2,5-Diamino-5,5-diphosphonovaleric Acid as a Ligand for an Osteotropic 188Re Radiopharmaceutical

Article abstract of DOI:10.1134/S1070363218090037

A modified method for the preparation of 2,5-diamino-5,5-diphosphonovaleric acid (DADP5) has been developed in the search for new synthetically available organic ligands to produce ¹⁸⁸Re radiopharmaceuticals with an increased accumulation in the bone tissue. Interaction of the obtained acid with ¹⁸⁸Re was studied by radio-TLC. An optimal system for separating unbound ¹⁸⁸Re and labeled complex in a yield of at least 95% was found. The biological distribution of ¹⁸⁸Re-DADP5 was studied based on direct radiometric data. The osteotropicity of ¹⁸⁸Re-DADP5 and its increased accumulation in bone fracture sites, which represent oncological pathology models, was detected at a level comparable to known radiopharmaceuticals.

Full text of DOI:10.1134/S1070363218090037

ISSN 1070-3632, Russian Journal of General Chemistry, 2018, Vol. 88, No. 9, pp. 1780–1785. © Pleiades Publishing, Ltd., 2018.
Original Russian Text © G.S. Tsebrikova, V.V. Ragulin, V.E. Baulin, K.E. German, A.O. Malysheva, O.E. Klement’eva, G.E. Kodina, A.A. Larenkov,
E.A. Lyamtseva, N.A. Taratonenkova, M.V. Zhukova, A.Yu. Tsivadze, 2018, published in Zhurnal Obshchei Khimii, 2018, Vol. 88, No. 9, pp. 1431–1437.
Dedicated to the 110th anniversary of M.I. Kabachnik’s birth
2,5-Diamino-5,5-diphosphonovaleric Acid as a Ligand
for an Osteotropic 188Re Radiopharmaceutical
G. S. Tsebrikovaa*, V. V. Ragulinb, V. E. Baulina,b, K. E. Germana,
A. O. Malyshevac, O. E. Klement’evac, G. E. Kodinac, A. A. Larenkovc,
E. A. Lyamtsevac, N. A. Taratonenkovac, M. V. Zhukovaa, and A. Yu. Tsivadzea
a A.N. Frumkin Institute of Physical Chemistry and Electrochemistry, Russian Academy of Sciences,
Leninskii pr. 31/4, Moscow, 119071 Russia
*e-mail: tsebrikova@yandex.ru
b Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka, Moscow oblast, Russia
c Burnazyan Federal Medical Biophysical Center, Federal Medical Biological Agency of Russia, Moscow, Russia
Received June 28, 2018
Abstract―A modified method for the preparation of 2,5-diamino-5,5-diphosphonovaleric acid (DADP5) has
been developed in the search for new synthetically available organic ligands to produce 188Re radiopharma-
ceuticals with an increased accumulation in the bone tissue. Interaction of the obtained acid with 188Re was
studied by radio-TLC. An optimal system for separating unbound 188Re and labeled complex in a yield of at
least 95% was found. The biological distribution of 188Re-DADP5 was studied based on direct radiometric data.
The osteotropicity of 188Re-DADP5 and its increased accumulation in bone fracture sites, which represent
oncological pathology models, was detected at a level comparable to known radiopharmaceuticals.
Keywords: osteotropic radiopharmaceuticals, rhenium-188, 2,5-diamino-5,5-diphosphonovaleric acid, biological
distribution
DOI: 10.1134/S1070363218090037
Radionuclide therapy of oncological diseases is one
of the most intensively developing fields of nuclear
medicine [1–3]. Due to its nuclear-physical characteristics
(T1/2 16.7 h, Eβ 2.12 MeV, 80%), radionuclide 188Re
falls under the definition of an ideal for use in
radionuclide therapy. In addition, the presence of both
the β- and γ-component (0.155 MeV) of 188Re radiation
allows, along with having the therapeutic effect, to
perform visualization using commercially produced
gamma cameras and, thus, to obtain information on the
radiopharmaceutical distributions in the patient’s body
and the treatment results [1, 2, 4]. This has led to the
appearence of a variety of 188Re-based radiopharmaceuticals
over the past decade. Radiopharmaceuticals containing
radionuclide 188Re are mainly used for the treatment
of bone metastases, liver cancer, and brain carcinoma
[5, 6].
metastases [7–10]. In view of phosphonate groups’
ability to bind to hydroxyapatite, which is the main
component of the inorganic matrix of bone, they are
used as functional groups in organic ligands for the
target delivery of radionuclides to bone tissues. In the
international practice, 188Re-HEDP based on 1-hyd-
roxyethylidene diphosphonic acid (HEDP) became one
of the most promising radiopharmaceuticals for
palliative treatment of bone metastases [11, 12]. Phos-
phorene, 188Re, a Russian radiopharmaceutical based on
1-hydroxyethylidene diphosphonic acid, is undergoing
the final stage of clinical trials [13, 14]. There is another
known osteotropic 188Re radiopharmaceutical named
“Zoleren, 188Re” based on zoledronic acid also
containing a geminal diphosphonic moiety [15–18].
