Synthesis of two stereoisomeric polydentate ligands, trans and cis cyclopentane-1,2-diaminotetraacetic acids, and complexation by 111In and 153Sm

Article abstract of DOI:10.1016/S0040-4020(01)01198-X

Two polyaminocarboxylic acid chelating agents were synthesized. Complexation properties regarding ¹¹¹In and ¹⁵³Sm, two radionuclides suitable for applications in immunoscintigraphy and radioimmunotherapy were investigated. The synthesis of aminodiacetic acid derivatives 7a and 7b involved preliminary stereoselective synthesis of the corresponding amines, cis and trans cyclopentane-1,2-diamines. ¹¹¹In labelling confirmed the complexation abilities of the two ligands. An additional comparative study to probe the relationship between ligand structure and metal complex was performed with ¹⁵³Sm.

Full text of DOI:10.1016/S0040-4020(01)01198-X

TETRAHEDRON
Pergamon
Tetrahedron 58 82002) 1131±1136
Synthesis of two stereoisomeric polydentate ligands,
trans and cis cyclopentane-1,2-diaminotetraacetic acids,
and complexation by In and 153Sm
111
a,b
b
a
c
Sebastien G. Gouin, Jean-FrancËois Gestin, Kevin Joly, Anthony Loussouarn, Alain Reliquet,
a
Â
Jean Claude Meslina and David Deniauda,p
a
Á Â Á
Laboratoire de Synthese Organique, Faculte des Sciences et des Techniques, UMR CNRS 6513, 2, rue de la Houssiniere,
BP 92208, 44072 Nantes cedex, France
Â
b
INSERM U463, Chimie des bioconjugues, 9, quai Moncousu, 44093 Nantes cedex, France
cCHELATEC SAS, Institut de Biologie, 9, quai Moncousu, 44093 Nantes cedex, France
Received 19 September 2001; revised 16 November 2001; accepted 3 December 2001
AbstractÐTwo polyaminocarboxylic acid chelating agents were synthesized. Complexation properties regarding 111In and 153Sm, two
radionuclides suitable for applications in immunoscintigraphy and radioimmunotherapy were investigated. The synthesis of aminodiacetic
acid derivatives 7a and 7b involved preliminary stereoselective synthesis of the corresponding amines, cis and trans cyclopentane-1,2-
diamines. 111In labelling con®rmed the complexation abilities of the two ligands. An additional comparative study to probe the relationship
between ligand structure and metal complex was performed with 153Sm. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
8precursors of BCAs) with a semi-rigid structure. This
type of structure is essential to preorganisation, an important
ligand property that increases the stability of the metal
complex. Preorganisation 8the tendency for a free ligand
to adopt a favourable conformation for complexation of a
metal ion)21 minimises the degree of freedom of donor
atoms, so that the structure of the chelate before complexa-
tion is similar to that with complex. Thus, the metal
complexes of trans-CDTA 8cyclohexanediaminetetraacetic
acid) are often two to three times more stable than those of
EDTA, because of the restricted movement of the amino-
diacetic arms with CDTA.22,23 Moreover, preorganisation of a
polydentate chelator provides increased kinetic inertness of
the metal complex as well as high thermodynamic stability.
Polyaminocarboxylate groups, which have often been used
for the design of polydentate ligands such as ethylene-
diamine tetraacetic acid 8EDTA) and diethylenetriamine-
pentaacetic acid 8DTPA), generally show high af®nity for
metal cations.1,2 These ligands are widely used as chelating
agents in fundamental research3 or as diagnostic tools in
the pharmaceutical industry4,5 and are particularly suitable
for magnetic resonance imaging 8MRI),6±10 nuclear
medicine,11±13 and more recently scintigraphy14 or radio-
therapy,15±18 when coupled to a metallic radionuclide
capable of visualising or destroying a malignant tumour.
Such applications are highly ef®cient if the radioactive
metal is speci®cally directed at the cancer cells. Thus,
immunoscintigraphy 8IS) and radioimmunotherapy 8RIT)
with radiolabelled antibodies linked chelate allow relatively
speci®c diagnostic and therapeutic targeting of certain
cancers and their recurrences.19 In this context, various
preclinical and clinical studies have demonstrated the
bene®t of using the af®nity enhancement system 8AES)
associating a bispeci®c antibody with a bivalent hapten
bearing a bifunctional chelating agent 8BCA).20
The purpose of this study was to prepare chelates with a
more rigid structure than that of CDTA. Two original
stereoisomeric ligands with a cis and trans con®guration
were synthesised according to two parallel pathways: cis-
and trans-cyclopentane-1,2-diamine-N,N,N0,N0-tetraacetic
acid. The complexation properties of these two new
compounds were con®rmed with samarium-153 and
indium-111.
