Rhenium(I)- and technetium(I) tricarbonyl complexes anchored by bifunctional pyrazole-diamine and pyrazole-dithioether chelators

Article abstract of DOI:10.1016/j.jorganchem.2004.09.033

The novel pyrazolyl containing ligands 4-(HOOC)pz(CH₂) ₂NH(CH₂)₂NH₂ (L¹) and 4-(HOOCCH₂)-3,5-Me₂pz(CH₂) ₂NH(CH₂)₂NH₂

Full text of DOI:10.1016/j.jorganchem.2004.09.033

Journal of Organometallic Chemistry 689 (2004) 4764–4774
www.elsevier.com/locate/jorganchem
Rhenium(I)- and technetium(I) tricarbonyl complexes anchored by
bifunctional pyrazole-diamine and pyrazole-dithioether chelators
*
´
Rute F. Vitor, Susana Alves, J.D.G. Correia, Antonio Paulo, Isabel Santos
´ ´
Departamento de Quımica, ITN, Estrada Nacional, 10, 2686-953, Sacavem Codex, Portugal
Received 23 August 2004; accepted 14 September 2004
Available online 14 October 2004
Abstract
The novel pyrazolyl containing ligands 4-(HOOC)pz(CH2)2NH(CH2)2NH2 (L1) and 4-(HOOCCH2)-3,5-Me2pz(CH2)2NH-
(CH2)2NH2 (L2), and 3,5-Me2pz(CH2)2S(CH2)2SCH2CH3 (L3), 3,5-Me2pz(CH2)2S(CH2)2SCH2COOEt (L4) and 3,5-Me2pz(CH2)2S-
(CH2)2SCH2COOH (L5) were synthesized, and their ability to stabilise complexes with the fac-[M(CO)3]+ (M = Re,99mTc) moiety
was evaluated. Reactions of L1–L5 with the Re(I) tricarbonyl starting materials (NEt4)2[Re(CO)3Br3] and/or [Re(CO)5Br] afforded
complexes fac-[Re(CO)3(j3-L)] (L = L1–L5 (1–5)), which contain the pyrazolyl ancillary ligands coordinated in a tridentate fashion.
Complexes 1–5 were characterized by the common analytical techniques, which included single crystal X-ray diffraction analysis in
the case of 4. The structural analysis of 4 confirmed the tridentate coordination mode of the pyrazole-dithioether ligand, which is
facially coordinated to the Re(I) centre through the nitrogen from the pyrazole ring and the two thioether sulphur atoms, without
involvement of the terminal ester functional group. The distorted octahedral coordination environment around the metal is com-
pleted by the three facial carbonyl ligands. The radioactive congeners of complexes 1, 3 and 4, fac-[99mTc(CO)3(j3-L)]+ (L = L1
(1a), L3 (3a), L4 (4a)), have been prepared by reacting the precursor fac-[99mTc(CO)3(H2O)3]+ with the corresponding ligands,
and their identity confirmed by HPLC comparison with the rhenium surrogates. Complexes 1a and 3a have been challenged in
the presence of a large excess of histidine or cysteine, in order to evaluate their in vitro stability. Only a negligible displacement
was observed, indicating that pyrazole-diamine and pyrazole-dithioether chelators provide a high kinetic inertness and/or stability
to organometallic complexes with the fac-[99mTc(CO)3]+ moiety.
ꢀ 2004 Elsevier B.V. All rights reserved.
Keywords: Rhenium; Technetium; Carbonyl; Pyrazole; Bifunctional chelators; Radiopharmaceuticals
1. Introduction
ity for the three CO ligands and a high substitution labil-
ity for the three water molecules. The advent of these
organometallic synthons motivated a strong research ef-
fort on the finding of bifunctional ligands adequate to
stabilise the metallic cores and to covalently bind recep-
tor seeking molecules. So far, medium hard bi(tri)dentate
ligands containing nitrogen (i.e., pyridines, imidazoles,
amines), oxygen (i.e., carboxylates), sulphur (i.e., thio-
ether, thione) or phosphorus donor atoms have been ex-
plored [5–15]. The chemical and biological information
obtained from all these studies demonstrated that the
use of tridentate chelators, as well as the presence of aro-
matic amines like imidazole, can significantly improve
The introduction of the low-valent fac-[M(CO)3-
(H2O)3]+ (M = Tc or Re) synthons has introduced a
new avenue for the development of radioactive products
for diagnostic (99mTc) and therapeutic (186/188Re) medi-
cal applications, providing impetus for exploring unu-
sual ligands, bonds and approaches [1–4]. So far, the
explored chemistry has shown a high substitution stabil-
*
Corresponding author. Tel.: +351 21 994 6201; fax: +351 21 994
1455.
E-mail address: isantos@itn.mces.pt (I. Santos).
0022-328X/$ - see front matter ꢀ 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2004.09.033

R.F. Vitor et al. / Journal of Organometallic Chemistry 689 (2004) 4764–4774
4765
the stability and biological properties of the complexes
(i.e., blood clearance or excretion rate). Depending on
the physico-chemical properties of the final organometal-
lic building blocks, different bioactive molecules were la-
belled, like small peptides, sugars, steroids or CNS
receptor antagonists [16–18]. To the best of our knowl-
edge, there is only one example of a neurotensin analog
labelled with the moiety fac-[99mTc(CO)3]+ which has
been evaluated in patients, in spite of the versatility
and unique features of the tricarbonyl approach [18b].
To succeed on using these new labelling tools in the
development of clinically relevant radioactive probes,
the introduction of novel chelator systems remains of
paramount importance. By introducing new chelators,
one can tune the physico-chemical properties of the final
complexes (e.g. charge, size and lipophilicity) and im-
prove their kinetic and thermodynamic stability, which
are determinant for potential medical applications.
Aiming to contribute for the finding of novel bifunc-
tional ligands suitable for the stabilisation of the fac-
[M(CO)3]+ (M = 99mTc or Re) cores, our group has
reported recently the chemistry and radiochemistry of
symmetric and asymmetric tridentate pyrazolyl contain-
ing ligands (Fig. 1) towards these organometallic moie-
ties, as well as the biological behaviour of some of the
most promising building blocks [19,20]. This study dem-
onstrated that symmetric ligands of the bis(pyrazolyl)
type, with N3 or N2S donor atom sets, behave in an
ambivalent way and can act as bi- or tridentate, depend-
ing on the reaction conditions, namely time and temper-
ature. On contrary, the N3 and N2S donor asymmetric
ligands, respectively, of the pyrazolyl-diamine or pyraz-
olyl-thioether-amine types, always coordinate as triden-
tate ligands to the fac-[M(CO)3]+ moiety (M = Re,
99mTc).
properties of the complexes with those of the appended
targeting biomolecule.