Recently a study of a new organic ligand, specifically
trans-1,2-cyclohexyl dinitrilotetramethylenephosphonic
acid, as a component of both a 68Ga-based diagnostic
radiopharmaceutical and a 188Re-based therapeutic
medication was described [19].
Complexes of phosphonic acids with various
radionuclides are used for early diagnostics of bone
1780

2,5-DIAMINO-5,5-DIPHOSPHONOVALERIC ACID AS A LIGAND
1781
Despite some progress in the development of
osteotropic 188Re radiopharmaceuticals, the search for
new synthetically available organic ligands to obtain
radiopharmaceuticals with increased specificity for
bone tissues remains an urgent task.
of new type compounds 2 that combine the amino-
diphosphonic and aminocarboxylic groups in the
molecule as potential 188Re ligands. The synthesis of
ligands 2 is distinguished by a relatively simple method
for introducing an aminodiphosphonic function into the
target molecule. In addition, an aminodiphosphonic
moiety can be considered as a structural analog of an
amino acid group containing a second phosphonic
group, which can significantly affect the physiological
and complexing activity of this class of compounds
[21, 25].
In order to find new osteotropic radiopharma-
ceuticals, the synthesis of organic ligands with a com-
bination of aminocarboxylic and geminal diphosphonic
moieties in one molecule (compound 1) was described
[20–24]. The obtained results suggest the investigation
OH
HO P O
HO
OH
HO P O
CxHy
OH
OH
O
O
HO P O
HO P O
OH
NH2
OH
NH2
HO
CH3
H2N
CxHy
N
HO P O
OH
HO P O
OH
HO P O
OH
HO P O
OH
N
2
1
Zoledronic acid
HEDP
Aminodiphosphonic and amino acid groups in the
ligand can both be involved in binding of the
radionuclide and transport it to bone tissues. Therefore,
radiopharmaceuticals containing this type of com-
pounds can be promising for diagnostics and/or treat-
ment of cancer, depending on the radionuclides used.
In this paper, a modified method for the synthesis of
2,5-diamino-5,5-diphosphonovaleric acid (DADP5) 3
(Scheme 1) is proposed and, for the first time, the
results of radiochemical and biological studies of a
DADP5-based 188Re radiopharmaceutical are reported.
aminocarboxylic acid 3 suggests its possible existence
as various zwitterionic forms or salts in an aqueous
solution, depending on the pH of the medium. In this
view, it is of interest to recover the acid both as
hydrochloride 3 and as free amino acid 3a. It should be
noted that, at the intrinsic pH ca. 1, only one form of
the compound is present in the aqueous solution of free
1
amino acid 3a, as supported by H, 13C, and 31P NMR
spectroscopy data. In the 13C NMR spectrum of amino
acid 3a a quite rare spin-spin coupling of the
phosphorus nuclei with the carbons of the molecule
(apart from the C2 atom of the aminocarboxylic function)
through 1, 2, 3, and even 5 bonds is observed. These
signals are symmetrical triplets, which points at the
magnetic equivalence of both phosphorus atoms in the
free amino acid molecule 3a. Unlike 3a, spectral data
of amino acid hydrochloride 3 indicate the presence of
two amino acid forms with two nonequivalent
The Michael addition of the acetamidomalonic
ester to acrylonitrile results in the formation of nitrile 4
that contains a protected amino acid function as an
acetamidomalonic ester moiety. The latter was
converted to aminodiphosphonic acid 5 by addition of
two phosphorous acid molecules according to a
modification of an earlier published procedure [26].
1
phosphorus atoms, as supported by H, 13C, and 31P
NMR spectroscopy data. For example, the 13C NMR
spectrum of amino acid hydrochloride 3, at intrinsic
pH ca. 1, contains a carbon C5 signal at 56.74 ppm as a
doublet of doublets with characteristic coupling
Attempt to recrystallize acid 5 containing the
acetamidomalonic moiety results in the loss of the
ester group and decarboxylation with the formation of
aminodiphosphonic acid 6 containing an N-acetyl-
aminocarboxylic ester moiety. Acid hydrolysis of acid
5, as well as of acid 6, gives the desired acid 3
(Scheme 1).