This paper reports the synthesis of two chelating agents
2. Results and discussion
2.1. Synthesis of ligands
Keywords: chelating agent synthesis; polyaminocarboxylic acid; cyclopen-
tane-1,2-diamine; radionuclides.
p
Corresponding author. Tel.: 133-2-51125457; fax: 133-2-51125402;
e-mail: david.deniaud@chimie.univ-nantes.fr
Commercially available cyclopentene was used as the
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020801)01198-X

1132
S. G. Gouin et al. / Tetrahedron 58 72002) 1131±1136
Scheme 1. Synthesis of cyclopentane-1,2-diamine dihydrochloride 4a and 4b. Reagents and conditions: 8i) MsCl, Et3N, CH2Cl2, 08C, 4 h, then rt, 3 h;
8ii) NaN3, 15-crown-5, DMF, 858C, 24 h; 8iii) Pd8OH)2, MeOH, HCl 2N, H2, rt, 8 h; 8iv) Pd/C 10%, EtOH, H2, rt, 6 h.
starting reagent for the synthesis of cis- and trans-cyclo-
pentane-1,2-diaminotetraacetic acid 8Scheme 1). The key
step in this synthetic process was the preparation of the
two corresponding cyclopentane-1,2-diamine dihydro-
chlorides, 4a and 4b.
performed in dimethylformamide at 858C for 24 h requires
the presence of a catalytic amount of 15-crown-5 to provide
the expected compounds with a yield of around 85%.35
However, the reduction of vicinal diazides raised several
problems. Only trans-cyclopentane-1,2-diamine 5 could
be isolated 890% yield) when hydrogenation was performed
under atmospheric pressure with palladium on charcoal in
methanol. Unfortunately, this compound proved extremely
unstable and degraded upon use, even under an inert
atmosphere. Starting with compound 3a, regardless of the
operating conditions 8Pd on charcoal, PtO2, SnCl3, LiAlH4,
etc.), it was impossible to obtain cis-diamine. The diamine
was too unstable and degraded during the reaction, or as cis
vicinal diamines are excellent ligands for metal chelation,
the catalyst may have been poisoned during the reaction. As
a result, palladium hydroxide on charcoal was used in acid
medium 8Pearlman's catalyst) to obtain protected diamines
in the form of dichlorohydrates 4a and 4b, giving yields
respectively of 88 and 91%.36 Thermogravimetric analyses,
allowed determination of the number of water molecules
complexed to the diamines.
The preparation of cyclopentane-1,2-diamine, as performed
in previous reports, required long and relatively inef®cient
synthesis or involved drastic acid conditions.24±26 A recent
patent ®led by Abbott Laboratories mentions stereoselective
synthesis, but does not describe the experimental protocol.27
Otherwise, the group of Husson has reported the selective
synthesis of trans-cyclopentane-1,2-diamine alone by
means of a double Curtius rearrangement, a process using
a very expensive starting product, trans-cyclopentane-1,2-
dicarboxylic acid, and achieving a relatively poor overall
yield.28
Our approach is rapid, ef®cient and stereoselective for the
preparation of cis- and trans-cyclopentane-1,2-diamine
dihydrochlorides 4a and 4b according to a similar protocol.
The cis- and trans-cyclopentane-1,2-diol compounds 1a and
1b were obtained according to methods previously
described in the literature. For diol cis 1a, a Sharpless oxida-
tion29±31 was performed using osmium tetroxide, and for
diol trans 1b the reaction involved the formation of an
intermediate epoxide.32 Using cyclopentane-1,2-diols 1a
and 1b, the corresponding compounds 3a and 3b were not
obtained directly by the Mitsunobu reaction, a method often
employed for the synthesis of azides.33,34 The hydroxyl
functions of compounds 1a and 1b were activated in
methanesulfonyl derivatives and converted into diazides
3a and 3b by treatment with sodium azide. This reaction
After the synthesic key step of cis- and trans-cyclopentane-
1,2-diamines dihydrochlorides, the amine functions were
alkylated by ethyl bromoacetate according to the conditions
described by Studer37,38 8KI and K2CO3) to provide tetra-
esters 6 8Scheme 2), with yields of 55% for 6a and 68%
for 6b.
