Synthesis of a novel lipophilic gadolinium complex as a potential MRI contrast agent

Article abstract of DOI:10.1055/s-2006-950281

The synthesis of a novel lipophilic diethylentriaminotetracetic(DTTA)- dodecane gadolinium complex is reported. The Gd-DTTA-dodecane complex is able to form mixed micelles with 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and a non-ionic surfactant like Tween 80. This novel multicomponent system can find potential application in magnetic resonance angiography (MRA). Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-950281

LETTER
2815
Synthesis of a Novel Lipophilic Gadolinium Complex as a Potential MRI
Contrast Agent
a
a
b
c
c
a
A
N
ovel Lipophili
n
c
G
adolinium
d
C
omplex fo
r
r
M
RI ea Masotti,* Laura Remollino, Maria Carafa, Carlotta Marianecci, Eleonora Santucci, Giancarlo Ortaggi
a
Department of Chemistry, University ‘La Sapienza’, 00185 Rome, Italy
Fax +39(06)233234321; E-mail: andrea.masotti@uniroma1.it
b
c
Department of Scienze del Farmaco, Faculty of Pharmacy, University ‘G. D’Annunzio’, 66100 Chieti, Italy
Department of Studi di Chimica e Tecnologia delle Sostanze Biologicamente Attive, Faculty of Pharmacy, University ‘La Sapienza’,
0185 Rome, Italy
0
Received 6 July 2006
Polyaminopolycarboxylic Gd(III) complexes are the most
Abstract: The synthesis of a novel lipophilic diethylentriamino-
tetracetic(DTTA)-dodecane gadolinium complex is reported. The
Gd-DTTA-dodecane complex is able to form mixed micelles with
2–
widely used contrast agents in MRI with Gd(DTPA) be-
ing the most common (Figure 1).2 Several other Gd
complexes have been reported in the last decades5
–4
,6
1
,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and a non-
ionic surfactant like Tween 80. This novel multicomponent system (Figure 1) but the synthesis of novel contrast agents with
can find potential application in magnetic resonance angiography improved properties are required for specific applications
(
MRA).
in magnetic resonance angiography (MRA).7
Key words: contrast agent, gadolinium complex, mixed micelles,
magnetic resonance imaging, magnetic resonance angiography
One of the most important aims of MRI is the imaging of
the cardiovascular system.8 The contrast agent must per-
sist in the bloodstream for a long time after administration
to patients and several strategies are currently employed:
,9
Magnetic resonance imaging (MRI) is a powerful and
valuable non-invasive diagnostic technique providing im-
ages of selected parts of the human body. A great part of
MRI scans are performed employing a contrast agent, an
exogenous compound able to enhance the relaxation rates
of water protons and to improve the MRI images.
10
11
serum protein binders and polymeric or dendrimeric
Gd complexes, which stay confined in the blood vessels
1
4,12,13
owing to their large dimension. Moreover, liposomes
14,15
or micelles
have also been used. Several formulations7
using Gd-DTPA-cholesterol have been reported recently
(
Figure 1) and other lipophilic Gd complexes bearing one
or two aliphatic chains have been studied and have given
promising results as MRA contrast agents.
HOOC
HOOC
COOH
COOH
15,16
N
N
N
Here we report the synthesis of the novel Gd complex 4
containing a dodecyl chain as a lipophilic moiety. Due to
the hydrophobic nature of dodecane, the resulting Gd(III)
complex 4 is easily incorporated into liposomes or mi-
celles.
COOH
DTPA
COOH
HOOC
N
N
N
N
Me(CH2)11Br
H2N
N
H
NH2
H2N
N
H
N
(CH2)11Me
HOOC
COOH
MeOH/aq NaOH
5 °C, 6 h
DOTA
9
1
2
–OOC
COO–
Gd3+
–OOC
N
N
COO–
HOOC
HOOC
BrCH2COOH (ex.)
THF/aq NaOH
N
N
N
(CH2)11Me
2
2
Na+
–OOC
N
COOH
9
5 °C, 6 h
COOH
NHCOO
Gd-DTPA-Cholesterol
3
COO–
–OOC
3+
N
Gd
GdCl3 (ex.)
aq MeOH/NaOH
0 °C, 24 h
N
Figure 1 Chemical structure of common polyaminopolycarboxylic
ligands used in MRI
3
–OOC
9
N
(CH2)11Me
4
COO– Na+
Scheme 1 Synthesis of Gd-DTTA-dodecane complex 421
SYNLETT 2006, No. 17, pp 2815–2817
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7
.1
0
.2
0
0
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Advanced online publication: 09.10.2006
DOI: 10.1055/s-2006-950281; Art ID: G22506ST
©
Georg Thieme Verlag Stuttgart · New York