In this paper, we report on the synthesis and char-
acterization of the novel asymmetric pyrazolyl contain-
ing ligands 4-(HOOC)pz(CH2)2NH(CH2)2NH2 (L1),
4-(HOOCCH2)-3,5-Me2pz(CH2)2NH(CH2)2NH2 (L2),
3,5-Me2pz(CH2)2S(CH2)2SCH2CH3 (L3), 3,5-Me2pz(C-
H2)2S(CH2)2SCH2COOEt (L4) and 3,5-Me2pz(CH2)2S-
(CH2)2SCH2COOH (L5), as well as on the corresponding
Re(I) tricarbonyl complexes fac-[Re(CO)3(j3-L)] (L = L1
–L5 (1–5)), which were obtained by reacting L1–L5 with
(NEt4)2[Re(CO)3Br3] and/or [Re(CO)5Br]. Herein, it will
be also reported on the synthesis of the radioactive com-
plexes fac-[99mTc(CO)3(j3-L)]+ (L = L1 (1a), L3 (3a), L4
(4a)), which were identified by HPLC comparison with
the rhenium congeners.
2. Experimental
Chemicals and solvents were of reagent grade and
were used without further purification, unless stated
otherwise. The organometallic precursors [Re(CO)5Br]
and (NEt4)2[Re(CO)3Br3] were prepared according to
published methods [21,22]. The radioactive synthon
[
99mTc(CO)3(H2O)3]+ was obtained as described
elsewhere [2]. Na99mTcO4 in saline solution was eluted
from a 99Mo/99mTc generator from MDS Nordion S.A.,
Belgium. The compounds N-tert-butoxycarbonyl-1,2-
ethanediamine, ethyl 2-formyl-3-oxopropionate, ethyl
3-acetyl-4-oxopentantanoate and 1-(3-thia-5-hydroxy-
pentyl)-3,5-dimethylpyrazole (3,5-Me2pz(CH2)-S(CH2)2-
OH) were synthesized according to procedures described
in the literature [23–26], although introducing slight
modifications in some of the syntheses.
Taking into account the in vitro and in vivo stability
and biological profile of the complexes isolated with
asymmetric pyrazolyl tridentate ligands [20], we selected
these frameworks for designing novel bifunctional chela-
tors to be used on the labeling of biologically active sub-
strates with the fac-[M(CO)3]+ (M = 99mTc or 186/188Re)
moieties. A great advantage of these systems is their ver-
satility which is expected to allow, with retained coordi-
nation sphere, the covalent coupling of the biomolecules
either at the pyrazolyl ring or at the aliphatic side chain.
Moreover, an easy introduction of different substituents
can also be helpful on adjusting the physico-chemical
1H and 13C NMR spectra were recorded on a Varian
Unity 300 MHz spectrometer; 1H and 13C chemical
shifts were referenced with the residual solvent reso-
nances relative to tetramethylsilane. IR spectra were re-
corded as KBr pellets or in CsI cells on a Bruker, Tensor
27 spectrometer. C, H and N analysis were performed
on an EA110 CE Instruments automatic analyser.
Column chromatography was performed in silica gel
60 (Merck). HPLC analysis were performed on a Shim-
adzu C-R4A chromatography system equipped with a
Berthold-LB 505 c-detector and with a tunable absorp-
tion UV, using a Macherey-Nagel C18 reversed-phase
X
N
N
X
N
NH2
N
N
N
X=NH,S
X=NH, S
Fig. 1. Symmetric and asymmetric pyrazolyl containing chelators.

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R.F. Vitor et al. / Journal of Organometallic Chemistry 689 (2004) 4764–4774
column (Nucleosil 10 lm, 250 · 4 mm) and a gradient of
methanol/0.1% CF3COOH or acetonitrile/0.1% CF3CO-
OH as eluent with a flow rate of 1.0 ml/min. The meth-
anol/TFA gradient has been used to analyze complexes
1/1a, while an acetonitrile/TFA gradient was applied in
the study of complexes 3/3a and 4/4a. Method: t = 0–3
min: 0% MeOH or acetonitrile; 3–3.1 min: 0–25%
MeOH or acetonitrile; 3.1–9 min: 25% MeOH or aceto-
nitrile; 9–9.1 min: 25–34% MeOH or acetonitrile; 9.1–20
min: 34–100% MeOH or acetonitrile; 20–22 min: 100%
MeOH or acetonitrile; 22–22.1 min: 100–0% MeOH or
acetonitrile; 22.1–30 min: 0% MeOH or acetonitrile.
moved under vacuum and the residue extracted with
methanol. The solids were filtered off and the superna-
tant vacuum dried, yielding a yellow solid formulated
as L1. Yield: 37 mg (0.19 mmol, 37%).
L2. This compound was synthesized as above de-
scribed for L1, starting from NH(DNS)(CH2)2NHBoc
(2.590 g, 6.63 mmol), 4-(EtOOCCH2)3,5Me2-pz(CH2)2-
OH (3.0 g, 13.26 mmol), DEAD (1.732 g, 9.94 mmol)
and PPh3 (2.609 g, 9.95 mmol), although its purification
required different procedures. Unlike L1, DNS and BOC
protected L2 was always contaminated with PPh3, even
after the attempted purification by column chromatog-
raphy (ethylacetate (30–100%)/hexane). Despite this
contamination, confirmed by TLC and 1H NMR spectr-
oscopy analysis, the collected product was used in the
deprotection steps without further purification. Thus,
for DNS-deprotection, part of the obtained solid
(1.410 g) was treated as above described for L1. To the
resulting reaction mixture was added a saturated NaH-
CO3 solution followed by extraction (3·) with CH2Cl2.
The organic phases were collected, dried over MgSO4,
filtered and the solvent evaporated. The residue was first
purified by successive precipitation of triethylammo-
nium salts, 2,4-dinitrobenzenesulfonyl impurities, and
triphenylphosphine in ethyl acetate/hexane and in dieth-
ylether. The final supernatant was evaporated under
vacuum and the solid obtained was dissolved in ethyl
acetate and a layer of hexane placed over it. After cool-
ing the solution overnight, 400 mg of a yellow crystalline
product was isolated. This solid was dried and used in
the next step. Hydrolysis of the ester functional group
was achieved by refluxing the product in THF with ex-
cess NaOH (ca. 10 equiv.) overnight. After evaporation
of the solvent, the residue was dissolved in water,
washed with diethylether (4·) and dichloromethane
(2·), and finally neutralized with 0.01 N HCl solution.
