Synthesis, radiolabelling and biological evaluation of terminal oxamide derivatives of mercaptoacetyltriglycine

Article abstract of DOI:10.1002/jlcr.568

^99mTc-MAG₃ is widely used in clinical nuclear medicine as a potential replacement of ¹³¹I-OIH for renal function studies. The terminal carbonylglycine in the MAG₃ backbone is assumed to be essential for maintain

Full text of DOI:10.1002/jlcr.568

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2002; 45: 407–421.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.568
Research Article
Synthesis, radiolabelling and biological
evaluation of terminal oxamide derivatives of
mercaptoacetyltriglycine
S.M. Okarvi*, P. Torfs, P. Adriaens and A.M. Verbruggen
King Faisal Specialist Hospital & Research Centre, Cyclotron &
Radiopharmaceuticals Dept., MBC-03, PO Box 3354, Riyadh 11211,
Saudi Arabia
Summary
99mTc-MAG3 is widely used in clinical nuclear medicine as a potential
replacement of 131I-OIH for renal function studies. The terminal carbonylgly-
cine in the MAG3 backbone is assumed to be essential for maintaining its
efficient renal handling characteristics. A number of MAG3-derivatives have
been prepared and evaluated in which the terminal carbonylglycine sequence is
substituted by an oxamide moiety in order to study the effect of the modified
carbonylglycine sequence on the renal handling characteristics. These
‘oxamide’ derivatives have been synthesized starting from mercaptoacetic acid
or cysteamine using the common synthetic procedures of peptide chemistry.
These thiol-protected MAG3-precursors were labelled with 99mTc by an
exchange method using tartrate as a complexing agent. Biodistribution studies
in mice showed that some of these agents were cleared rapidly from the blood
and efficiently excreted into the urine and displayed comparable renal excretion
characteristics to those of 99mTc-MAG3. Copyright # 2002 John Wiley &
Sons, Ltd.
Key Words: technetium-99m; oxamide derivatives; MAG3; radiolabelling;
renal agents
*Correspondence to: S. M. Okarvi, King Faisal Specialist Hospital & Research Centre, Cyclotron
& Radiopharmaceuticals Dept., MBC-03, PO Box 3354, Riyadh 11211, Saudi Arabia. E-mail:
sokarvi@kfshrc.edu.sa
Copyright # 2002 John Wiley & Sons, Ltd.
Received 5 November 2001
Revised 13 December 2001
Accepted 15 January 2002

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S. M. OKARVI ET AL.
1. Introduction
99mTc-MAG3 (mercaptoacetyltriglycine) has been developed as a
potential substitute for 123I and 131I-Hippuran (OIH) and it is now
considered as the radiopharmaceutical of choice for the evaluation of
transplant kidney, tubular necrosis, routine renal function and for
imaging studies in clinical nuclear medicine.1–3
It has been hypothesized that the terminal carbonylglycine sequence
in the MAG3 backbone is largely responsible for its efficient renal
characteristics, since it is likely to be involved in the interaction with the
renal tubular transport proteins.4,5 The gold standard OIH and p-amino
hippuric acid (PAH) also contain the same carbonylglycine sequence.
This structural entity was generally believed to be essential in these
compounds for an efficacious fit with the receptor proteins of the
tubular transport system.6 However, it is now apparent that a free
carboxylate in the MAG3 backbone is one of the key features required
for receptor recognition by the transporter proteins.7 Thus, besides
some specific distribution of the amide bonds, the presence of a free
carboxylate group seems to be necessary in MAG3-like compounds for
preserving the efficient renal excretion characteristics. In the light of the
above observations, it seemed of interest to investigate the renal
characteristics of MAG3 derivatives in which the terminal carbonylgly-
cine sequence (–CO–N–CH2–COOH) has been modified by an oxamide
moiety (–CH2–N–CO–COOH).
The present study was undertaken in order to evaluate the effect
that modification of the terminal carbonylglycine of MAG3 would
have on the biological behavior and to elucidate the structural
requirements for an efficient interaction of 99mTc-MAG3-like agents
with the tubular transport system. For this purpose, we have
synthesized a number of S-protected derivatives of MAG3. These are
called ‘oxamide’ derivatives of MAG3 (OMAG3), and differ from the
parent MAG3 compound with respect to the positioning of one or both
of the amido groups and, besides the terminal oxamide moiety, contain
only two amido groups in their structure. In this way, it is possible to
synthesize four different OMAG3-derivatives (Figure 1). These
new ligands were labelled with 99mTc by an exchange method and
the labelling mixtures were analyzed by reversed-phase HPLC.
