d, 2H, J = 6.9 Hz; ArH),
.43 (d, 2H, J = 6.9 Hz; ArH), 4.19 (s, 4H; CH2), 4.04 ppm (s, 2H; CH2).
triclinic, space group P1, a = 8.1655(6), b = 10.5274(4), c = 12.3713(6) Å,
o
o
o
3
a = 75.104 (4) , β = 79.386(5) , g = 89.774(4) , V = 1009.08 Å , ρcalcd
13
1
o
C{ H} NMR (126 MHz, DMSO-d6, 25 C): d = 162.7 (C=O), 153.9 (PyrC),
45.9 (PyrC), 144.1 (PyrC), 130.9 (ArC), 129.0 (ArC), 127.7 (ArC), 122.4
3
-1
1
.362 Mg/m , l 1.54184 Å, T = 100(10) K, Z = 2, µ 1.957 mm , Semi-
1
empirical from equivalents (1.00000 and 0.58327 transmission), Full-
(
PyrC), 57.8
C22H17GaN3O6]+ m/z 488.037 (experimental), 488.037 (calculated). Anal.
Calcd for C22H16ClGaN3O6·2H2O: C, 47.22; H, 3.60; N, 7.51. Found: C,
(CH2),
54.4 ppm
(CH2).
HR-MS(ESI/O-TOF):
2
matrix least-squares on F , 274 parameters, 0 restraints, F(000) = 432,
[
1
1600 measured reflections, 4130 independent reflections (Rint = 0.0685),
2
final R indices [I>2s(I)] R1 = 0.0599, wR = 0.1720, final R indices (all data)
R1 = 0.0639, wR2 = 0.1861, Goodness-of-fit on F2 = 1.081. [CCDC:
4
7.72; H, 3.66; N, 6.56.
2
004698].
3
H2L ·xHCl: 2-chlorotrityl polymer-bound resin beads (0.516 g) were
suspended in DCM. Boc-Lys(Fmoc)-OH protected amino acid (0.241 g,
1
Crystal Data for [GaL (OH)]·5H2O: C21H28GaN3O10, 0.544 x 0.323 x 0.313
0
.514 mmol) was dissolved in DCM (10 mL), and DIPEA (3 x) was added.
3
mm , monoclinic, space group P 21/n, a = 11.6817(2), b = 16.2098(3), c =
The mixture was added to the resin beads and gently shaken overnight.
The beads were washed with DCM (3 x 5 mL) to remove excess reagents
and then incubated with methanol (5 mL) for 30 minutes to deactivate any
unreacted resin. The resin was washed with DCM (3 x), DMF (3 x) and
DCM (3 x) and allowed to dry. The Fmoc group was then cleaved with 20%
piperidine in DMF (2 x 5 mL), stirring the resin for 2 x 10 min at RT, and
then washed with DMF (3 x) and DCM (3 x) and allowed to dry. Methyl 6-
o
o
o
3
1
1
2.2210(3) Å, a = 90 , β = 91.268(2) , g = 90 , V = 2313.58(8) Å , ρcalcd
3
-1
.585 Mg/m , l 0.71073 Å, T = 130.0(1) K, Z = 4, µ 1.252 mm , Semi-
empirical from equivalents (1.00000 and 0.75153 transmission), Full-
2
matrix least-squares on F , 352 parameters, 8 restraints, F(000) = 1144,
1
4031 measured reflections, 4060 independent reflections (Rint = 0.0202),
2
final R indices [I>2s(I)] R1 = 0.0328, wR = 0.0853, final R indices (all data)
R1 = 0.0352, wR2 = 0.0866, Goodness-of-fit on F2 = 1.052. [CCDC:
(
(
bromomethyl)picolinate (0.356 g, 3 eq, 1.54 mmol) was dissolved in DCM
5 mL) and DIPEA (3 eq.). The solution was added to the resin and left
2
004697].
shaking overnight. Cleavage of compound (8) from the resin beads was
1
3
Crystal Data for [GaL Cl]: C21H17ClGaN3O4, 0.361 x 0.267 x 0.135 mm ,
1
o
performed using general method 1. H NMR (500 MHz, DMSO-d6, 25 C):
d =7.86 (d, J = 7.7 Hz, 2H; PyrH), 7.79 (t, J = 7.7 Hz, 2H; PyrH), 7.45 (d, J
monoclinic, space group I 2/a, a = 14.4262(2), b = 9.08430(10), c =
o
o
o
3
3
1
1.6400(5) Å, a = 90 , β = 99.306(2) , g = 90 , V = 4091.91(10) Å , ρcalcd
=
7.5 Hz, 2H; PyrH), 4.68 (s, 4H; CH2), 3.92 (s, 6H; CH3), 3.86 (m,
3
-1
.560 Mg/m , l 1.54184 Å, T = 130.00(10) K, Z = 8, µ 3.336 mm , Semi-
1
H; -NH2CH), 3.12 – 3.03 (m, 2H; -NH2CH2), 1.90 – 1.29 ppm (m, 6H; CH2).
