Large-scale synthesis of no-carrier-added [123I]mIBG, using two different stannylated precursors

Article abstract of DOI:10.1002/jlcr.1668

The clinical advantages of no-carrier-added (n.c.a) radioiodinated meta-iodobenzylguanidine ([*I]mIBG) over its carrieradded (c.a.) analogue have previously been reported. A large-scale synthesis of n.c.a. [ ¹²³I]mIBG was therefore investigated

Full text of DOI:10.1002/jlcr.1668

Research Article
Received 19 February 2009,
Revised 1 July 2009,
Accepted 1 July 2009
Published online 18 August 2009 in Wiley Interscience
(
www.interscience.wiley.com) DOI: 10.1002/jlcr.1668
Large-scale synthesis of no-carrier-added
1
23
[
precursors
I]mIBG, using two different stannylated
a
Daniel D. Rossouw and Lebohang Macheli
Ã
b
The clinical advantages of no-carrier-added (n.c.a) radioiodinated meta-iodobenzylguanidine ([*I]mIBG) over its carrier-
1
23
added (c.a.) analogue have previously been reported. A large-scale synthesis of n.c.a. [ I]mIBG was therefore investigated
in this study, using a slightly adapted literature method. Two bis (t-butyloxycarbonyl)-protected (bis-Boc) stannylated
benzylguanidine precursors were prepared. The bis-Boc-trimethylstannyl precursor was used to optimize radioiodination
conditions. N-chlorosuccinimide (NCS) was used as oxidant. An HPLC method was developed to monitor radioiodination
and de-protection steps. Amounts of 200 g precursor and 2000 g NCS resulted in HPLC yields of Boc-protected
radioiodinated compounds in excess of 90%. De-protection was carried out with trifluoroacetic acid at 1101C. A robust solid
phase extraction method was developed to purify reaction mixtures. Radiochemical yields at radioactivity levels ranging
between 1900 and 3280 MBq were 8572.2% (n = 4). A twice scaled up reaction at 5340 MBq gave a similar yield.
ꢀ
1
Radiochemical purities were in excess of 98% and the specific activity estimated at approximately 1 TBq.lmol . Yields
obtained from an HPLC-purified bis-Boc-tributylstannyl precursor were generally lower and ranged from 61 to 81%. Results
obtained in this study suggest that n.c.a [ I]mIBG could be synthesized on a GBq scale.
1
23
Keywords: mIBG; 123I; no-carrier-added; stannylated; precursors
Introduction
generally consistently in excess of 90%, n.c.a. radioiodination
yields are generally more variable. The radioiodination method
The diagnostic and therapeutic applications of radioiodinated of choice should therefore be selected very carefully. Various
Ã
meta-iodobenzylguanidine (mIBG) in oncology and cardiology methods for the synthesis of n.c.a. [ I]mIBG have been
1
are well documented . Currently, isotopic exchange is the
,2
documented using various labelling precursors such as
3,4,6
and
3
–5
7
8
radioiodination method of choice.
During the past 10–15 3-tributylstannyl-, 3-trimethylstannyl, 3-trimethylsilyl
7
,9
years the synthesis and applications of no-carrier-added (n.c.a.) 3-bromobenzylguanidine derivatives, as well as a polymer-
à 3–9
I]mIBG, as well as other 4-substituted mIBG analogues,
10,11
5
supported 3-benzylguanidinium reagent. More recently, the
[
have also been described. It has been suggested that n.c.a. utilization of the fluorous labelling strategy, using a highly
Ã
13
[
added (c.a.) analogue. In oncology, the n.c.a. product shows an
I]mIBG might have certain clinical advantages over its carrier- fluorinated tin precursor, was also described. This method,
however, makes use of relatively complicated precursor synth-
apparent higher uptake in neuroblastoma and pheochromo- esis procedures as well as fairly expensive fluorous solid-phase
cytoma cells. Furthermore, the administration of high doses of extraction cartridges. A few methods also describe the use of
4
1
2
1
31
8,11
cold mIBG during therapeutic applications of c.a. [ I]mIBG protected guanidine precursors.