The brown solid, obtained after evaporation of the
aqueous solution, was extracted with methanol. The sol-
ids were filtered off and the supernatant vacuum dried.
The residue was purified by column chromatography
(MeOH, 100%). The obtained oil (0.104 g) was dissolved
in neat TFA for BOC deprotection, and allowed to react
for 2 h. After evaporation of the TFA, the residue was
dissolved in water and neutralized with 30% NaOH.
Evaporation of the water, extraction of the residue with
THF (3·), and final evaporation of the solvent, yielded a
white-yellowish solid, corresponding to L2 (72 mg, 0.30
mmol).
2.1. Synthesis of the ligands
2.1.1. 4-(HOOC)-pz(CH2)2NH(CH2)2NH2 (L1) and 4-
(HOOCCH2)-3,5-Me2pz(CH2)2NH(CH2)2NH2(L2)
4-(EtOOC)pz(CH2)2OH and 4-(EtOOCCH2)Me2-
pz(CH2)2OH. A solution of 2-hydroxyethylhydrazine
(20 mmol) in EtOH (100 mL) was added dropwise to
a solution of ethyl 2-formyl-3-oxopropionate or ethyl
3-acetyl-4-oxopentanoate (20 mmol) in EtOH (20 mL),
at 0 ꢁC. After overnight reaction at room temperature,
the solvent was vacuum removed and the compounds
obtained as yellow oils. Yields: 4-(EtOOC)pz(CH2)2OH,
3.500 g, 95%; 4-(EtOOCCH2)Me2pz(CH2)2OH, 4.400 g,
97%.
NH(DNS)(CH2)2NHBoc. N-tert-Butoxycarbonyl-
1,2-ethanodiamine (345 mg, 2.15 mmol), 2,4-
dinitrobenzenesulfonylchloride (DNSCl) (626 mg, 2.35
mmol) and pyridine (0.23 mL, 2.85 mmol) were dis-
solved in CH2Cl2. The reaction was left at room temper-
ature for 4 h. The resulting suspension was filtered off,
and the CH2Cl2 solution washed three times with
H2O. After removing the CH2Cl2, the solid residue ob-
tained was purified by column chromatography (ethyl-
acetate (30–100%)/hexane) yielding
a white/yellow
solid. Overall yield: 471 mg (1.21 mmol, 56%).
L1. NH(DNS)(CH2)2NHBoc (200 mg, 0.51 mmol),
4-(EtOOC)pz(CH2)2OH (189 mg 1.02 mmol) and dieth-
ylazodicarboxylate (DEAD) (134 mg, 0.77 mmol) were
dissolved in dry THF, and PPh3 (202 mg, 0.77 mmol)
added to the resulting solution. The reaction mixture
was allowed to react overnight at room temperature.
After this time, the solvent was removed under vacuum
and the obtained solid purified by column chromatogra-
phy (ethylacetate (50–100%)/hexane). The solid (161 mg,
0.29 mmol) was treated with HSCH2COOH (35 mg,
0.38 mmol) and NEt3 (0.080 ml, 0.58 mmol) in CH2Cl2
at room temperature for 30 min, to remove the protect-
ing DNS group. The mixture was vacuum dried and the
residue purified by column chromatography (MeOH/
CH2Cl2 (20:80)), yielding a yellow solid. The BOC pro-
tecting group was removed with TFA, while the sapon-
ification of the ethyl ester was achieved using NaOH.
The mixture was neutralized with 1 N HCl, the water re-
L1, 1H NMR (D2O): d 7.80 (s, H(3,5)pz, 1H); 7.64 (s,
H(3,5)pz, 1H); 4.27 (t, CH2, 2H); 3.24 (t, CH2, 2H);
3.11–3.00 (m, CH2, 4H). 13C NMR (D2O): 168.9
(COOH); 142.0 (C(3,5)pz); 134.5 (C(3,5)pz); 118.1
(C(4)pz); 47.7 (CH2); 47.4 (CH2); 44.5 (CH2); 35.4
(CH2). IR (cmÀ1): m(C@O) 1690.
1
L2, H NMR (CD3OD): d 4.07 (t, CH2, 2H); 3.23 (s,
CH2, 2H); 2.99 (t, CH2, 2H); 2.88 (m, CH2, 2H); 2.79

R.F. Vitor et al. / Journal of Organometallic Chemistry 689 (2004) 4764–4774
4767
(m, CH2, 2H), 2.20 (s, CH3, 3H); 2.13 (s, CH3, 3H). 13
C
to 100% ethylacetate and to 100% methanol). Yield:
72% (1.00 g, 3.30 mmol).
NMR (CD3OD): d 179.5 (COOH); 147.9 (C(3,5)pz);
139.4 (C(3,5)pz); 113.6 (C(4)pz); 46.7 (CH2); 39.6
(CH2); 32.5 (CH2); 11.7 (pz-CH3); 9.7 (pz-CH3). 13C
NMR (D2O): d 183.2 (COOH); 150.6 (C(3,5)pz); 141.9
(C(3,5)pz); 115.4 (C(4)pz); 50.5 (CH2); 49.1 (CH2);
47.8 (CH2); 40.3 (CH2); 34.3 (CH2); 13.3 (pz-CH3);
11.4 (pz-CH3); IR (cmÀ1): m(C@O)1683.
1H NMR (CDCl3): d 5.82 (s, H(4)-pz, 1H), 4.14 (m,
CH2, 4H), 3.25 (s, CH2, 2H), 2.92 (t, CH2, 2H), 2.75 (t,
CH2, 2H), 2.57 (t, CH2, 2H), 2.20 (s, CH3, 3H), 2.16 (s,
CH3, 3H), 1.25 (t, CH3, 3H);13C RMN (CDCl3): d
(ppm) 170.2 (C@O); 147.8 (C(3,5)pz); 139.2 (C(3,5)pz);
105.0 (C(4)pz); 61.37 (OCH2CH3); 48.6 (CH2C@O);
33.4 (CH2); 32.4 (CH2); 32.0 (CH2); 31.4 (CH2); 14.1
(CH3); 13.4 (pz-CH3); 11.1 (pz-CH3). IR (cmÀ1):
m(C@O) 1731; Anal. Calc. for C13H22N2O2S2: C, 51.46;
H, 7.26; N, 9.24. Found: C, 51.42; H, 7.34; N, 9.42%.