empirical from equivalents (0.692 and 0.451 transmission), Full-matrix
1
3
1
o
C{ H} NMR (126 MHz, DMSO-d6, 25 C): d = 174.1, 171.0, 164.7, 162.4,
51.3, 147.2, 138.9, 128.7, 124.9, 56.3, 54.2, 53.3, 52.7, 51.9, 35.8, 30.8,
0.3, 29.5, 28.2, 23.0, 21.7 ppm. HR-MS(ESI/O-TOF): [C22H28N4O6+H]+
2
least-squares on F , 271 parameters, 0 restraints, F(000) = 1952, 14985
1
3
measured reflections, 4289 independent reflections (Rint = 0.0205), final R
2
indices [I>2s(I)] R1 = 0.0323, wR = 0.0852, final R indices (all data) R1 =
m/z 445.209 (experimental), 445.209 (calculated). The compound (8)
dissolved in HCl (5 M, 15 mL) and heated at reflux for 18 h. A white solid
that formed was collected by filtration and washed with cold water to give
2
2
0
.0330, wR = 0.0858, Goodness-of-fit on F = 1.059. [CCDC: 2004695].
1
3
1
o
Crystal Data for [GaL F]·5H2O: C21H27FGaN3O9, 0.377 x 0.320 x 0.203
H2L as the HCl salt (0.14 g, 61%). H NMR (500 MHz, DMSO-d6, 25 C):
d = 8.00 (d, J = 6.8 Hz, 4H; PyrH), 7.81 (d, J = 8.6 Hz, 2H; PyrH), 4.69 (s,
3
mm , monoclinic, space group P 21/n, a = 11.7761(5), b = 16.0638(6), c =
o
o
o
3
1
2.1853(4) Å, a = 90 , β = 91.841(3) , g = 90 , V = 2303.89(15) Å , ρcalcd
4
6
1
2
H; CH2), 3.85 (s, 1H; -NH2CH), 3.32 (d, 2H; -NH2CH2), 1.92-1.21 ppm (s,
H; CH2). 13C{1H} NMR (126 MHz, DMSO-d6, 25 oC): d = 171.3, 165.7,
3
-1
1.598 Mg/m , l 0.71073 Å, T = 130.0(1) K, Z = 4, µ 1.261 mm , Semi-
empirical from equivalents (1.00000 and 0.74069 transmission), Full-
51.2, 147.8, 139.4, 128.7, 124.8, 56.8, 54.7, 52.0, 34.5, 31.2, 29.8, 23.1,
2.0 ppm. HR-MS(ESI/O-TOF): [C20H24N4O6+H]+ m/z 417.177
2
matrix least-squares on F , 326 parameters, 9 restraints, F(000) = 1144,
1
6907 measured reflections, 6130 independent reflections (Rint = 0.0223),
(
experimental), 417.177 (calculated).
2
final R indices [I>2s(I)] R1 = 0.0356, wR = 0.0904, final R indices (all data)
7
This article is protected by copyright. All rights reserved.

European Journal of Inorganic Chemistry
10.1002/ejic.202000547
FULL PAPER
R1 = 0.0427, wR2 = 0.0952, Goodness-of-fit on F2 = 1.063. [CCDC:
W. Babich, J. Zubieta, Bioconjugate Chem. 2006, 17, 579-
589.
2
004696].
[
[
11]
12]
A. W. Addison, T. N. Rao, J. Reedijk, J. van Rijn, G. C.
Verschoor, J. Chem. Soc., Dalton Trans. 1984, 1349-1356.
a) P. G. Wenthold, R. R. Squires, J Phys. Chem. 1995, 99,
2002-2005; b) J. Emsley, Chem. Soc. Rev. 1980, 9, 91-124;
c) C. Stein, R. Oswald, P. Sebald, P. Botschwina, H. Stoll,
K. A. Peterson, Mol. Phys. 2013, 111, 2647-2652.
G. Sheldrick, Acta Cryst. 2015, A71, 3-8.
Acknowledgements
We would like to thank the Melbourne Mass Spectrometry and
Proteomics Facility (MSPF) of The Bio21 Molecular Science and
Biotechnology Institute at The University of Melbourne for the
support of mass spectrometry analysis. Financial support from an
Australian Research Council Linkage Grant (LP150100656)
where the Industry Partner was Clarity Pharmaceuticals is
acknowledged. Professor Rodney J. Hicks is acknowledged for
his support of this research.
[
13]
[14]
[15]
G. Sheldrick, Acta Cryst. 2015, C71, 3-8.
O. V. Dolomanov, L. J. Bourhis, R. J. Gildea, J. A. K.
Howard, H. Puschmann, J. Appl. Cryst 2009, 42, 339-341.
Keywords: bioinorganic chemistry • fluorides • gallium • imaging
agents • radiopharmaceuticals
[
1]
a) S. M. Ametamey, M. Honer, P. A. Schubiger, Chem. Rev.