The biodistribution studies were performed on mice. This paper
describes the chemistry, labelling and biological characteristics of the
OMAG3-derivatives.
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SYNTHESIS, RADIOLABELLING AND
409
Figure 1. Structure of MAG3 and its oxamide derivatives
Results and discussion
Synthesis/chemistry
Due to the poor chemical stability of the thiol group, mercaptoacetyl-
triglycine and analogs are usually synthesized as thiol-protected
precursors. An ideal S-protecting group for the study of MAG3-
derivatives, which may require relatively complex and harsh synthesis
procedures, should be stable during the chemical synthesis and
withstand the strong reagents used for the removal of amine or
carboxylate protective groups (CBZ and BOC, etc.). Moreover, it
should be sufficiently removable, either prior to, or during, the
radiolabelling process.8
As outlined in Schemes 1 and 2, the synthesis of the oxamide
derivatives 8 and 14 started from mercaptoacetic acid, and the thiol-
function of the oxamide derivatives was protected with an S-benzyl
group in order to ensure the feasibility of the chemical synthesis.
The synthesis of the other two derivatives 19 and 27 (Schemes 3 and 4,
respectively), started from cysteamine, and the thiol-groups of the
oxamide derivatives were protected with the more stable and lipophilic
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S. M. OKARVI ET AL.
Scheme 1. Synthesis of N-(S-benzylmercaptoacetyl)N0-oxalylglycylethylenedia-
mine (8)
p-methoxybenzyl and diphenylmethyl groups so as to enhance the
solubility of the intermediates in organic solvents. The synthesis of
compound 19 was complicated, mainly due to the poor solubility of
certain intermediate reagents in the organic solvents used. Finally, a
different strategy was employed (i.e., preparation of intermediates 17
and 20, Scheme 3) for the efficient synthesis of this compound. Unlike
the synthesis of other oxamide derivatives, tert-butyloxalyl chloride was
used to introduce a terminal oxamide group in 19; this was done for
reasons of chemical stability.
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SYNTHESIS, RADIOLABELLING AND
411
Scheme 2. Synthesis of N-Benzylmercaptoacetylglycyl-N0-oxalylethylenedia-
mine (14)
In the preparation of compound 27 with an S-benzyl protective
group, one of the intermediates, i.e., S-benzyl-N-oxalylcysteamine
(C6H5–CH2–S–CH2–CH2–N–CO–COOH), was found to be insoluble
in organic solvents and was ineffective in DCC-mediated coupling
reactions with amines. However, the solubility problem was resolved by
the use of a more lipophilic S-diphenylmethyl protecting group.
The BOC-group was found to be a useful protecting group for the
amino function. In addition, the ease with which it can be removed}by
the simple treatment with HBr/HOAc without affecting the other
protecting groups (S-benzyl and ethyl ester, etc.) }makes it a protecting
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S. M. OKARVI ET AL.
Scheme 3. Synthesis of N-oxalylglycylglycyl-S-p-methoxybenzylcysteamine (19)
group of choice for the synthesis of MAG3-derivatives. Activation of
the carboxylic function was realized by the conventional HOBT/DCC
or NHS/DCC-mediated reactions. For introduction of a terminal
oxamide moiety, it was necessary that only one of the carboxylic
functions of oxalic acid construct an amide function. For this purpose,
ethyloxalyl chloride was used (one step prior to the final synthesis step,
Schemes 1, 2 and 4), enabling the formation of an amide bond on the
terminal carbonylglycine moiety in developing the oxamide derivatives
(8, 14 and 27). The ethyl ester protection was selectively removed in the
last step of the synthesis (Schemes 1, 2 and 4) by mild alkaline
hydrolysis, without affecting the integrity of the molecules.