The cis-diethylpiperazin-2-one-N,N0-diacetate
8
was
formed by intramolecular cyclisation with one of the
aminoacetate arms of the adjacent nitrogen. This accounted
for the modest yield obtained with compound 6a
8Scheme 3). Cyclisation was not observed with
Scheme 2. Synthesis of ligands 7a±b and corresponding complexes. Reagents and conditions: 8i) ethyl bromoacetate, K2CO3, KI, CH3CN, 608C, 48 h; 8ii) HCl
3N, re¯ux, 12 h; 8iii) SmCl3 or InCl3, 1 h or 30 min, pH 5.5±5.8, 378C.

S. G. Gouin et al. / Tetrahedron 58 72002) 1131±1136
1133
Scheme 3. Synthesis of cis-diethylpiperazin-2-one-N,N0-diacetate 8. Reagents and conditions: 8i) ethyl bromoacetate, K2CO3, KI, CH3CN, 608C, 48 h.
trans-cyclopentane-1,2-diamine 6b because of the spatial
separation of the two nitrogen atoms. Finally, hydrolysis
of the ester functions was performed in hydrochloric acid
3 Mto provide the two polyaminocarboxylic acid ligands 7a
and 7b with quantitative yields. After six steps, the overall
yield was around 30% for 7a and 7b.
added to a range of 1, 2, 5 and 50 equiv. of each chelating
agent 8EDTA, CDTA, 7a and 7b).
The results of the experiments are summarised in Table 1.
The four ligands show considerable differences in
reactivities, even though all the samarium was complexed
with a high ligand concentration 850 equiv.). The mean
complexation percentages for all ligands with 1 mol equiv.
of radionuclide are attributable to a de®ciency of donor
atoms in each ligand, i.e. samarium vacant co-ordination
sites occupied by electron lone pair of the oxygen atom
from water molecules. Compound 7b and EDTA can be
considered as poor ligands for lanthanides, whereas
CDTA is an ef®cient complexing agent as ligand-to-metal
ratio equal 2. Ligand 7a showed very low af®nity for 153Sm,
even at relatively high concentrations 85 equiv.). The differ-
ence between compounds 7a and 7b is related to the spatial
position of the aminodiacetic arms on the carbon skeleton.
When the polyaminocarboxylate groups are in cis position
on the cyclopentane, semi-emperical calculations with
the AM1 method clearly show a considerable reduction in
the size of the complexation cage as compared to trans
After the synthesis and characterisation of these two new
chelates, it was necessary to determine their capacity for
complexing radioactive metals.
2.2. Complexation tests
The preparation of complexes for immunoscintigraphy, a
major diagnostic technique, involved the use of 111In
[half-life of 67.4 h, g emission with an energy of 173 keV
883%), 247 keV 894%)]. This radionuclide was chosen
Ê
because of its relatively medium size 8Rˆ0.80 A) and the
fact that indium complexes are generally hexaco-
ordinated.39 Thus, 111In was suitable for determining the
capacity of ligands 7a and 7b to complex medium sized
metals, which possess six co-ordination sites. Radioactive
indium complexes were formed by the reaction in buffered
medium of 1 mol equiv. of In31 82£1022 mCi) with
1 mol equiv. of each chelating agent. Incubation for
30 min at 378C resulted in 100% complexation of 111In
with 7a and 7b. These results are quite similar to those
obtained under the same conditions with EDTA and
CDTA. This procedure showed the aptitude of ligands 7a
and 7b to complex, with a rapid kinetic formation, medium-
sized metals with six co-ordination sites. The ef®cacy of
these ligands will be then evaluated by stability tests in
serum medium and competition tests with good indium
complexes.
Ê
analogue 7b 83.1 versus 3.8 A). This indicates that the
cavity for 7a is too small and not suf®ciently ¯exible to
accept lanthanides such as 153Sm. The difference in
samarium complexation by CDTA and 7b could be due to
the markedly greater ¯exibility of cyclohexane in adapting
to radionuclide size.