1
1
constants JPC = 137.6 and JPC = 138.4 Hz, which
confirms the magnetic nonequivalence of phosphorus
atoms at the fifth carbon atom. In addition, the
presence of the second form is evidenced by the
signals of all carbon atoms, including the carbonyl
carbon atom of the aminocarboxylic moiety of amino
The presence of two amino groups and several acid
functions in the molecule of aminodiphosphonic
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 9 2018

1782
TSEBRIKOVA et al.
Scheme 1.
OH
O
O
HO P
H2N
N
COOEt
COOEt
NHAc
COOEt
NHAc
COOEt
H3PO3
HO P
OH
OH
4
5
HO P O
H2N
_EtOH
O
HCl, H2O
_CO2
OH
NH2
O
HO P
OH
AcNHCH(COOEt)2
OH
P O
HO
3
N
H2N
COOEt
NHAc
P
O
HO
OH
6
1
acid 3 (δC1 169.16 and *171.42 ppm). The H and 31P
NMR spectra also indicate the presence of two forms
of amino acid hydrochloride 3.
pharmacokinetics data indicate the osteotropicity of the
radiopharmaceutical and its increased accumulation in
bone fracture sites representing oncological pathology
models (see the table). The obtained coefficient of
differential accumulation (CDA) [2, 5] for 188Re-
DADP5 is comparable with and even slightly higher
than those for “Zoleren, 188Re” and “Phosphorene, 188Re.”
31P NMR examination of free amino acid 3a in
aqueous solutions demonstrated a complex dependence
of the chemical shift of the phosphorus nuclei signal
on the pH of the medium, with diastereotopy of
phosphorus atoms.
EXPERIMENTAL
The preparation of acid 3 labeled with the radio-
isotope 188Re was carried out by mixing solutions of
2,5-diamino-5,5-diphosphonovaleric acid 3, sodium
perrhenate (Na188ReO4) from the 188W/188Re generator
GREN-1, and tin dichloride as a reducing agent, with a
ligand:tin ratio of 3.5. The yield of the labeling
reaction was determined by the known radio-TLC
method [4, 27]. Thin-layer (TLC) and instant thin-
layer (ITLC) chromatography in a silica-gel/acetone
system, as well as paper chromatography in the
Whatman 1–acetone and Whatman 3MM–0.9% NaCl
were tried. It was found that the ITLC-acetone system
on glass fiber strips impregnated with silica gel
wherein the perrhenate ions move with the solvent
front and the 188Re complex remains at the start,
demonstrates the best reproducibility of results and the
separation of unbound 188Re and labeled complex, the
latter in a yield of at least 95%.
1H, 31P, and 13C NMR spectra were recorded on a
Bruker DPX-200 Fourier spectrometer, using TMS as
an internal reference and 85% H3PO4 as an external
reference. The melting points were determined on a
block apparatus in an open capillary. The TLC of
individual compounds and reaction masses was carried
out on Silufol plates, on Merck glass plates with
0.2 mm layers of UV-254 silica gel (eluent 3–7%
chloroform–isopropanol), as well as on Alufol
(Kavalier) plates, with spots development in iodine
vapor, under UV light, or using a ninhydrin solution
for amino acids analysis.
Acrylonitrile, acetamidomalonic ester, and phos-
phorus tribromide were provided by Reacor Ltd. (Alfa
Aesar). Phosphorous acid was thoroughly dried before
use.