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SYNTHESIS, RADIOLABELLING AND
413
Scheme 4. Synthesis of N-oxalyl-N0-oxalyl-S-diphenylmethylcysteamine-ethyle-
nediamine (27)
Labelling with 99mTc
Initially it was our intention to synthesize all the OMAG3-derivatives in
this study with an S-benzyl protective group}known for its high
stability during synthesis, as well as the ease of removal (to provide free
thiol) during radiolabelling process at elevated temperature.8 However,
two of the OMAG3-derivatives contain in their structure an
S-diphenylmethyl or p-methoxybenzyl protecting groups to ensure the
feasibility of the chemical synthesis. Labelling of different OMAG3-
derivatives with 99mTc was achieved by an exchange method in the
presence of stannous chloride and sodium tartrate at different pH
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S. M. OKARVI ET AL.
values. Preferentially, a rather high pH (10 or above) of the labelling
mixtures was chosen for the oxamide derivatives (except for 27) in
order to promote deprotonation of the amide nitrogens; this
enhances the labelling yield as well as minimizes the formation of
side-products. For derivatives 8 and 19 (with an S-benzyl and p-
methoxybenzyl group, respectively, and containing in their structure
one carbonyl group on the ethylene-bridge preceding the terminal
glycine moiety), chelation with 99mTc resulted in the formation of one
main radiochemical species with a relatively short retention time on RP-
HPLC (about 6 min for complexes 8 and 19 versus 13 min for 99mTc-
MAG3). The other two complexes 14 and 27 on the other hand, with a
terminal N-oxalylethylenediamine moiety (–N–CH2–CH2–N–CO–
COOH), showed relatively long retention times (13 and 16 min) and the
optimal labelling efficiency for these derivatives was obtained
at pH 11 and 4, respectively. The radio-HPLC analysis revealed that
besides the formation of a single peak, a few minor peaks were also
formed. It appears that the presence of an ethylene-bridge sequence
(without a carbonyl group) prior to the terminal glycine moiety has a
pronounced effect on the labelling characteristics of these ligands
with 99mTc, as it was also the case with the diamide derivatives of
99mTc-MAG3.9
In another series of experiments, mixtures of equimolar amounts of
MAG3 and OMAG3 after exchange labelling (under the same
conditions as described above) with 99mTc were analyzed by HPLC in
order to determine the relative labelling strength of 99mTc-OMAG3
derivatives versus 99mTc-MAG3. The results suggest that the 99mTc-
complex of 19 (where all the amides bonds are reversed compared to
99mTc-MAG3) showed a higher labelling strength than that of 99mTc-
MAG3, whereas the other 99mTc-OMAG3 derivatives, particularly 14
and 27, clearly exhibit a lower labelling strength than that of 99mTc-
MAG3, as the percentage of these 99mTc-OMAG3 derivatives formed
were rather low in MAG3-OMAG3 competition experiments. Although
these results indicate the weaker binding strength of most 99mTc-
OMAG3 ligands compared to the parent 99mTc-MAG3 complex, under
the optimized labelling conditions (high pH and no competition with
other strong chelating agents) sufficiently stable complexes of OMAG3-
derivatives with 99mTc can be formed. In addition, HPLC-isolated peaks
of 99mTc-OMAG3 complexes were re-analyzed at different time intervals
by HPLC and it was found that these complexes remained stable for at
least 5 h after isolation.
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SYNTHESIS, RADIOLABELLING AND
415
In vivo biodistribution
The biodistribution studies of the 99mTc-labelled oxamide derivatives
were performed in mice at 10 and 30 min post-injection. For each 99mTc-
compound, the main component of the labelling reaction mixture was
isolated by radio-HPLC analysis and after appropriate dilution with
saline, it was co-injected with [131I]-OIH. The OIH was added as an
internal biological standard with a well-known biodistribution profile to
allow rejection of results in animals with impaired renal function. An
ideal tracer agent for renal function studies should possess biological
characteristics such as a high plasma clearance, rapid uptake in the
kidneys and immediate transport to the urine and negligible retention in
the liver, intestines and other body organs after the perfusion phase.