This approach appears
to be very sensible as the sparing solubility of free guanidines
5
might result in pharmacological side effects. In radioimaging,
1
23
n.c.a. [ I]mIBG gives a significantly higher myocardial uptake in aprotic organic solvents could complicate the synthesis
associated with better contrast between the heart and of lipophilic precursors. When selecting the most appropriate
radioiodination method, issues such as the ease of preparation
6
neighbouring organs. The nuclear medicine community could
Ã
certainly benefit from the availability of n.c.a. [ I]mIBG, as its and stability of the precursor and the accomplishment
limited availability might be the reason for the lack in progress of optimal radiochemical yields should all be considered.
in larger-scale clinical research efforts. This prompted us to
9
investigate the synthesis of this product.
In South Africa, iThemba LABS is the sole producer of c.a.
a
Radionuclide Production Group, iThemba LABS, PO Box 722, 7129 Somerset West,
South Africa
1
23
[
I]mIBG. Owing to the location of this facility the product
b
reaches distant users only 24 h post production. Consequently,
activities supplied to all users are calibrated at 12:00 h following
the production day. This necessitates a large-scale production
with high yields in order to compensate for decay. Whereas
Department of Chemistry, National University of Lesotho, PO Box 0180, 00100
Roma, Lesotho
*Correspondence to: Daniel D. Rossouw, Radionuclide Production Group,
iThemba LABS, PO Box 722, 7129 Somerset West, South Africa.
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23
radiolabelling yields for c.a. [ I]mIBG via isotope exchange are E-mail: niel@tlabs.ac.za
J. Label Compd. Radiopharm 2009, 52 499–503
Copyright r 2009 John Wiley & Sons, Ltd.

D. D. Rossouw and L. Macheli
Halodesilylation reaction yields are generally lower than
3
The entire radiosynthesis sequence is shown in Scheme 1.
but silylated precursors are more Radioiodination conditions were based upon those described in
stable than their stannylated counterparts. A bis(t-butyloxycar- literature, using N-chlorosuccinimide (NCS) as oxidant. Reac-
bonyl) (bis-Boc) protected trimethylstannylated benzylguanidine tions were performed at room temperature instead of 701C in
precursor, however, was claimed to be very stable at a low order to prevent the possible cleavage of the protecting groups
,14
halodestannylation yields,
8
8
storage temperature. We eventually decided upon the latter during radioiodination. Precursor 1 was used to roughly
method in which a halo-destannylation procedure with a Boc- optimize reaction conditions with regards to the precursor
protected precursor, using various radioisotopes of iodine and NCS content. Reactions were monitored on HPLC (column
1
23
211
(
excluding
I), as well as
At, had been successfully A, Method B). The RT data in Table 1 show that two or three
8
employed. Since the maximum scale of radioiodination was radioiodinated species were formed (RT = 30–35 min). One of
only 37 Mbq, the primary goal of this study was to establish these species (RT = 33.5 min) was only formed when precursor 2
whether this method was adaptable for a larger-scale prepara- was used (see discussion later). The relative intensities of the
1
23
tion of n.c.a. [ I]mIBG. This necessitated an optimization of other two peaks followed a random distribution, the one having
radioiodination conditions. In addition, we also synthesized and the longer RT always being predominant. They were assumed to
1
23
utilized a Boc-protected tributylstannyl precursor in order to be the mono- and bis-Boc-derivatives of [ I]mIBG because
compare radiochemical yields with those obtained from the treatment with trifluoroacetic acid (TFA) resulted in the
protected trimethylstannyl analogue. High Performance Liquid disappearance of both species with the simultaneous formation
1
23
chromatography (HPLC) methods were also developed to of only one product ([ I]mIBG).
determine the chemical purities of precursors and to monitor
Low and inconsistent HPLC radiochemical yields were
the progress of radioiodination and de-protection steps. In an obtained using 50–100 ug of precursor together with
attempt to simplify the purification of crude reaction mixtures, 100–300 ug of NCS (Table 2). Increasing the NCS content to
we also developed and applied a solid phase extraction 2000 ug, while maintaining the same levels of precursor,
procedure, as opposed to the more conventional HPLC resulted in higher but still somewhat inconsistent yields.
purification. The latter could be cumbersome and time- Increasing the precursor content to 200 ug resulted in consis-
consuming, especially when handling large amounts of radio- tently high HPLC yields at radioactivity levels up to nearly
activity.