2
816
A. Masotti et al.
LETTER
To the best of our knowledge 4 is the first example of a
Gd-DTTA complex attached to a dodecyl chain.
Scheme 1 reports the synthesis of 4 starting from com-
mercially available 1 by coupling to bromododecane in al-
kaline solution. The hydrophobic derivative 2 was further
reacted with an excess of bromoacetic acid to give 3 as a
(4) Masotti, A.; Mangiola, A.; Sabatino, G.; Maira, G.; Denaro,
L.; Conti, F.; Ortaggi, G.; Capuani, G. Int. J. Immunopathol.
Pharmacol. 2006, 19, 11.
(5) Reichert, D. E.; Lewis, J. S.; Anderson, C. J. Coord. Chem.
Rev. 1999, 184, 3.
6) Thunus, L.; Lejeune, R. Coord. Chem. Rev. 1999, 184, 125.
7) Lattuada, L.; Lux, G. Tetrahedron Lett. 2003, 44, 3893.
(
(
white solid. Reaction of 3 with GdCl afforded 4 in 46%
(8) Kroft, L. J. M.; de Roos, A. J. Magn. Reson. Imaging 1999,
10, 395.
3
overall yield. Complex 4 is soluble in water up to 50 mg/
mL and is able to form aggregates when mixed with a
phospholipid (DMPC) and a neutral surfactant like Tween
(
9) Bogdanov, A. A. Jr.; Lewin, M.; Weissleder, R. Adv. Drug
Deliv. Rev. 1999, 37, 279.
(
10) Ladd, D. L.; Hollister, R.; Peng, X.; Wei, D.; Wu, G.;
Delecki, D.; Snow, R. A.; Toner, J. L.; Kellar, K.; Eck, J.;
Desai, V. C.; Raymond, G.; Kinter, L. B.; Desser, T. S.;
Rubin, D. L. Bioconjugate Chem. 1999, 10, 361.
(11) Krause, W.; Hackmann-Schlichter, N.; Maier, F. K.; Müller,
R. Top. Curr. Chem. 2000, 210, 261.
12) Glogard, C.; Stensrud, G.; Hovland, R.; Fossheim, S. L.;
Klaveness, J. Int. J. Pharm. 2002, 233, 131.
(13) Alhaique, F.; Bertini, I.; Fragai, M.; Carafa, M.; Luchinat,
C.; Parigi, G. Inorg. Chim. Acta 2002, 331, 151.
8
0 (in a 1:1:1 ratio). The mixture was diluted 1:10 with
water and bath-sonicated for 30 minutes at 70 °C. Parti-
cles with mean diameter of 49.8 ±5.6 nm
a
(
polyindex = 0.35 ± 0.05) were obtained and measured by
dynamic light scattering (Zetasizer Nano ZS 90, Malvern,
UK).
(
T1 relaxation times were obtained by the inversion recov-
ery method and r relaxivity from a linear least squares re-
1
gression analysis of relaxation rate (1/T ) vs C (mM) by
(14) Tournier, H.; Hyacinthe, R.; Schneider, M. Acad. Radiol.
1
eff
2002, 9 (Suppl. 1), S20.
means of a Minispec PC-120b (Bruker GmbH, Rhein-
(
15) Glogard, C.; Hovland, R.; Fossheim, S. L.; Aasen, A. J.;
Klaveness, J. J. Chem. Soc., Perkin Trans. 2 2000, 1047.
16) Anelli, P. L.; Lattuada, L.; Lorusso, V.; Schneider, M.;
Tournier, H.; Uggeri, F. MAGMA 2001, 12, 114.
(17) Lauffer, R. B. Chem. Rev. 1987, 87, 901.
(18) Gouin, S.; Winnik, F. M. Bioconjugate Chem. 2001, 12, 372.
(19) Hovland, R.; Glogard, C.; Aasen, A. J.; Klaveness, J. Org.
Biomol. Chem. 2003, 1, 644.
stetten, Germany). Complex 4 shows a high relaxivity
–
1 –1
(
r = 21.7 mM s in Tris buffer, pH 8, 20 MHz). This re-
1
(
laxivity value is extremely high compared to the relaxivity
–
1 –1 17
of Gd-DTPA (r = 3.7 mM s ), and it is indirect evi-
1
dence of a micellar self-organization of 4 in water. In fact,
such high relaxivity is only achieved with multimeric Gd
2
,3
complexes like dendrimers or polymers. Moreover,
(
20) Hovland, R.; Aasen, A. J.; Klaveness, J. Org. Biomol. Chem.
mixed micelles obtained with complex 4 show a high re-
2003, 1, 1707.
–
1 –1
laxivity (r = 19.4 mM s ) comparable to the Gd-DTPA-
1
(
21) Compound 2: A solution of 1-bromododecane (20 g, 80
mmol) in EtOH (100 mL) was added over 1 h to a stirred
solution of diethylentriamine 1 (8.25 g, 80 mmol) in EtOH
(100 mL) at r.t. NaOH (0.1 M) was added to the reaction
mixture until the pH >7. The resulting solution was heated at
–
1 –1
cholesterol derivative (r = 25 mM s ) recently reported
in the literature. No free Gd ions were detected by as-
1
7
3+
1
8
saying complex 4 with Arsenazo III dye. Hence, the high