2.1.2. 3,5-Me2pz(CH2)2S(CH2)2SCH2CH3(L3)
To a solution of 3,5-Me2pz(CH2)2S(CH2)2OH (400
mg, 2.02 mmol) in chloroform was added PBr3 (0.19
mL; 2.00 mmol) and the resulting solution refluxed for
24 h under N2. After cooling to room temperature, the
reaction mixture was washed with 20 mL of 10% NaH-
CO3 and the collected organic phase was dried over
magnesium sulphate. Removal of the solvent under vac-
uum gave 3,5-Me2pz(CH2)2S(CH2)2Br as a brown/yel-
low oil. Yield: 329 mg (1.25 mmol, 63%).
2.1.4. 3,5-Me2pz(CH2)2S(CH2)2S(CH2CO2H)(L5)
To a solution of L4 (117 mg, 0.39 mmol) in THF was
added NaOH (77 mg, 1.93 mmol), dissolved in the min-
imum volume of water, and the resulting mixture ref-
luxed overnight. After cooling to room temperature,
the reaction mixture was neutralized with 1N HCl and
the solvents were removed under vacuum. After wash-
ing the resulting residue with water, compound L5 was
recovered as a white oil. Yield: 66 mg (0.24 mmol, 62%).
1H NMR (CDCl3): d 5.75 (s, H(4)-pz, 1H), 4.14 (t,
CH2, 2H,), 3.21 (s, CH2, 2H), 2.86 (t, CH2, 2H), 2.77
(t, CH2, 2H), 2.65 (t, CH3, 3H), 2.20 (s, CH3, 3H),
2.16 (s, CH3, 3H). 13C RMN (CDCl3): d (ppm) 172.4
(C@O); 147.6 (C(3,5)pz); 139.6 (C(3,5)pz); 105.4
(C(4)pz); 47.8 (CH2C@O); 34.3 (CH2); 32.4 (CH2);
30.6 (CH2); 30.0 (CH2); 12.8 (CH3); 10.9(pz-CH3); IR
(cmÀ1): m(C@O) 1703.
1
3,5-Me2pz(CH2)2S(CH2)2Br. H NMR (CDCl3): d
5.82 (s, H(4)-pz, 1H), 4.15 (t, CH2, 2H), 3.36 (t, CH2,
2H), 3.00 (t, CH2, 2H), 2.70 (t, CH2, 2H), 2.26 (s,
CH3, 3H), 2.23 (s, CH3, 3H).
Under N2, dry ethanol was added to metallic sodium
(105 mg, 4.56 mmol), and the mixture was stirred at
room temperature until complete conversion to sodium
ethoxide. To this mixture was added dropwise an etha-
nolic solution of ethanethiol (0.50 ml, 4.56 mmol), fol-
lowed by addition of 3,5-Me2pz(CH2)2S(CH2)2Br (1.20
g, 4.56 mmol) in ethanol. The reaction mixture was stir-
red overnight at room temperature and, after this time,
the solvent was removed under vacuum. The resulting
oil was dissolved in chloroform and washed with water.
After drying over magnesium sulphate, chloroform was
removed under vacuum yielding 3,5-Me2pz(CH2)2
S(CH2)2SCH2CH3 (L3) as a yellow oil, which was fur-
ther purified by chromatography on silica gel (eluent:
gradient from 100% ethyl acetate to 100% MeOH).
Yield: 737 mg (3.02 mmol, 66%).
3,5-Me2pz(CH2)2S(CH2)2SCH2CH3 (L3). 1H NMR
(CDCl3): d 5.82 (1H, s, H(4)-pz), 4.14 (m, CH2, 2+2H),
3.25 (s, CH2, 2H), 2.92 (t, CH2, 2H), 2.75 (t, CH2, 2H),
2.57 (t, CH2, 2H), 2.2 (s, CH3, 3H), 2.16 (s, CH3, 3H),
1.25 (t, –CH2CH3, 3H); 13C NMR (CDCl3): d (ppm)
147.4 (C(3,5)pz); 138.9 (C(3,5)pz); 104.5 (C(4)pz); 48.3
(CH2); 31.73 (CH2); 31.71 (CH2); 31.2 (CH2); 25.5
(CH2); 14.4 (CH3); 13.1 (pz-CH3); 10.8 (pz-CH3). Anal.
Calc. for C11H20N2S2: C, 53.69; H, 8.20; N, 11.48.
Found: C, 54.14; H, 8.70; N, 12.04%.
2.2. Synthesis of the rhenium complexes
2.2.1. [Re(CO)3(j3-(4-HOOC)pz(CH2)2NH(CH2)2-
NH2)] Br (1) and [Re(CO)3(j3-(4-HOOCCH2)3,5-
Me2pz(CH2)2NH(CH2)2NH2)]Br (2)
[ReBr(CO)5] (100 mg, 0.25 mmol) was reacted with
equimolar amounts of the compounds L1 and L2 in
refluxing H2O for 2 h. The complexes precipitate, as
white solids from the aqueous solutions, upon concen-
tration and cooling in an ice bath.
Complex 1, Yield: 95 mg (0.17 mmol, 68%). 1H NMR
(D2O): d 8.22 (s, H(3)pz, 1H); 8.20 (s, H(5)pz, 1H); 6.62
(s, br, NH, 1H); 4.94 (s, br, NH2, 1H); 4.43 (m, CH2,
1H); 4.25 (m, CH2, 1H); 4.05 (s, br, NH2, 1H); 3.52
(m, CH2, 1H); 2.92 (m, CH2, 1H); 2.76 (m, CH2, 2H);
2.53 (m, CH2, 1H); 2.14 (m, CH2, 1H). 13C-RMN
(D2O): 196.0 (ReCO); 195.8 (ReCO); 195.6 (ReCO);
168.0 (COOH); 149.3 (C(3)pz); 139.4 (C(5)pz); 119.2
(C(4)pz); 57.0 (CH2); 55.2 (CH2); 54.3 (CH2); 42.8
(CH2). IV (cmÀ1): m(C„O), 2010, 1885 (v.br); m(C@O)
1690. HPLC (gradient 0.1% TFA/MeOH): Rt = 18.2
min.