008, 108, 1501-1516; b) J. K. Willmann, N. van Bruggen,
L. M. Dinkelborg, S. S. Gambhir, Nat. Rev. Drug Discovery
008, 7, 591-607.
2
2
[
[
2]
3]
B. E. Smart, J. Fluorine Chem. 2001, 109, 3-11.
a) B. D. Darwent, Bond Dissociation Energies in Simple
Molecules, GPO, 1970; b) T. L. Cottrell, The Strengths of
Chemical Bonds. 2nd ed, Butterworths Sci. Pubs., 1958.
W. J. McBride, R. M. Sharkey, H. Karacay, C. A. D'Souza,
E. A. Rossi, P. Laverman, C.-H. Chang, O. C. Boerman, D.
M. Goldenberg, J. Nucl. Med. 2009, 50, 991-998.
[
[
4]
5]
a) C. A. D'Souza, W. J. McBride, R. M. Sharkey, L. J.
Todaro, D. M. Goldenberg, Bioconjugate Chem. 2011, 22,
1
793-1803; b) P. Laverman, W. J. McBride, R. M. Sharkey,
A. Eek, L. Joosten, W. J. G. Oyen, D. M. Goldenberg, O. C.
Boerman, J. Nucl. Med. 2010, 51, 454-461; c) W. J.
McBride, C. A. D'Souza, H. Karacay, R. M. Sharkey, D. M.
Goldenberg, Bioconjugate Chem. 2012, 23, 538-547; d) W.
J. McBride, C. A. D'Souza, R. M. Sharkey, H. Karacay, E.
A. Rossi, C.-H. Chang, D. M. Goldenberg, Bioconjugate
Chem. 2010, 21, 1331-1340; e) W. J. McBride, R. M.
Sharkey, D. M. Goldenberg, EJNMMI Res. 2013, 3, 36; f)
D. Shetty, S. Y. Choi, J. M. Jeong, J. Y. Lee, L. Hoigebazar,
Y.-S. Lee, D. S. Lee, J.-K. Chung, M. C. Lee, Y. K. Chung,
Chem. Commun. (Cambridge, U. K.) 2011, 47, 9732-9734.
a) R. Bhalla, C. Darby, W. Levason, S. K. Luthra, G.
McRobbie, G. Reid, G. Sanderson, W. Zhang, Chem. Sci.
[
[
6]
7]
2
014, 5, 381-391; b) R. Bhalla, W. Levason, S. K. Luthra,
G. McRobbie, G. Sanderson, G. Reid, Chemistry 2015, 21,
688-4694; c) F. M. Monzittu, I. Khan, W. Levason, S. K.
Luthra, G. McRobbie, G. Reid, Angew. Chem., Int. Ed. 2018,
7, 6658-6661.
4
5
a) E. Boros, C. L. Ferreira, J. F. Cawthray, E. W. Price, B.
O. Patrick, D. W. Wester, M. J. Adam, C. Orvig, J. Am.
Chem. Soc. 2010, 132, 15726-15733; b) E. Boros, C. L.
Ferreira, B. O. Patrick, M. J. Adam, C. Orvig, Nucl. Med.
Biol. 2011, 38, 1165-1174; c) E. Boros, C. L. Ferreira, D. T.
T. Yapp, R. K. Gill, E. W. Price, M. J. Adam, C. Orvig, Nucl.
Med. Biol. 2012, 39, 785-794; d) C. F. Ramogida, J. F.
Cawthray, E. Boros, C. L. Ferreira, B. O. Patrick, M. J.
Adam, C. Orvig, Inorg. Chem. 2015, 54, 2017-2031.
[
8]
D. M. Weekes, C. F. Ramogida, M. d. G. Jaraquemada-
Peláez, B. O. Patrick, C. Apte, T. I. Kostelnik, J. F. Cawthray,
L. Murphy, C. Orvig, Inorg. Chem. 2016, 55, 12544-12558.
X. Zeng, D. Coquière, A. Alenda, E. Garrier, T. Prangé, Y.
Li, O. Reinaud, I. Jabin, Chemistry 2006, 12, 6393-6402.
a) S. R. Banerjee, M. K. Levadala, N. Lazarova, L. Wei, J.
F. Valliant, K. A. Stephenson, J. W. Babich, K. P. Maresca,
J. Zubieta, Inorg. Chem. 2002, 41, 6417-6425; b) S. James,
K. P. Maresca, D. G. Allis, J. F. Valliant, W. Eckelman, J.
[
[
9]
10]
8
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European Journal of Inorganic Chemistry
10.1002/ejic.202000547
FULL PAPER
Entry for the Table of Contents
Gallium Fluoride-18 Complexes as Radiopharmaceuticals
The potential of gallium(III) complexes with acyclic pentadentate bis-dipicolinic acid containing ligands (H
2
L1-3) to form ternary
complexes with fluoride, [GaL1-3F] was investigated with a view to developing new methods for radiolabelling molecules with fluorine-
1
8.
9
This article is protected by copyright. All rights reserved.