Table 1. Effect of ligand concentration on chelator-labelling ef®ciency
Mole equivalent
%
153Sm chelated
EDTA
CDTA
7a
7b
1
2
5
50
20
53
58
96
33
98
99
99
5
21
50
54
95
These promising results led us to study the in¯uence of the
chelating structure, i.e. the effect of cage size on complexa-
tion. One of the objectives of our research is to prepare BCA
suitable for radioimmunotherapy and complexed by lantha-
nides. Ligand geometry needs to be optimal, so that the
complexation cavity could be subsequently enlarged to
increase the number of co-ordination sites. Because of its
11
21
90
[
153Sm]ˆ1.5 nmol mL21
reaction periodˆ1 h; pHˆ5.5±5.8; tempera-
;
tureˆ378C; ®nal chelation volumeˆ500 mL; 0.1 Msodium acetate buffer.
Ê
3. Conclusion
greater size 8Rˆ0.96 A) and number of co-ordination sites
88±10 co-ordination sites), 153Sm was chosen to determine
the in¯uence of nitrogen-nitrogen distance on complexa-
tion. Accordingly, comparative complexation tests were
performed between EDTA, CDTA 8its semi-rigid homo-
logue), and our two ligands 7a and 7b to determine the
ratio of chelating agent to radionuclide needed to achieve
maximum 153Sm chelation ef®ciency and avoid free 153Sm
contamination in solutions. To form 153Sm chelating agent
complexes, a ®xed quantity of 153Sm stock solution was
In summary, two new stereoisomeric polydentate ligands
were developed by a process involving rapid, ef®cient,
and stereoselective synthesis. Their good complexation
ability was demonstrated for medium size cations such as
111In suitable for immunoscintigraphic applications. Tests
with samarium preliminary to the preparation of
bifunctional chelating agents for radioimmunotherapy
showed the major in¯uence of cavity geometry on the

1134
S. G. Gouin et al. / Tetrahedron 58 72002) 1131±1136
complexation rate and the more favourable characteristics
of trans than cis geometry. To develop an ef®cient ligand for
153Sm, our research will now be directed at synthesising a
compound with polyaminocarboxylate arms in trans
position and a greater number of co-ordination functions.
162 817), 101 832), 83 8100), 55 853); IR 8KBr) 2941 8s),
1344 8vs), 1181 8s), 980 8s).
4.3. General procedure for preparation of 1,2-diazido-
cyclopentane )3)
Sodium azide 830.8 mmol) and 15-crown-5 80.1 equiv.) was
added to a stirred solution of 1,2-dimethylsulfonyloxycyclo-
pentane 2 86.4 mmol) in anhydrous DMF 830 mL). The
mixture was heated at 858C for 24 h under Ar. After cooling,
the solution was poured into water 850 mL), extracted with
dichloromethane 850 mL), and washed with water
84£50 mL). Organic phase was collected, dried 8MgSO4),
and the solvent removed under vacuum. The residue was
puri®ed by ¯ash chromatography over silica using dichloro-
methane as eluent to afford 3 as colourless oil.
4. Experimental
4.1. General
All reagents were purchased from Acros Organics and
Aldrich. All chemicals were reagent grade and used without
further puri®cation, and all solvents were freshly distilled
before use. The CNRS Analysis Laboratory 8Vernaison)
performed the elemental analyses. Column chromatography
was conducted over silica gel 60 840±63 mm), available
from E. Merck. Thin-layer chromatography was performed
on 0.5 mm£20 cm£20 cm E. Merck silica gel plates 860
F-254). Melting points measured using a Reichert micro-
1
4.3.1. cis-1,2-Diazidocyclopentane )3a). Yield 83%; H
NMR 8CDCl3) d 1.50±2.10 8m, 6H, 3CH2), 3.82 8m, 2H,
2CH); 13C NMR 8CDCl3) d 20.0 81C, CH2CH2CH2), 28.0
82C, CH2CH2CH2), 64.5 82C, CH); MS 8FAB1), m/z 8%)
152 8100, M1).
1
scope are uncorrected. The 13C and H NMR spectra were
recorded at room temperature using a Bruker AC200
operating at 50 and 200 MHz, respectively. Chemical shifts
8d) are given in ppm down®eld from tetramethylsilane as
internal standard. Mass spectra were determined with a
Hewlett Packard 5989 spectrometer. TLC FAB-MS were
obtained on a Jeol SX 102 8m-nitrobenzyl alcohol matrix).