The results of the biodistribution of different 99mTc-OMAG3
derivatives are summarized in Table 1. Both the 99mTc-complexes of 8
and 19 (containing a carbonyl on the ethylene-bridge prior to the
terminal glycine moiety) exhibited renal excretion characteristics that
are comparable with 99mTc-MAG3, as shown by their rapid clearance
from the blood and high urinary excretion at both time points. The
percentage of injected dose for compounds 8 and 19 in the urine was 90
and 87% at 30 min post-injection, respectively, versus 87% for 99mTc-
MAG3. The radioactivity in other body organs at both time points was
almost the same (Table 1). In a baboon, no distinct liver uptake was
observed for these derivatives but clearance from the blood was slower
than in mice, which underlines the inter-species variability. In contrast,
the 99mTc-complexes of 14 and 27 (both are lacking a carbonyl group on
the ethylene-bridge which is connecting the second and third nitrogen
atoms), displayed poor affinity for the renal system, as shown by their
poor renal excretion (15%) at both studied time points (Table 1). It was
Table 1. Biodistribution (n=5) of different oxamide derivatives of 99mTc-MAG3
at 10 and 30 min post-injection in mice
% of injected dose in the organs
Urinary system
Kidneys
Liver
Intestines
Blood
10
30
10
30
10 30
10
30
10 30
99mTc-MAG3
99mTc-8
75
78
79
14
12
87
90
87
15
15
7
4
4
1
1
2
1
1
1
1
3
1
2
2
1
1
2
1
1
32
50
4
1
1
51
76
2
3
2
6
1
1
1
1
1
1
99mTc-19
99mTc-14
99mTc-27
40 10
3
3
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S. M. OKARVI ET AL.
found that these complexes excreted mainly via the hepatobiliary system
(liver and intestines). The results demonstrate that the absence of an
amide bond on the ethylene-bridge prior to the terminal glycine moiety
greatly impaired the renal excretion characteristics of these derivatives.
From the in vivo biodistribution, it may be concluded that the 99mTc-
complexes of 8 and 19 show an identical biological behavior in mice,
both at 10 and 30 min post-injection. Moreover, these results resembled
closely those of 99mTc-MAG3 as a renal agent (i.e., rapid blood
clearance, high urinary excretion and negligible retention in other body
organs). These findings are also in agreement with our previous study of
9
the diamide derivatives of 99mTc-MAG3 and further support the
hypothesis that the presence of at least one carbonyl group between the
second and third nitrogen atoms is essential in MAG3-like compounds
for a favorable biological profile. Furthermore, these results seem to
suggest that the presence of a terminal carbonylglycine sequence is not
strictly required for efficient extraction of 99mTc-MAG3-like agents by
the kidneys and excretion to the urine.
As described above, the complexes of 99mTc-8 and 99mTc-19 were
eluted earlier on HPLC (ꢀ6 min versus 13 min for 99mTc-MAG3)
consistent with the higher polarity of these compounds compared to
99mTc-MAG3. However, these complexes displayed a comparable
migration pattern in the electrophoresis experiments (Table 2).
Furthermore, they showed a biological behavior similar to that of
99mTc-MAG3. On the other hand, the complexes (99mTc-14 and 99mTc-
27) displayed comparable HPLC retention times to 99mTc-MAG3 but
exhibited a significantly different biological behavior and migration
pattern during electrophoresis at pH 9 (Table 2). It is worth mentioning
that the HPLC analysis of the unlabelled ligands 8 and 14 (with an
S-benzyl-group) revealed a retention time similar to S-benzyl-MAG3.
These results indicate a significant variation in forming the complexes
with 99mTc by these two sorts of ligands. However, the structural
Table 2. Migration of 99mTc-OMAG3-derivatives by electrophoresis at different
pH of electrolyte solution (migration towards the anode in cm)
pH3
pH6
pH9
99mTc-MAG3
99mTc-8
1.7
2.3
1.9
1.5
1.7
4.3
3.6
3.4
3.5
3.5
3.0
3.0
3.7
1.5
1.5
99mTc-19
99mTc-14
99mTc-27
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SYNTHESIS, RADIOLABELLING AND
417
differences between these two sets of OMAG3-derivatives (8 and 19
versus 14 and 27) appear to be minimal, namely one amide function is
reversed in 14 compared to 8 and one amide function is reversed in 27
compared to 19 (Figure 1). One major difference, however, is the
presence of a terminal oxalylglycinamide moiety (–N–CO–CH2–N–CO–
COOH) in the compounds 8 and 19 versus an N-oxalylethylenediamine-
N0-amide sequence (–CO–N–CH2–CH2–N–CO–COOH) in 14 and 27,
which may be responsible for the differences both in radiochemical and
biological characteristics of these complexes.