2.1.3. 3,5-Me2pz(CH2)2S(CH2 )2S(CH2CO2Et) (L4)
L4 was synthesized as above described for L3, starting
from ethyl 2-mercaptoacetate (0.50 mL, 4.56 mmol) and
3,5-Me2pzCH22S(CH2)2Br (1.20 g, 4.56 mmol). L4 was
obtained as a yellow oil after purification by chromatog-
raphy on silica gel (eluent: gradient from 100% CH2Cl2
Complex 2, Yield: 90 mg (0.15 mmol, 60%). 1H NMR
(CD3OD): d 6.78 (br. tr, NH, 1H); 5.38 (br. t, NH2, 1H);
4.48 (dt, CH2, 1H); 4.11 (m, CH2, 1H); 3.91 (br.t, NH2,

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R.F. Vitor et al. / Journal of Organometallic Chemistry 689 (2004) 4764–4774
1H), 3.45 (m, CH2, 1H); 3.27 (s, CH2, 2H), 2.89 (m,
CH2, 1H); 2.79–2.62 (m, CH2, 3H), 2.44 (m, CH2,
1H), 2.36 (s, CH3, 3H), 2.27 (s, CH3, 3H). 13C NMR
(CD3OD): 194.7 (ReCO); 194.5 (ReCO); 178.7 (COOH);
153.1 (C(3,5)pz); 143.0 (C(3,5)pz); 116.7 (C(4)pz); 55.8
(CH2); 47.9 (CH2) 43.5 (CH2); 43.4 (CH2); 33.2 (CH2),
14.4 (CH3); 10.2 (CH3). IV (cmÀ1): m(C„O), 2027,
1992, 1900, 1874; m(C@O) 1678. Anal. Calc. for
C14H20N4O5BrRe: C, 28.48; H, 3.41; N, 9.49. Found:
C, 28.58; H, 3.57; N, 9.58%.
3.91; N, 4.27%. HPLC (gradient 0.1% TFA/CH3CN):
Rt = 17.1 min.
2.2.4. [Re(CO)3(j3-(3,5-Me2pz(CH2)2S(CH2)2S(CH2-
CO2H)))]Br (5)
Complex 5 was synthesized as above described for
3, starting from [Re(CO)5Br] (93 mg, 0.23 mmol)
and L5 (66 mg, 0.24 mmol). 5 was purified by recrys-
tallization from THF/n-hexane. Yield: 65 mg (0.10
mmol, 43%).
1H NMR (CD3OD): d (ppm) 6.24 (s, H(4)pz, 1H);
4.72 (m, CH2, 1H); 4.23–3.97 (m, CH2, 2H); 3.94–3.89
(m, CH2, 1H); 3.80–3.70 (m, CH2, 1H); 3.53–3.41 (m,
CH2, 2H); 3.01 (m, CH2, 1H); 2.62 (m, CH2 + CH3,
1 + 3H); 2.36 (m, CH2, 3H); 2.01 (m, CH2, 1H); 13C
NMR (CD3OD): d (ppm) 190.3 (ReCO); 169.7 (C@O);
156.4 (C(3,5)pz); 146.6 (C(3,5)pz); 110.3 (C(4)pz); 49.2
(O-CH2); 41.3 (CH2); 37.6 (CH2); 34.9 (CH2); 32.4
(CH2); 17.0 (pz-CH3); 12.2 (pz-CH3). IR (KBr,
m/cmÀ1): m(C„O) 2036, 1944, m(C@O) 1702; Anal. Calc.
for C14H18N2O5S2ReBr: C, 26.90; H, 2.88; N, 4.49.
Found: C, 27.2; H, 3.02; N, 4.52%. HPLC (gradient
0.1% TFA/CH3CN): Rt = 16.4 min.
2.2.2. [Re(CO)3(j3-(3,5-Me2pz(CH2)2S(CH2)2S(CH2-
CH3)))]Br (3)
A solution of [Re(CO)5Br] (100 mg, 0,25 mmol) and
ligand L3 (65 mg, 0.27 mmol) in dry methanol was ref-
luxed overnight under N2. After this time, methanol
was removed under vacuum, and the resulting residue
was washed with THF. The remaining solid was ex-
tracted into water and, after centrifugation, the result-
ing solution was vacuum dried yielding complex 3 as a
white microcrystalline solid. Yield: 69 mg (0.12 mmol,
48%).
1H NMR (CD3OD): d (ppm) 6.23 (s, H(4)pz, 1H);
4.73 (m, CH2, 1H); 3.96 (m, CH2, 1H); 3.78 (m, CH2,
1H); 3.38 (m, CH2CH3, 2H); 3.23 (m, CH2, 1H); 3.05
(m, CH2, 2H); 2.61 (m, CH2, 1H); 2.57 (s, CH3, 3H);
2.35 (s, CH3, 3H); 2.01 (m, CH3, 1H); 1.43 (t, CH2CH3,
3H); 13C NMR (CD3OD): d (ppm) 160.0 (C@O); 156.17
(C(3,5)pz); 146.57 (C(3,5)pz); 110.3 (C(4)pz); 37.3
(CH2); 34.4 (CH2); 34.0 (CH2); 32.4 (CH2); 17.1
(CH2CH3); 13.6 (pz-CH3); 12.11 (pz-CH3). IR (cmÀ1):
m(C„O) 2039, 1919; Anal. Calc. for C14H20N2O3S2-
ReBr: C, 28.26; H, 3.37; N, 4.71. Found: C, 28.01; H,
3.31; N, 4.65%. HPLC (gradient 0.1% TFA/CH3CN):
Rt = 18.4 min.
2.3. Synthesis of the 99mTc(I) complexes (1a, 3a and 4a)
General method. In a glass vial under nitrogen, 100 lL
of a 10À3 M (L1) aqueous solution or 100 lL of a 10À2
M (L2 and L3) ethanolic solution of the ligands were
added to 900 ll of [99mTc(OH2)3(CO)3]+ (1–2 mCi) in
PBS. The reaction was incubated at 100 ꢁC for 60 min
and then analyzed by HPLC.
Cysteine and histidine challenge. Aliquots of 100 ll of
the 99mTc complexes were added to 900 ll of 10À3 M or
10À2 M cysteine or histidine solutions in PBS (pH 7.4),
with final ligand concentrations of 10À5 M (L1) and
10À4 M (L3), respectively. The solutions were incubated
at 37 ꢁC and aliquots were removed at 1, 2, 4 and 6h, at
which time HPLC analysis was run.
2.2.3. [Re(CO)3(j3-(3,5-Me2pz(CH2)2S(CH2)2S(CH2-
CO2Et)))]Br (4)
A solution of (NEt4)2[Re(CO)3Br3] (100 mg, 0.13
mmol) and L4 (40 mg, 0.13 mmol) in dry methanol
was refluxed overnight under N2. After removal of
methanol, the residue was dissolved in water from which
complex 4 precipitated as a white microcrystalline solid.