3300 MBq. The HPLC yields were also backed up by good and
consistent isolated yields (see later). These optimized conditions
were also applied to the radioiodination of the tributylstannyl
precursor 2. Silica gel purified 2 resulted in the formation of a
Results and discussion
0
The intermediate N, N -bis(tert-butyloxycarbonyl)-3-iodobenzyl-
guanidine (bis-Boc-mIBG) was synthesized from 3-iodobenzyl
alcohol using the Mitsunobu protocol, following a procedure
that was reported for an analogous compound. N,N -bis(tert-
butyloxycarbonyl)-3-trimethylstannylbenzylguanidine (bis-Boc-
mTMSBG 1) was synthesized and purified according to a slightly
considerable amount of
a radioiodinated impurity with
1
23
RT = 33.5 min (Method B), leading to poor [ I]mIBG radio-
chemical yields (see Table 3). The impurity was identified as
123
Boc-m-[ I]iodobenzylamine since TFA treatment of an
1
1
0
HPLC-facilitated isolated fraction led to the formation of m-
123
[
I]iodobenzylamine (RT = 8.5 min). HPLC-purified precursor 2
8
adapted literature method. It was obtained in a yield of 43%
did not generate the impurity, suggesting that the latter
had resulted from the presence of a trace amount of its Boc-
stannylated analogue in the silica gel purified precursor 2.
with a chemical purity of about 94% as determined by HPLC
Method A (see Table 1 for retention time (RT) data). The purified
product contained a trace (less than 1%) of bis-Boc-mIBG. Bis-
Boc-3-tributylstannylbenzylguanidine (bis-Boc-mTBSBG 2) was
synthesized according to conventional methods. Successive
silica gel column chromatography yielded 2 with a chemical
purity of about 92% as determined by HPLC (column B, Method
C). Additional HPLC purification was required for optimal
radioiodination yields (see later). Both precursors remained
stable in methanol solutions kept at ꢀ101C for periods
exceeding two months.
Scheme 1. Radiosynthesis of n.c.a. [123I]mIBG from precursors bis-Boc-mTMSBG 1
(R = trimethylstannyl) or bis-Boc-mTBSBG 2 (R = tributylstannyl).
Table 1. Peak retention times and anticipated identities of various species in HPLC chromatograms
HPLC column
A
HPLC method
A
Retention time (min)
Anticipated species
17.0
bis-Boc-mIBG
bis-Boc-mTMSBG
2
2.1
2.9
1
23
A
B
[
I]iodide
benzylguanidine
4
8
.2
.5
1
m-[ I]iodobenzylamine
23
1
23
13.5
30.5
33.5
35.0
[
mono-Boc-[ I]mIBG
I]mIBG
1
23
1
Boc-m-[ I]iodobenzylamine
23
1
23
bis-Boc-[ I]mIBG
bis-Boc-mTBSBG
B
C
16.5
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Copyright r 2009 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2009, 52 499–503

D. D. Rossouw and L. Macheli
1
23
123
Table 2. Radiochemical yields (RCY) of Boc-[ I]mIBG and [ I]mIBG from bis-Boc-mTMSBG 1 as a function of precursor and
N-chlorosuccinimide (NCS) quantities
a
b
HPLC RCY
Isolated RCY
Mass precursor
mg)
Mass NCS
Starting radioactivity
(MBq)
(
(mg)
(%)
(%)
ND
ND
ND
ND
ND
ND
5
1
1
5
5
1
2
2
4
0
100
100
300
2000
2000
2000
2000
2000
4000
37–140
30–140
37–180
3974.2
12711.1
50728.2
87718.3
60737.9
74722.9
9871.4
90
(n = 2)
(n = 3)
(n = 3)
(n = 5)
(n = 3)
(n = 4)
(n = 4)
(n = 1)
(n = 1)
00
00
0
115–130
325–850
484–2170
1900–3280
6530
0
00
00
00
00
8572.2
69
86
(n = 4)
(n = 1)
(n = 1)
5340
99
a
123
As assessed by analytical HPLC, sum of all Boc-[ I]mIBG species in chromatogram expressed as percentage of total number of
radiopeaks.
b
123
Isolated yield of n.c.a. [ I]mIBG after TFA de-protection and Sep-Pak purification, expressed as percentage of the starting
activity (decay-corrected).ND = not determined.
1
23
123
Table 3. Radiochemical yields (RCY) of Boc-[ I]mIBG and [ I]mIBG from bis-Boc-mTBSBG 2, using 200 mg precursor and
000 mg N-chlorosuccinimide
2
a
b
Precursor purification
method
Starting radioactivity
(MBq)
HPLC RCY
(%)
Isolated RCY
(%)
Silica gel
122
27
32
40
91
98
85
ND
43
56
70
81
61
2
2
370
886
HPLC C18
2225
2
3
564
467
a
123
As assessed by analytical HPLC, sum of all Boc-[ I]mIBG species in chromatogram expressed as percentage of total number of
radiopeaks.
b
123
Isolated yield of n.c.a. [ I]mIBG after TFA de-protection and Sep-Pak purification, expressed as percentage of the starting
activity (decay-corrected). ND = not determined.