2-Cyanoethylacetamidomalonic ester (4). 0.05 g
(2 mmol) of sodium metal was added, with stirring, to
a mixture of 10.9 g (50 mmol) of acetamidomalonic
The 188Re-DADP5 biological distribution was
evaluated from direct radiometric data. The obtained
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 9 2018

2,5-DIAMINO-5,5-DIPHOSPHONOVALERIC ACID AS A LIGAND
1783
Distribution in the organs and tissues in rats with the bone pathology model in 1 and 3 h after the injection of “Zoleren,
188Re,” “Phosphorene, 188Re,” and 188Re-DADP5, in % of injected activity
“Zoleren, 188Re”
“Phosphorene, 188Re”
DADP5, 188Re
Organ
1 h
3 h
1 h
3 h
1 h
3 h
Blood,%/g
Liver
1.7
11.3
17.1
02.4
42.2
00.6
01.0
01.5
00.8
01.7
08.2
01.9
44.2
00.3
00.6
02.0
00.4
01.0
04.0
01.8
42.1
00.8
01.8
02.3
00.3
01.0
04.3
02.7
19.6
00.9
01.6
01.8
00.4
01.6
10.2
03.1
18.5
00.3
00.7
02.3
00.2
01.0
12.3
03.7
17.3
00.2
00.5
02.5
Kidneys
Stomach
Bladder
Thigh (norm)
Thigh (fracture)
Coefficient of differential accumulation
3
ester in 20 mL of ethanol, whereafter 3.6 mL
(55 mmol) of freshly distilled acrylonitrile was slowly
added dropwise. The resulting clear solution was
stirred for 10–15 h. The reaction was monitored by
TLC [until the acetamidomalonic ester spot dis-
appeared (Rf 0.6–0.7, 5:1 chloroform:acetone)]. The
reaction mixture was cooled, neutralized with a 2 N
HCl solution to pH ca. 6–7 and evaporated in vacuo.
The syrupy residue was partitioned between
chloroform (50 mL) and water (20 mL). The organic
phase was additionally washed with 20 mL of water,
dried with sodium sulfate, and evaporated in vacuo.
The residue was crystallized from diethyl ester. Yield
10.3 g (76%), mp 93–94°C (mp 92–94°C [28], 94–95°C
[29]).
CH2), 4.09 q (4H, CH2O, JHH = 6.9 Hz). 31P NMR
spectrum (DMSO-d6 + drop of TFA): δP 14.5 ppm.
Recrystallization of ester acid 5 from water resulted
in a partial loss of the ester group and decarboxylation
with the formation of aminodiphosphonic acid 6
containing an N-acetylaminocarboxylic ester moiety.
1H NMR spectrum of acid mixture 5 + 6 (D2O), δ,
ppm: 1.12 t (CH3, 3JHH = 7.3 Hz), 1.16* t (CH3, 3JHH
=
6.9 Hz), 1.88 s (Ac), 1.89* s (Ac), 2.10–2.45 m (CH2)
3
(5 + 6), 3.82* t (1H, CH, JHH = 6.9 Hz), 4.00–4.25 m
(CH2O) (5 + 6). 31P NMR spectrum (D2O), δP, ppm:
17.34*, 17.48, 17.90* [The signals marked with an
asterisk correspond to acid 6 (8–25% depending on the
duration of boiling in water)]. Acid hydrolysis of ester
acid 5 and of acid mixture 5+6 results in the formation
of desired amino acid 3.
3-Amino-3,3-diphosphonopropylacetamidomalonic
ester (5). 4.1 mL (44 mmol) of phosphorus tribromide
was slowly added dropwise with stirring to a
suspension of 3.6 g (44 mmol) of phosphorous acid
and 6.0 g (22 mmol) of nitrile 4 in 30 mL of anhydrous
dioxane at 5–10°C. The resulting mixture was stirred
at room temperature and left without stirring for a day.
The bulk of the dioxane over the resulting gelatinous
product was decanted, and 15 mL of acetic acid was
added to the residue at cooling. The resulting mixture
was stirred for about 1 h, then poured onto ice
(ca. 20 mL), and concentrated by evaporation in vacuo.
20 mL of ethanol was added to the oily residue and the
resulting white powdery product was recrystallized
from aqueous ethanol. Yield 5.3 g (56%), mp 192–193°C
2,5-Diamino-5,5-diphosphonovaleric acid (DADP5,
3). A mixture of 4.3 g (10 mmol) of ester acid 5 and
15 mL of 6N HCl was boiled for 8–10 h. The reaction
mixture was evaporated in vacuo, and the residue was
co-evaporated with water and chromatographed using
a cation exchanger (eluent 1 N HCl). Ninhydrin-
positive eluate was evaporated in vacuo, and the
residue was treated with 1N HCl–acetone (1 : 10), and
2.6 g (75%) of amino acid 3 were recovered as
hydrochloride, mp 105–110°C (foaming followed by
solidifying), 303–307°C (decomp.). 1H NMR spectrum
(D2O, pH ca. 1), δ, ppm (the signals marked with an
asterisk correspond to the second minor form): 1.72–
1
1
2.17 m (4H, CH2), 3.85 m and *4.00 m (1H, CH). H
(decomp.). H NMR spectrum (DMSO-d6 + drop of
3
NMR spectrum (D2O + NH4OH, pH ca. 9), δ, ppm:
TFA), δ, ppm: 1.13 t (6H, CH3, JHH = 6.9 Hz), 1.70–
1.97–2.42 m (4H, CH2), 3.58 t (CH, 3JHH = 8.5 Hz). 13C
1.85 m (2H, CH2), 1.88 s (3H, Ac), 2.35–2.50 m (2H,
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 9 2018

1784
TSEBRIKOVA et al.