values of relaxivity suggest that the Gd complex may be
heptadentate with two water molecules coordinated to the
metal (q = 2). Moreover, a favorable molecular reorienta-
tional time (t ) and a low water residence time (t ) may
95 °C for 6 h, stirred at r.t. for 18 h, and then the solvent was
evaporated under reduced pressure. The crude oil was
purified by distillation collecting the fraction with a boiling
r
m
point of 265–270 °C, which furnished 2 as a transparent oil
account for the high relaxivity as reported for similar
1
(
9.46 g, 41%). H NMR (300 MHz, D O): d = 0.96 (CH , t,
2
3
1
9,20
compounds.
In conclusion, we have reported the syn-
3 H), 1.37 (CH , br, 18 H), 1.56 (CH , m, 2 H), 2.51 (CH N,
2
2
2
thesis and characterization of the novel lipophilic Gd
complex 4. This derivative can easily be incorporated into
supramolecular systems like mixed micelles, a new and
very promising class of blood pool MRI/MRA contrast
agents.
t, 2 H), 2.73 (CH
2
N, t, 2 H), 2.83 (CH N, br, 4 H), 2.87
2
1
3
(
2
CH N, t, 2 H). C NMR (300 MHz, D O): d = 13.41, 22.03,
2
2
6.88, 28.97, 29.19 (br m), 29.55, 31.28, 41.08, 48.73, 48.90,
+
49.40, 51.86. ESI-MS: m/z = 272.3 [M + H] . Anal. Calcd
for C H N : C, 70.77; H, 13.74; N, 15.48. Found: C, 71.01;
1
6
37
3
H, 13.93; N, 15.53. Compound 3: To a solution of 2 (2.7 g;
0 mmol) in THF (250 mL), was added bromoacetic acid
13.9 g, 0.1 mol, 10 equiv) in H O (100 mL) over 2 h; the pH
1
(
2
Acknowledgment
of the reaction mixture was maintained at 12 by the constant
addition of NaOH (0.1 M). The mixture was heated at 95 °C
for 6 h, then the solvent was evaporated under reduced
pressure. The milky residue was treated with HCl until the
solution was pH 1 and the resulting acidic solution was
filtered. The solid was washed several times with cold EtOH
Financial support from MIUR (Ministero dell’Università e della
Ricerca)
is
gratefully
acknowledged
(FIRB
2001-
RBNE01MBEC).
References and Notes
and dissolved again in H O (pH 8). The solution was treated
with HCl until a precipitate formed. The white solid was
2
(
1) Rinck, P. A. Magnetic Resonance in Medicine; Blackwell
Scientific Publications: Oxford, UK, 1993.
filtered, washed several times with cold H O, and dried in a
2
1
vacuum desiccator (1.1 g; 22%). H NMR (300 MHz, D O):
2
(
2) Merbach, A. E.; Tóth, É. The Chemistry of Contrast Agents
in Medical Magnetic Resonance Imaging; John Wiley &
Sons Ltd: Chichester, 2001.
d = 0.65 (CH , t, 3 H), 1.04 (CH , br, 20 H), 2.24 (CH N, m,
3
2
2
13
2
H), 2.32 (CH N, m, 8 H), 2.83 (CH COOH, br, 8 H). C
2
2
NMR (300 MHz, D O): d = 14.18, 22.77, 25.22, 27.82,
2
(
3) Caravan, P.; Ellison, J. J.; McMurry, T. J.; Lauffer, R. B.
Chem. Rev. 1999, 99, 2293.
2
9.52, 29.80 (br m), 32.06, 51.18, 52.26, 52.65, 55.10, 58.46,
2+
59.02, 59.41, 179.34. ESI-MS: m/z = 262.96 [M + Na] .
Synlett 2006, No. 17, 2815–2817 © Thieme Stuttgart · New York

LETTER
Anal. Calcd for C H N O : C, 57.24; H, 9.01; N, 8.34.
A Novel Lipophilic Gadolinium Complex for MRI
2817
mL and absolute EtOH (100 mL) was added. The precipitate
was washed several times with EtOH, filtered, and dried in
vacuo to obtain the complex 4 as a white solid (0.12 g, 46%).
2
4
45
3
8
Found: C, 57.17; H, 9.24; N, 8.33. Compound 4: A solution
of GdCl ·6H O (0.148 g, 0.4 mmol) in H O (20 mL) was
3
2
2
3
+
added dropwise to a solution of 3 (0.2 g, 0.4 mmol) in H O
ESI-MS: m/z = 219.20 [M + Gd] . Anal. Calcd for
2
(
100 mL) and NaOH (2 M, 5 mL); the pH of the reaction
C H N O Gd·4H O: C, 39.55; H, 6.78; N, 5.76. Found: C,
2
4
41
3
8
2
mixture was maintained at 12 by the constant addition of
NaOH (2 M). After 6 h the solution was concentrated to 25
40.01; H, 6.93; N, 5.84.
Synlett 2006, No. 17, 2815–2817 © Thieme Stuttgart · New York