A Perkin±Elmer TGS2 thermogravimetric analyser was
used to obtain TGA thermograms, that were run in air
atmosphere from room temperature to 3008C at a scan rate
of 28C/min. The IR spectra were obtained using a Bruker
Vector 22 spectrometer.
4.3.2. trans-1,2-Diazidocyclopentane )3b). Yield 86%; 1H
NMR 8CDCl3) d 1.50±2.20 8m, 6H, 3CH2), 3.74 8m, 2H,
2CH); 13C NMR 8CDCl3) d 20.9 81C, CH2CH2CH2), 29.3
82C, CH2CH2CH2), 67.0 82C, CH); MS 8FAB1), m/z 8%)
152 8100, M1).
4.4. General procedure for preparation of cyclopentane-
1,2-diamine dihydrochloride )4)
A mixture of 3 81.58 mmol), 5 mL of methanol, 140 mg
80.2 mmol) of 20% palladium hydroxide on carbon
8Pearlman's catalyst), and 5 mL of 2N hydrochloric acid
was stirred under hydrogen pressure 81 atm) for 8 h. The
catalyst was ®ltered and the ®ltrate concentrated to dryness
to afford a white amorphous solid.
4.2. General procedure for preparation of 1,2-dimethyl-
sulphonyloxycyclopentane )2)
To a solution of cyclopentane-1,2-diol 1 89.8 mmol) in
dichloromethane 860 mL) was added triethylamine
848.9 mmol) at 08C under Ar. The reaction was stirred at
08C for 10 min, and methanesulfonyl chloride 848.9 mmol)
was added dropwise during 10 min. The reaction was stirred
at 08C for 4 h and allowed to warm to room temperature for
3 h. The organic phase was washed with 1 Mhydrochloric
acid 82£50 mL), 2 Msodium hydroxide 850 mL), and
50 mL of water. The organic phase was dried 8MgSO4),
®ltered, and evaporated. 2 was crystallised from ethanol
as a white solid.
4.4.1. cis-Cyclopentane-1,2-diamine dihydrochloride
trihydrate )4a). Yield 88%; mp 2708C; H NM R 8DO) d
1
2
1.93 8m, 4H, CH2CH2CH2), 2.26 8m, 2H, CH2CH2CH2),
3.94 8m, 2H, 2CH); 13C NM R 82DO) d 22.4 81C,
CH2CH2CH2), 30.5 82C, CH2CH2CH2), 56.3 82C, CH);
MS 8CI), m/z 8%) 136 8100, M12HCl±3H2O); MS 8EI),
m/z 8%) 101 812), 82 834), 56 895), 36 8100); IR 8KBr)
3520 8s), 3349 8s), 1500 8s), 1090 8s); TGA room tempera-
ture to 3008C, % water loss 23.8%.
4.2.1. cis-1,2-Dimethylsulfonyloxycyclopentane )2a).
1
Yield 90%; Mp 698C; H NMR 8CDCl3) d 1.60±2.20 8m,
4.4.2. trans-Cyclopentane-1,2-diamine dihydrochloride
)4b). Yield 91%; mp 2808C; H NM R 8DO) d 1.86 8m,
6H, 3CH2), 3.09 8s, 6H, 2CH3), 5.00 8m, 2H, 2CH); 13C
NMR 8CDCl3) d 18.4 81C, CH2CH2CH2), 28.6 82C,
CH2CH2CH2), 38.7 82C, CH3), 80.5 82C, CH); MS 8CI),
m/z 8%) 276 8100, M11NH41); MS 8EI), m/z 8%) 162
813), 101 834), 83 8100), 55 862); IR 8KBr) 2975 8s), 2951
8s), 1362 8vs), 1392 8s).
1
2
4H, CH2CH2CH2), 2.33 8m, 2H, CH2CH2CH2), 3.79 8m,
2H, 2CH); 13C NM R 8DO) d 25.2 81C, CH2CH2CH2),
2
33.2 82C, CH2CH2CH2), 58.7 82C, CH); MS 8CI), m/z 8%)
136 8100, M12HCl); IR 8KBr) 3400 8s), 3339 8s), 1492 8s),
1010 8s); TGA room temperature to 3008C, % water loss
0%.
4.2.2. trans-1,2-Dimethylsulfonyloxycyclopentane )2b).