Materials and methods
General
Commercially available chemicals were of reagent grade and were used
without purification unless otherwise stated. Thin-layer chromatogra-
phy (TLC) with different solvent mixtures was carried out using
precoated-TLC silica gel plates (Merck, 60F 254) to verify the purity of
the products. Compounds were detected with UV light at 254 nm, or by
exposing the TLC-chromatograms to iodine vapors. Column chroma-
tography was run on a silica gel 60A (Merck 230–400 meshes). The
1
structures of the synthesized ligands were confirmed with H NMR
spectroscopy obtained on a Jeol FX 9OQ spectrometer (Joel, Japan)
using CDC13, DMSO-d6 or D2O as solvents. The final products were
dried in a vacuum desiccator over phosphorus pentoxide. Animal
experiments were performed according to the Belgian code of practice
for the care and use of experimental animals.
Synthesis/chemistry
Detailed synthetic pathways of the oxamide derivatives are described
elsewhere.10 For reasons of simplicity only the chemistry part is
mentioned here. The chemistry necessary for the synthesis of the
oxamides was mainly based on standard peptide chemistry techniques,
e.g., use and choice of protecting groups, standard activation, coupling
and deprotection procedures.11,12 The general chemistry for the
preparation of different oxamide derivatives of MAG3 is described
below.
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S. M. OKARVI ET AL.
N-(S-benzylmercaptoacetyl)N0-oxalylglycylethylenediamine (8). The
method for the preparation of 8 is depicted in Scheme 1. Condensation
of S-benzylmercaptoacetic acid with N-tert-butoxycarbonyl-ethylene-
diamine (BOC-EDA) 2 (prepared from ethylenediamine and di-tert-
butyldicarbonate in 1:9 molar ratios in triethylamine) in the presence of
1-hydroxybenzotriazole (HOBT) and 1,3-dicyclohexylcarbodiimide
(DCC) produced 3, which was deprotected by HBr/HOAc to give N-
benzylmercaptoacetyl-ethylenediamine hydrobromide 4. This product
was reacted with carbobenzyloxyglycine (CBZ-glycine) in the presence
of HOBT/DCC to 5, followed by the selective removal of the CBZ-
group with HBr/HOAc 6. Reaction of ethyloxalyl chloride with 6 under
Schotten–Baumann conditions13 resulted in the ethyl ester derivative 7,
which was hydrolyzed with base to the corresponding acid 8.
N-(S-benzylmercaptoacetylglycyl N0-oxalylethylenediamine (14). The
synthesis of compound 14 is outlined in Scheme 2. Commercially
available S-benzylmercaptoacetic acid was recrystallized from ethyl
acetate and converted to N-hydroxysuccinimidyl ester 9 with NHS/
DCC. Coupling of this active ester with glycine under alkaline
conditions produced S-benzylmercaptoacetylglycine (MAG1) 10. Acti-
vation of the carboxylic group with HOBT/DCC and subsequent
coupling of 10 with BOC-EDA 2 provided 11, which was deprotected by
HBr/HOAc to 12. Reaction of ethyloxalyl chloride in the presence of
diisopropylethylamine (DIPEA) with 12 under Schotten–Baumann
conditions followed by alkaline hydrolysis of the ester group 13 gave
the oxamide derivative 14.
N-oxalylglycylglycyl-S-p-methoxybenzylcysteamine (19). The prepara-
tion of compound 19 is shown in Scheme 3. Cysteamine hydrochloride
was converted into S-p-methoxybenzylcysteamine hydrobromide 20 by
the treatment of Na/NH3 in the presence of p-methoxybenzyl chloride.
The intermediate, glycylglycinebenzyl ester p-toluenesulfonate 15, was
prepared by the condensation of p-toluenesulfonic acid with glycylgly-
cine and benzyl alcohol in benzene. Reaction of this compound with
ethyloxalyl chloride and tert-butanol provided diester 16. Hydrogena-
tion of the benzyl ester resulted in monoester/monoacid derivative 17.
Coupling of 17 with 20 in the presence of HOBT/DCC and Et3N gave
tert-butyl ester derivative 18. Lastly, the tert-butyl ester was hydrolyzed
by reaction with HBr/HOAc to give the corresponding acid 19.
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SYNTHESIS, RADIOLABELLING AND
419
N-oxalyl-N0-oxalyl-S-diphenylmethylcysteamine ethylenediamine (27).