Yield: 45 mg (0.07 mmol, 53%).
2.4. X- ray diffraction
White crystals of complex 4 were obtained by recrys-
tallization from
a saturated water solution, and
1H NMR (CD3OD): d (ppm) 6.25 (s, H(4)pz, 1H);
4.73 (m, CH2, 1H); 4.33 (m, CH2, 2H); 3.94 (m, CH2,
1H); 3.77 (m, CH2, 1H); 3.47 (m, CH2, 2H); 3.00 (m,
CH2, 2H); 2.62 (s, CH3, 3H); 2.52 (m, CH2, 2H); 2.35
(s, CH3, 3H); 2.02 (m, CH2, 1H,); 1.32 (t, CH3,
3H).13C NMR (CD3OD): d (ppm) 192.6 (Re-CO);
168.4 (C@O); 156.36 (C(3,5)pz); 146.7 (C(3,5)pz);
110.4 (C(4)pz); 63.8 (OCH2CH3); 41.0 (CH2); 37.5
(CH2); 35.0 (CH2); 32.4 (CH2); 17.0 (OCH2CH3); 14.4
(pz-CH3); 12.2 (pz-CH3). IR (cmÀ1): m(C„O), 2036,
1947; m(C@O) 1721; Anal. Calc. for C16H22N2O5S2-
ReBr: C, 29.42; H, 3.37; N, 4.29. Found: C, 29.57; H,
mounted in thin-walled glass capillaries. Data were col-
lected at room temperature on an Enraf-Nonius CAD-4
diffractometer with graphite-monochromated Mo Ka
radiation, using an x-2h scan mode. The crystal data
are summarized in Table 1.
The data were corrected for Lorentz and polariza-
tion effects, and empirically for absorption by W scans
[27]. The heavy atom positions were located by Patter-
son methods using SHELXS-97 [28]. The remaining
atoms were located in successive Fourier-difference
maps and refined by least-squares refinements on F2
using SHELXL-97 [29]. Two remaining residual peaks

R.F. Vitor et al. / Journal of Organometallic Chemistry 689 (2004) 4764–4774
4769
Table 1
Crystallographic data for complex 4
3. Results and discussion
Empirical formula
M
C16H26BrN2O7S2Re
688.62
Triclinic
Following our previous work [19,20], and focused on
the labelling of biologically relevant molecules, we syn-
thesized novel asymmetric pyrazolyl containing ligands
with N3 and NS2 donor atom sets and with a carboxy-
late functional group for direct coupling of biomole-
cules. The asymmetric and bifunctional pyrazolyl
ligands with N3 donor atom sets, L1 and L2, were pre-
pared by the multi-step synthetic procedure depicted in
Scheme 1. A key step on the preparation of L1 and L2
was the synthesis of the functionalised 1-ethylaminepy-
razole precursors, 4-(EtOOC)pz(CH2)2OH and 4-(EtO-
OCCH2)Me2pz(CH2)2OH, which were obtained by
cyclization reactions between the corresponding dialde-
hyde or diketone compounds with 2-hydroxyethylhidra-
zine, following well established procedures for the
synthesis of pyrazole derivatives [24]. The ligands L1
and L2 were finally obtained by a Mitsunobu reaction
[31], i.e., by reacting the 2-hydroxyethylpyrazole precur-
sors with NH(DNS)(CH2)2NHBoc, followed by re-
moval of the protecting DNS and BOC groups with
mercaptoacetic acid and TFA, respectively.
The related asymmetric ligands of the pyrazole-
dithioether type, i.e., with NS2 donor atom sets,
3,5-Me2pz(CH2)2S(CH2)2S(CH2CO2Et) (L4) and 3,5-
Me2pz(CH2)2S(CH2)2S(CH2CO2H) (L5), were synthe-
sized as indicated in Scheme 2. Being aware of possible
competition of the carboxylate group in the coordina-
tion to the fac-[M(CO)3]+ moieties, the ligand 3,5-
Me2pz(CH2)2S(CH2)2SCH2CH3 (L3) was also prepared
in order to compare its coordination behaviour with
the one of the functionalised congeners L4 and L5. As
depicted in Scheme 2, the preparation of L3 and L4 in-
volved 3,5-Me2pz(CH2)2S(CH2)2OH as a common start-
ing material [26]. Reaction of this compound with PBr3
afforded the brominated analogue, which by treatment
Crystal system
Space group
ꢀ
P1
˚
a (A)
9.8592(10)
11.0784(17)
11.8537(18)
66.412(12)
76.308(11)
85.189 (11)
˚
b (A)
˚
c (A)
a (ꢁ)
b (ꢁ)
c (ꢁ)
3
˚
˚
V (A)
1152.7(3) A
Z
2
1.984
7.233
Dc (g cmÀ3
)
l(Mo Ka) (mmÀ1
)
No. reflections measured
No. unique reflections
4616
4383 (0.0182)a
0.0368
0.0841
b
R1
wR2
a
Value of R(int).
The values were calculated for data with I > 2r(I).
b
were assigned as oxygen atoms of two water molecules.
The solvent oxygen atoms were refined anisotropically
and the corresponding hydrogen atoms were ignored.
With exception of the carbonyl oxygen O5, all the
non-hydrogen atoms were refined anisotropically; The
O5 atom is disordered and split positions have been
considered in the structure calculation with a site occu-
pation of 0.52 and 0.48, respectively. Because of this
disorder, their refinement was performed isotropically
with an imposed C9–O5 distance. The contributions
of the hydrogen atoms were included in calculated
positions, constrained to ride on their carbon atoms
with group Uiso values assigned. Atomic scattering fac-
tors and anomalous dispersion terms were as in
SHELXL-97 [29]. The drawings were made with
ORTEP-3 [30].
O
O
R
R
( )
OEt
n
O
OH
H2N
N
H
i
O
DNs
H
N
R
R
O
( )
H
O
( )
DNs
N
iii
N
( )
OEt
NHBoc
EtO
EtO
n
N
N
NH2
N
N
NHBoc
iv,v
ii
n
R
R
n
R
N
N
R
OH
L1 (n = 0, R = H)
L2 (n = 1, R = Me)
Scheme 1. Synthesis of (4-HOOC)pz(CH2)2NH(CH2)2NH2 (L1) and (4-HOOCCH2)-3,5-Me2pz(CH2)2NH(CH2)2NH2 (L2). (i) Ethanol, 0 ꢁC. (ii)
DEAD, PPh3, THF, room temperature. (iii) HSCH2CO2H, NEt3, CH2Cl2, room temperature. (iv) TFA, room temperature. (v) NaOH, THF, H2O,
reflux, overnight.