1
Yield 91%; Mp 958C; H NMR 8CDCl3) d 1.75±2.35 8m,
4.4.3. trans-Cyclopentane-1,2-diamine )5). To a stirred
solution of trans-1,2-diazidocyclopentane 83b) 82.07
mmol) in ethyl alcohol 815 mL), Pd 10% on charcoal was
added 850 mg) and the mixture was hydrogenated at
atmospheric pressure at room temperature for 6 h. The
6H, 3CH2), 3.07 8s, 6H, 2CH3), 5.07 8m, 2H, 2CH); 13C
NMR 8CDCl3) d 21.0 81C, CH2CH2CH2), 30.6 82C,
CH2CH2CH2), 38.5 82C, CH3), 84.9 82C, CH); MS 8CI),
m/z 8%) 276 8100, M11NH41); MS 8EI), m/z 8%) 258,

S. G. Gouin et al. / Tetrahedron 58 72002) 1131±1136
1135
catalyst was ®ltered off and washed with ethanol. Alcohol
was removed under vacuum, and the product was dried to
was dried under vacuum and kept under nitrogen. Acid 7
is a very hygroscopic compound.
afford a yellow oil 8yield 90%). 1H NM R 8DO) d 1.50±1.80
2
4.6.1.
cis-Cyclopentane-1,2-diamine-N,N,N0,N0-tetra-
8m, 8H, CH2CH2CH212NH2), 1.96 8m, 2H, CH2CH2CH2),
3.73 8m, 2H, 2CH); 13C NM R 82DO) d 20.2 81C,
CH2CH2CH2), 33.7 82C, CH2CH2CH2), 61.5 82C, CH);
MS 8CI), m/z 8%) 100 8100, M1).
1
acetic acid )7a). Yield 98%; H NM R 8DO) d 1.50±2.20
2
8m, 6H, 3CH2), 3.70±4.20 8m, 10H, 2CH14NCH2); 13C
NMR 8D2O) d 20.7 81C, CH2CH2CH2), 26.0 82C,
CH2CH2CH2), 54.5 84C, NCH2), 66.0 82C, CH), 172.6
84C, CvO); MS, m/z 8%) 332 8100, M1).
4.5. General procedure for the preparation of tetraethyl-
cyclopentane-1,2-diamine-N,N,N0,N0-tetraacetate )6)
4.6.2.
cis-Cyclopentane-1,2-diamine-N,N,N0,N0-tetra-
acetic acid )7b). Yield 100%; H NM R 8DO) d 1.60±
2.18 8m, 6H, 3CH2), 3.74±4.12 8m, 10H, 2CH14NCH2);
1
2
To a solution of dihydrochloride 4 82.2 mmol) in freshly
distilled acetonitrile 830 mL) were added potassium
carbonate 814.5 mmol) and potassium iodide 83.2 mmol).
After stirring the mixture for 18 h at 608C, ethyl bromo-
acetate 814.8 mmol) was added dropwise. The reaction
mixture was kept at this temperature over a period of 48 h
under Ar prior to cooling to room temperature, ®ltration,
and concentration under reduced pressure. The resulting
residue was partitioned between diethyl ether 8125 mL)
and 0.5 Mhydrochloric acid 8125 mL). The organic extract
was washed with 0.56 Msodium hydroxide 8125 mL), dried
8MgSO4), ®ltered and evaporated. The residue was puri®ed
by ¯ash chromatography on silica gel using a dichloro-
methane:ethyl acetate 89:1) mixture as eluent to give 6 as
a colourless oil.
13C NM R 8DO) d 23.5 81C, CH2CH2CH2), 34.0 82C,
CH2CH2CH2), 52.6 84C, NCH2), 65.3 82C, CH), 170.4
2
84C, CvO); MS, m/z 8%) 332 8100, M1).
4.7. Complexation tests
4.7.1. Complexation studies with 111In. To a ®xed quantity
of each chelating agent 837.7 nmol) in 0.1 Msodium acetate
buffer was added 2 mL 83£1022 nmol) of a radioactive
solution of 111InCl3 810 mCi mL21) and 2 mL 837.3 nmol)
of a solution of InCl3 818672.5 nmol mL21 in 0.05 Mhydro-
chloric acid). The unradioactive solution of InCl3 was used
to maintain a ®xed concentration of indium during the
experiment. The volume of each sample was adjusted to
500 mL with 0.1 Msodium acetate, and the solutions were
incubated at 378C for 30 min. The ®nal pH of each solution
ranged from 5.5 to 5.8, with a ®nal 111In concentration of
74.6 nmol mL21. The chelation yield was measured on a
Phosphorimager apparatus 8445SI) after thin-layer chroma-
tography on cellulose plates 8Merck 5552/0025) by elution
with 0.1 Msodium acetate, pH 5.8: methanol 81:1).