Boc-m-tributylstannylbenzylamine was probably formed as a by- neutralize the organic acids and raise the pH to approximately
product during the catalytic conversion of bis-Boc-mIBG to 6.3. At a lower pH the product was sometimes partially eluted
precursor 2 and is seemingly not easily separable from 2 via silica during the water wash step. Free radioiodide, the only major
gel chromatography. Even at trace level concentration it generated radioactive contaminant in TFA-treated reaction mixtures when
a relatively large amount of its radioiodinated counterpart.
Reaction mixtures were treated with TFA at 1101C for 15min in
using precursor 1, was quantitatively eluted with water. N.c.a.
1
23
[
I]mIBG was eluted with a 0.1% H PO /absolute ethanol
3 4
1
23
order to completely convert all Boc-species to [ I]mIBG. The de- (75:25) mixture and was present in the second to fourth 1 ml
protection was monitored by means of HPLC (Method B). The eluted fraction, rendering 3 ml in total. The amount of activity
1
23
retention time of [ I]mIBG was in accordance with that of retained by the Sep-Pak cartridge ranged between 3 and 5% of
authentic mIBG. The progress of the de-protection step was also the starting activity. The use of this biologically compatible eluant
once monitored at room temperature, using precursor 1. Under eliminates the need for an evaporation step, as would have been
this condition the radiochromatogram showed after 50min a the case if a toxic solvent such as methanol were used. It also
predominant peak at RT = 30.5 min (probably mono-Boc- minimises the possibility of the co-elution of non-polar impurities.
1
23
[
bis-Boc-[ I]mIBG). No [ I]mIBG was detected. After heating the usable product by adding phosphate buffer for pH control, as
I]mIBG) and only a trace of a peak at RT = 35.0min (probably The eluate could be readily converted into a pharmaceutically
1
23
123
1
23
mixture, the [ I]mIBG peak appeared at the expense of both of well as saline solution to reduce the ethanol content.
the formerly mentioned two. These observations suggest that the Under optimized conditions, precursor 1 gave consistent Sep-
de-protection only occurs partially at room temperature and Pak-isolated radiochemical yields, averaging 85% at radioactivity
support the earlier assumptions made regarding the identities of levels ranging from 1900 to 3280 MBq (see Table 2). When the
the formed species.
activity level was doubled by increasing the volume of radio-
TFA-treated reaction mixtures were purified on a C18 solid iodide, without increasing the precursor mass, the yield dropped
phase extraction cartridge (Sep-Pak). Reaction mixtures were (Table 2, second last entry). A single two-fold scale-up of the
treated with base prior to the Sep-Pak procedure in order to whole reaction at an activity level of 5340 MBq gave a similar
J. Label Compd. Radiopharm 2009, 52 499–503
Copyright r 2009 John Wiley & Sons, Ltd.
www.jlcr.org

D. D. Rossouw and L. Macheli
1
yield as before (Table 2, last entry). A semi-purified precursor 2 throughout. The H NMR spectra were collected on a Varian
Unity
gave relatively poor isolated radiochemical yields (see Table 3
Inova 400 MHz NMR spectrometer. TMS was added as
and discussion earlier). HPLC-purified 2 gave improved yields, a reference standard to sample solutions. Tin analysis was
albeit generally inferior to those given by precursor 1. Radio- done on a Jobin-Yvon Ultima Inductively Coupled Plasma
chemical purities of all isolated products were in excess of 98%. spectrometer (ICP). Radioactivity measurements were
Sep-Pak purification also removed the major cold substances carried out in a Vinten Isocal II Radionuclide Assay Calibrator.
of the reaction mixture, as verified by means of HPLC UV analysis. Sep-Pak C18 cartridges (500 mg C18, 3 cc) were obtained
The combined product-containing Sep-Pak fraction, obtained from Waters. Cartridges were conditioned by elution with
0
from a two-fold scaled-up reaction, was analysed for the presence 4 ml methanol, followed by 3 ml water. N, N -bis(tert-butylox-
of traces of NCS [Method B; 50ml (60 MBq) injected]. This injection ycarbonyl)-3-iodobenzylguanidine (bis-Boc-mIBG) was synthe-
volume related to a theoretically maximum amount of 66mg sized from 3-iodobenzyl alcohol, similarly to a literature
1
1
(
present. When compared with the HPLC chromatogram of a NCS
500nmol) of NCS, should all of the original 4000mg NCS be procedure .