4770
R.F. Vitor et al. / Journal of Organometallic Chemistry 689 (2004) 4764–4774
i
ii
S
S
S
N
N
OH
N
N
Br
N
N
SR
L3 (R = CH2CH3)
L4 (R = CH2COOEt)
R = CH2COOEt
S
iii
N
N
S
COOH
L5
Scheme 2. Synthesis of 3,5-Me2pz(CH2)2S(CH2)2SR (R = CH2CH3 (L3), CH2COOEt (L4), CH2COOH (L5)): (i) PBr3, CHCl3, reflux, 24 h. (ii) RSH
(R = CH2CH3, CH2COOEt), NaOEt, EtOH, room temperature, overnight. (iii) NaOH, THF/H2O, reflux, overnight.
with the adequate thiol yielded the final ligands L3 and
L4 in a straightforward way. L5 was prepared by the
hydrolysis of L4.
pyrazolyl based anchors act as tridentate ligands, as
we previously reported for related non-functionalised
parent complexes (Scheme 3) [19].
L1–L5 are air and water stable compounds that are
soluble in most common polar organic solvents, such
as alcohols or acetonitrile. While the pyrazole-diamine
ligands (L1 and L2) are quite soluble in water, the pyraz-
ole-dithioethers (L3–L5) have a poor solubility in this
solvent. Compounds L1–L5 were characterized by the
common analytical techniques.
Complexes 1–3 and 5 were preferentially synthesized
using [Re(CO)5Br] as the starting material. Although the
complexes could also be obtained starting from (NE-
t4)2[Re(CO)3Br3], as checked by following the reactions
1
by H NMR spectroscopy, separation of the tetraethyl-
ammonium salts from the complexes is not an easy task,
due their similar solubility in most common solvents. By
contrast, the successful synthesis of complex 4 bearing a
terminal ester functional group was only achieved when
L4 reacted with (NEt4)2[Re(CO)3Br3]. The reaction of
Reactions of the starting materials [Re(CO)5Br] and/
or (NEt4)2[Re(CO)3Br3], with L1–L5 led to the forma-
tion of cationic tricarbonyl complexes, 1–5, where the
+
+
N
S
N
NH
Re
EtO
L1
S
L3
N
NH2
CO
N
Re
OC
CO
O
OC
CO
CO
CO
Re
3
1
Br
OC
OC
H2O/reflux
MeOH/reflux
CO
+
CO
+
N
NH
Re
N
S
L2
L5
NH2
CO
N
L4
EtO
S
N
COOH
Re
OC
O
OC
CO
CO
CO
2
+
5
N
N
S
S
COOEt
Re
OC
CO
CO
4
2-
Br
L4
MeOH/reflux
Br
OC
OC
Re
Br
CO
Scheme 3. Synthesis of the rhenium complexes 1–5.

R.F. Vitor et al. / Journal of Organometallic Chemistry 689 (2004) 4764–4774
4771
the Re(I) pentacarbonyl precursor with L4 was always
accompanied by hydrolysis of the ester functional
group, which certainly reflects slower rate of reaction
for [Re(CO)5Br] compared to (NEt4)2[Re(CO)3Br3].
Compounds 1–5 are white microcrystalline solids,
stable towards air oxidation or hydrolysis, and are solu-
ble in most common polar organic solvents. Reflecting
their cationic character, 1–5 display a moderate to high
solubility in water. As expected, the complexes with the
pyrazole-diamine ligands (1–2) show an enhanced
water-solubility. The characterization of 1–5 involved
O5
O4
C3
C9
C2
C1
S2
Re
N1
1
IR, H and 13C NMR spectroscopies, and in the case
N2
of 4 also X-ray diffraction analysis.
The most significant feature of the IR spectra of com-
pounds 1–5 is the presence of strong bands due to the
m(CO) stretching mode, in the range 1874–2039 cmÀ1
and with the typical pattern for complexes with the
‘‘fac-Re(CO)3’’ moiety. In comparison with 1 and 2,
there is a slight increase of the m(CO) frequencies for
complexes 3–5. This is probably due to the poorer r-do-
nor character and better acceptor properties of thioe-
thers comparatively to amines. With the exception of
3, the IR spectra of the complexes show the presence
of medium to strong bands, spanning from 1678 to
1702 cmÀ1, which were attributed to the m(CO) stretch-
ing mode associated with the corresponding carboxylic
(1, 2 and 5) or ester functions (4). These frequencies
are quite close to the values found for the corresponding
free ligands. For complexes 4 and 5, this clearly shows
that the terminal ester or carboxylate groups of the lig-
ands are not involved in the coordination to the metal.
This behaviour was further corroborated by the 1H
NMR data collected for these complexes and by the
X-ray structural analysis of 4, as discussed below.
S1
Fig. 2. ORTEP view of complex 4.
for Re(I) than the ester or carboxylic functional groups,
respectively. In spite of some occasional overlap of reso-
nances, the presence in the 1H NMR spectra of 3–5 of a
series of multiplet signals due to the methylenic protons,
integrating each for one proton, are clearly consistent
with the (NS2) tridentate coordination mode for L3–L5.
The determination of the molecular structure of 4 by
X-ray diffraction analysis confirmed that L4 is acting as
a tridentate ligand through one nitrogen atom of the
pyrazolyl ring and the two sulphur atoms of the thioe-
thers, as can be seen in the ORTEP diagram presented
in Fig. 2. No intra- or intermolecular interaction involv-
ing the dangling ester function was found. The rhenium
atom is six-coordinated and displays an approximately
octahedral coordination geometry. The L4 ligand is fa-
cially coordinated, with the remaining coordination
positions occupied by the three CO ligands. As can be
verified by the values given in Table 2, the Re–C dis-
tances are almost identical, spanning from 1.915(7) to
1
The H NMR data obtained for complexes 1 and 2
are compatible with the tridentate coordination mode
of the pyrazole-diamine ligands, L1 and L2, respectively.
The chemical shifts and splitting of the diastereotopic
NH and methylenic protons are comparable to those
found for the previously reported fac-[Re(CO)3(j3-
(3,5-Me2pz(CH2)2NH(CH2)2NH2))], characterized in
solution and by X-ray diffraction analysis [19]. The reso-
nances due to the H(3,5) and methyl protons from the
pyrazolyl moiety of L1 and L2, respectively, are down-
field shifted relatively to the same resonances in the cor-
responding free ligands, which is consistent with the
involvement of the azole ring in the coordination to
the metal.