NMR spectrum (D2O, pH ca. 1), δC, ppm: 22.48, 22.85,
*25.17, *27.92, 49.07, *52.67, 56.74 dd (1JPC = 137.6,
The manipulations with animals were carried out under
chloral hydrate anesthesia. Animals were anesthetized
with intraperitoneal injection of chloral hydrate in
physiological saline, 400 mg per 1 kg of body weight.
During the experiments, the animals were kept under
standard conditions (special room, recommended diet,
free access to drinking water, natural lighting). A
solution of 188Re-DADP5 with a volume activity of
16.6 MBq/mL was injected into the tail veins of
animals in an amount of 0.2 mL (3.2 MBq per animal).
The content of radiopharmaceuticals in organs and
systems was determined by direct radiometry [1, 4]
1 and 3 h after the injection and indicated in % of the
injected activity. Radiometry of organs and tissues was
carried out using a Wizard 2480 gamma counter
(USA). The results of the 188Re-DADP5 biological
behavior, as compared with those for “Zoleren, 188Re”
and “Phosphorene, 188Re” are presented in the table
above.
31
1JPC = 138.4 Hz), 169.16, *171.42. P NMR spectrum
(D2O, pH ca. 1), δP, ppm: *12.77, 17.51. Found, %: C
17.28, 17.22; H 5.13, 5.28. N 7.97, 7.88. C5H14N2O8P2·
HCl·H2O. Calculated, %: C 17.33; H 4.94; N 8.08.
Recovery of 3 as a free amino acid was accom-
plished by treating the amino acid hydrochloride with
propylene oxide in an 1 : 2 aqueous ethanol solution.
Additional crystallization from water allowed the
1
recovery of free amino acid 3a, mp 313–314°C. H
NMR spectrum (D2O), δ, ppm: 2.07–2.52 m (4H,
3
13
CH2), 3.85 t (CH, JHH = 8.5 Hz). C NMR spectrum
(D2O), δC, ppm: 22.95 t (3JPC = 4.1 Hz), 23.33 t (2JPC
3.0 Hz), 49.47, 57.33 t (1JPC = 135.6 Hz), 169.48 t (5JPC
=
=
4.1 Hz). 31P NMR spectrum (D2O): δP 17.31 ppm.
Found, %: C 20.18, 20.30; H 5.05, 4.96; N 9.67, 9.60.
C5H14N2O8P2. Calculated, %: C 20.56; H 4.83; N 9.59.
Mass spectrum (LCMS), m/z: 293.1 [M + H]+
(calculated for C6H16N2O8P2: 292.1).
The work was performed in compliance with all
applicable international, national, and institutional
guidelines for the care and use of animals.
For radiochemical studies, a solution of [188Re]
sodium perrhenate obtained from the 188W/188Re
generator GREN-1 (the Leypunsky Institute of Physics
and Power Engineering, Russia) was used. To perform
the labeling reaction 15 mg of ligand 3 was dissolved
in 1 mL of water, and 3 mg of SnCl2·2H2O, 1 mL of
eluate from the generator with an activity of 37 MBq/mL,
and 150 μL of 0.5M NaOH were added in an argon
stream. The reaction mixture was held at room tempe-
rature for 30 min to complete the complexing reaction,
and the pH was adjusted to 5 by adding 80 μL of 0.5 M
NaOH to obtain a clear solution. The activity of the
solution of the radiopharmaceutical composition was
16.6 MBq/mL, the ligand concentration 6.73 mg/mL
(0.021 M), the concentration of SnCl2·2H2O 1.35 mg/mL
(0.006 M).
ACKNOWLEDGMENTS
The work was done with partial financial support
from the Program no. 34 of the Presidium of the
Rassian Academy of Sciences, the Russian Foundation
for Basic Research (grants nos. 18-33-00685 and 18-03-
0959), and the RF Ministry of Education and Science
within the framework of state assignments nos. 0081-
2014-0015 and 0090-2017-0024.
CONFLICT OF INTEREST
No conflict of interests was declared by the authors.
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