4.5.1. Tetraethyl cis-cyclopentane-1,2-diamine-N,N,N0,
N0-tetraacetate )6a). Yield 55%; 1H NMR 8CDCl3) d
1.26 8t, 12H, 4CH2CH3, Jˆ7.2 Hz), 1.30±2.00 8m, 6H,
3CH2), 3.38 8m, 2H, 2CH), 3.67 and 3.80 82d, 8H,
4NCH2, Jˆ17.4 Hz), 4.14 8q, 8H, CH2CH3, Jˆ7.2 Hz);
13C NMR 8CDCl3) d 14.3 84C, CH2CH3), 21.6 81C,
CH2CH2CH2), 28.4 82C, CH2CH2CH2), 53.8 84C, NCH2),
60.2 84C, CH2CH3), 62.9 82C, CH), 172.2 84C, CvO);
MS 8CI), m/z 8%) 445 8100, M11H); MS 8EI), m/z 8%)
444 813), 228 857), 168 865), 29 8100); Anal. Found: C,
56.52; H, 8.23; N, 6.44. Calcd for C21H36O8N2 requires C,
56.76; H, 8.11; N, 6.31%.
4.7.2. Complexation studies with 153Sm. Stock solutions of
each chelate 82, 0.2, 0.02, 0.002 mg mL21) were prepared in
0.1 Msodium acetate, pH 5.8. To form 153Sm chelating
agent complexes, 1 mL 80.74 nmol) of 153Sm stock solution
8140.5 mCi mL21) was added to a range of 1, 2, 5 and
50 equiv. of each chelating agent 8EDTA, CDTA, 7a and
7b), before adjustment of the volume to 500 mL. The ®nal
pH of each solution ranged from 5.5 to 5.8, with a ®nal
4.5.2. Tetraethyl trans-cyclopentane-1,2-diamine-N,N,
1
N0,N0-tetraacetate )6b). Yield 68%; H NMR 8CDCl3) d
153Sm concentration of 1.5 nmol mL21
.
1.24 8t, 12H, 4CH2CH3, Jˆ7.1 Hz), 1.35±1.96 8m, 6H,
3CH2), 3.29 8m, 2H, 2CH), 3.59 and 3.71 82d, 8H,
4NCH2, Jˆ17.4 Hz), 4.13 8q, 8H, CH2CH3, Jˆ7.1 Hz);
13C NMR 8CDCl3) d 14.3 84C, CH2CH3), 22.0 81C,
CH2CH2CH2), 27.8 82C, CH2CH2CH2), 53.2 84C, NCH2),
60.5 84C, CH2CH3), 66.6 82C, CH), 171.8 84C, CvO);
MS 8EI), m/z 8%) 444 87), 371 810), 228 813), 168 823),
116 819), 29 8100); Anal. Found: C, 56.64; H, 8.36; N,
6.28. Calcd for C21H36O8N2 requires C, 56.76; H, 8.11; N,
6.31%.
After incubation at 378C for 1 h, complexation was
measured on a phosphoimager 445SI after thin-layer chro-
matography on cellulose plates 8Merck 5552/0025) by
elution with 0.1 Msodium acetate, pH 5.8: methanol 81:1).
Acknowledgements
The authors are grateful to the French Ministry of
Education, the CNRS, and the Ligue Nationale Contre le
Cancer for ®nancial support.
4.6. General procedure for the preparation of cyclo-
pentane-1,2-diamine-N,N,N0,N0-tetraacetic acid )7)
A mixture of 6 80.6 mmol) and 30 mL of 3 Mhydrochloric
acid was stirred overnight under re¯ux. The condenser was
removed, and the reaction mixture was kept at 708C to
evaporate the ethanol. Additional 3 Mhydrochloric acid
830 mL) was then added, and the solution was heated to
dryness to give acid 7 as a white powdery solid, which
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