Compound 27 was prepared according to Scheme 4. Condensation of
S-diphenylmethyl-cysteamine hydrochloride 21 (prepared from ami-
noethanethiol hydrochloride and benzhydrol in TFA) with ethyloxalyl
chloride in DIPEA gave the ethyl ester derivative 22, which after
alkaline hydrolysis was converted into the acid 23. This acid was
activated on its carboxylic function by NHS/DCC and was then coupled
to BOC-EDA 2 to provide 24. Removal of the BOC-group by HBr/
HOAc produced the hydrobromide 25, which was reacted with
ethyloxalyl chloride to form the ethyl ester derivative 26. Alkaline
hydrolysis of the ester resulted in the formation of the diphenyl-
protected oxamide derivative 27.
Labelling with 99mTc
Labelling of the synthesized oxamide ligands was carried out by the
ligand exchange method. The ligand (1–2 mg) and sodium tartrate
(5 mg) were dissolved in 0.5 ml of phosphate buffer 0.5 M of the desired
pH (4–11) followed by addition of 100 mg of SnC12 ꢁ 2H2O in 25 ml of
0.05 M HCl. After the addition of 1–3 ml of generator eluate
(UltraTechnekow generator, Mallinckrodt Medical, The Netherlands)
containing 370–740 MBq (10–20 mCi) of 99mTcO4ꢂ, the reaction mixture
was heated for 10 min at 1008C and cooled to room temperature and
filtered through a 0.2-mm pore membrane filter (Acrodisc, Gelman
Sciences) prior to radio-HPLC analysis.
Analysis of 99mTc-labelled compounds
Analysis of labelled reaction mixtures was performed using RP-HPLC
on a Hypersil 5 mm ODS column (Shandon Scientific, UK) eluted with a
ternary gradient mixture of ethanol, 0.025 M phosphate buffer pH 5.85
and water at a flow rate of 1 ml/min. The HPLC system consisted of a
Merck-Hitachi L6200 intelligent pump and a 250 mm ꢃ 4.6 mm reversed
phase column. Radioactivity in the column effluent was monitored using
a 2-in NaI(T1) scintillation detector coupled to a single-channel
analyzer and a Rachel analysis program.
Electrophoresis of 99mTc-MAG3 and 99mTc-OMAG3 complexes was
performed by applying a potential of 300 V for 30 min using a 0.025 M
phosphate buffer (pH 3, 6 and 9) as the electrolyte solution. The
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S. M. OKARVI ET AL.
distribution of radioactivity was measured by cutting the strips into
1 cm segments and counting each segment in a g-counter.
Biological evaluation in mice
Biodistribution of the oxamides was studied in male NMRI mice (body
mass 25–35 g) at 10 and 30 min post-injection. The HPLC purified
product was diluted to a concentration of 148 kBq/ml (4 mCi/ml) with
sterile saline and 131I-OIH (Mallinckrodt Medical, The Netherlands)
was added as an internal biological standard to a concentration of
14.8 kBq/ml. The diluted tracer solution (0.1 ml) was injected via a tail
vein after sedation of the animals with Hypnorm1 (Duphar, The
Netherlands). The animals were sacrificed by decapitation at fixed time
intervals. The organs were dissected and the radioactivity in each organ
was measured. Radioactivity in each organ was expressed as a
percentage of injected radioactivity, which was equal to the sum of
the radioactivity in all organs. For calculation of radioactivity in total
blood, blood mass was assumed to be 7% of total body mass. Results
were corrected for background radiation, physical decay during
counting, and 131I crossover into the 99mTc-channel.
Conclusions
The results suggest that the renal excretion properties of the 99mTc-
complexes of 14 and 27 (without a carbonyl on the ethylene-bridge prior
to the terminal glycine) are inferior to those of 99mTc-MAG3. Moreover,
these compounds exhibited relatively poor labelling characteristics with
99mTc and hence do not satisfy the requirements for a suitable renal
agent. In contrast, the 99mTc-complexes of 8 and 19 (with one inverted
amide on the ethylene-bridge) labelled efficiently with 99mTc and
displayed the most efficient renal handling of the studied compounds
in mice, as characterized by their rapid renal excretion and negligible
retention in other body organs. It thus seems that for efficient handling
by the tubular system, 99mTc-MAG3-like compounds need in their
structure some specific distribution of the amide bonds and at least one
carbonyl group on the ethylene-bridge preceding the terminal glycine
moiety. Furthermore, it appears that the presence of a terminal
carbonylglycine sequence in MAG3-like compounds is not necessary
for the observation of efficient renal excretion characteristics.
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SYNTHESIS, RADIOLABELLING AND
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