˚
1.918(7) A, being comparable to the values found for
other Re(I) tricarbonyl complexes anchored by triden-
tate pyrazolyl-based ligands that we have previously re-
ported [19]. The Re–S bond distances, averaging 2.484
˚
A, are also normal and similar to the values reported
Table 2
˚
Selected bond lengths (A) and angles (ꢁ) for complex 4
Re–C(1)
Re–C(3)
Re–S(2)
1.915 (7)
1.916(7)
2.488(2)
1.144(8)
1.143(2)
Re–C(2)
Re–S(1)
Re–N(1)
C(2)–O(2)
1.918(7)
2.479(2)
2.206(5)
1.147(9)
C(1)–O(1)
C(3)–O(3)
For complexes 3–5 anchored by the pyrazole-dithio-
ether ligands L3–L5, the resonances due to the H(4)
and methyl protons from the pyrazolyl rings are also
downfield shifted comparatively to the corresponding
resonances in the spectra of the free ligands. This is also
a clear indication of the coordination of the azole ring to
the metal, showing in the case of complexes 4 and 5 that
the pyrazole group from L4 and L5 has a greater affinity
C(1)–Re–C(2)
C(2)–Re–C(3)
C(1)–Re–S(2)
C(2)–Re–S(1)
C(2)–Re–N(1)
C(3)–Re–S(2)
S(1)–Re–S(2)
S(2)–Re–N(1)
89.8(3)
86.7(3)
94.9(2)
93.4(2)
94.6(2)
96.0(2)
84.33(6)
80.59(13)
C(1)–Re–C(3)
C(1)–Re–S(1)
C(1)–Re–N(1)
C(2)–Re–S(2)
C(3)–Re–S(1)
C(3)–Re–N(1)
S(1)–Re–N(1)
88.0(3)
87.2(2)
175.1(3)
174.6(2)
175.3(2)
94.3(2)
90.38(14)

4772
R.F. Vitor et al. / Journal of Organometallic Chemistry 689 (2004) 4764–4774
Fig. 3. HPLC trace of complex 3 (254 nm) and c-trace of the radioactive congener 3a.
for other thioether containing rhenium(I) complexes
[19,32]. All the other metrical parameters of the struc-
ture of compound 4 are normal and do not deserve a
more exhaustive discussion.
dithioether ligand L3 is less favourable. After boiling
for 1 h, the complex fac-[99mTc(CO)3(j3-L3)]+ (3a)
(Rt = 18.7 min) was present, but mixed with a significant
amount of the unreacted precursor and also with a more
hydrophilic impurity (Rt = 15.2 min), which was not
identified. However, the radiochemical yield improved
considerably when the L3 concentration was increased
to 10À3 M. Under these conditions, complex 3a was ob-
tained in almost quantitative yield (>90%) (Fig. 3). The
effect of the concentration of L3 in the radiochemical
purity of complex 3a is summarized in Fig. 4.
The labelling of L4 has been also attempted using the
reaction conditions optimized for L3 (i.e. [L4] = 10À3 M,
100 ꢁC, 1 h). Using these conditions, the reaction pro-
ceeds with formation of fac-[99mTc(CO)3(j3-L4)]+ (4a)
(Rt = 17.3 min) but this compound is partially hydro-
lysed yielding the complex fac-[99mTc(CO)3(j3-L5)]+
(5a) (Rt = 16.8 min).
The possibility of preparing at non-carrier added le-
vel (99mTc) representative examples of the complexes
with the pyrazole-diamine (L1) and pyrazole dithioether
ligands (L3 and L4) has been evaluated. In these studies
the identity of the 99mTc complexes has always been
checked by HPLC comparison with the corresponding
rhenium complexes.
For L1, the corresponding radioactive complex fac-
[
99mTc(CO)3(j3-L1)]+ (1a) (Rt = 18.8 min) was obtained
almost quantitatively (>90%) by heating the fac-
[
99mTc(H2O)3(CO3)]+ precursor at 100 ꢁC in physiologi-
cal buffer (PBS; pH 7.4) and in the presence of a 10À4 M
concentration of L1. Under the same experimental con-
ditions the kinetic of the reaction with the pyrazole-
120
100
80
60
40
20
0
0
1
2
3
4
5
6
[L3] x 103 / M
Fig. 4. Radiochemical purity of 3a versus concentration of L3.

R.F. Vitor et al. / Journal of Organometallic Chemistry 689 (2004) 4764–4774
4773
100
80
60
Histidine
40
Cysteine
20
0
0
1
2
3
4
5
6
7
Time (h)
Fig. 5. Stability of 3a in the presence of histidine and cysteine ([aminoacid]/[L3] = 100).
The organometallic 99mTc-complexes 1a and 3a were
Acknowledgements
challenged in vitro in PBS buffer and in the presence of a
large excess of histidine or cysteine, which display great
affinity for the fac-[99mTc(CO)3]+ moiety. In both cases,
only a minor decomposition of the complexes could be
observed, even for the less stable pyrazole-dithioether
complex, 3a, as can be observed in Fig. 5.
Rute Vitor and Susana Alves thank the Fundac¸a˜o
ˆ
para a Ciencia e Tecnologia (National Foundation for
Science and Technology) for Ph.D. research grants. This
work was partially supported by Mallinckrodt-Tyco Inc.
These findings indicate that pyrazole-diamine and
pyrazole-dithioether chelators provide a high kinetic
inertness and/or stability to organometallic complexes
with the fac-[99mTc(CO)3]+ moiety.
References
[1] R. Alberto, R. Schibli, A. Egli, P.A. Schubiger, U. Abram, T.A.
Kaden, J. Am. Chem. Soc. 120 (1998) 7987.
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4. Concluding remarks
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metric bifunctional pyrazolyl containing ligands with
N3 and NS2 donor atom sets. These compounds react
with (NEt4)2[Re(CO)3Br3] and/or [Re(CO)5Br] afford-
ing cationic complexes of the type fac-[Re(CO)3(j3-
L)]. In these complexes the pyrazolyl anchors act as
tridentate ligands without any interference of the carb-
oxylate and/or ester functional groups, which stay
available for coupling to biological relevant molecules.
Preliminary results at non-carrier added level have
shown that is possible to synthesize radioactive com-
plexes anchored by these ligands with high yield and
high radiochemical purity. However, the pyrazole-
diamine ligands allow the synthesis of complexes with
higher specific activity than the pyrazole-dithioether
ligands.
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5. Supplementary material
Crystallographic data (excluding structure factors) for
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