standard (RT = 3.1 min), less than the detection limit of about HPLC analysis
5
nmol NCS/60MBq could be detected. This suggests that most
HPLC was performed on an Agilent 1100 Series pump,
equipped with HP 1100 Series Control Module for
of the NCS, if not all, was removed during the water elution step.
The harsh de-protection reaction conditions did not only lead to
the complete removal of the Boc groups, but also resulted in the
degradation of the precursor to the proton-destannylated
derivative benzylguanidine. This was validated by treating bis-
Boc-mTMSBG with TFA at 1001C and doing an HPLC analysis of a
methanol solution of the TFA-evaporated residue (Method B,
column A). A peak with the same RT as benzylguanidine was
displayed. The latter had been synthesized from benzylamine
hydrochloride and cyanamide according to the mIBG synthesis
a
binary gradient elution and a Rheodyne Model 7725 injector.
The column outlet was connected to a Spectra Series UV100
detector, set at 254 nm, which was coupled in series with
a Carroll&Ramsey Model 105S-1 CsI(Tl) radiation detector.
A Phenomenex Luna C18 (250 ꢁ 4.6 mm, 5 mm) [column A] and
a Phenomenex Synergi column C12 (150 ꢁ 4.6 mm, 4 mm)
[
column B] were used. Chromatograms were recorded on
a dual channel Chromatopac C-R8A from Shimadzu. The
following HPLC methods were used (all elutions were carried
out at 1 ml/min):
1
5
method of Wieland et al. A semi-quantitative analysis suggested
a near quantitative conversion of bis-Boc-mTMSBG to benzylgua-
nidine. In order to demonstrate that the latter co-elutes with the
other polar components during Sep-Pak purification, a radio-
iodination/de-protection/Sep-Pak procedure was simulated
under cold conditions. The amount of benzylguanidine in each
eluted fraction was determined by means of HPLC (Method B),
using a benzylguanidine standard. Approximately 92% of the
theoretically expected amount of benzylguanidine formed was
present in the first 9 ml water eluate. No detectable traces of
HPLC Method A: Mobile phase: A (water), B (acetonitrile).
–10 min: isocratic elution with 80% B; 10–20 min: linear
0
gradient change to 100% B; 20–30 min: isocratic elution with
1
00% B.
HPLC Method B: Mobile phase: A (water/methanol = 60/40 (v/
v), containing 1 g guanidinium carbonate and 1 ml acetic acid/
litre of mixture), B (water), C (methanol). 0–17 min: isocratic
elution with 100% A; 17–22 min: linear gradient change to 100%
B; 22–27 min: linear gradient change to 30% B/70% C;
27–30 min: linear gradient change to 100% C; 30–40 min:
isocratic elution with 100% C.
3 4
benzylguanidine were observed in the H PO /ethanol product
fractions. Inductively Coupled Plasma (ICP) analysis of the latter
showed the presence of trace amounts of tin (probably in the
form of trimethylstannyl trifluoroacetate) up to a level of about
HPLC Method C: Mobile phase: A (water), B (acetonitrile).
–3 min: isocratic elution with 75% B; 3–6 min: linear gradient
0
change to 100% B; 6–25 min: isocratic elution with 100% B.
9
ppm. After dilution with buffer and saline, this figure should
drop to about 3 ppm. At this level the product should probably
be safe for clinical use, but this should nevertheless be confirmed
by animal toxicity studies.
Chemistry
The specific activity (SA) was not directly determined, as the cold
mIBG content of the product fractions was below the detection limit
of the instrumentation. By quantifying the trace of bis-Boc-mIBG in
the bis-Boc-mTMSBG precursor, using HPLC (Method A) and a
0
N, N -bis(tert-butyloxycarbonyl)-3-trimethylstannylbenzylguanidine
(bis-Boc-mTMSBG) 1
bis-Boc-mIBG standard, and assuming that it would all be converted A mixture of bis-Boc-mIBG (57 mg; 0.12 mmol), hexamethylditin
to mIBG upon TFA treatment, a SA value of approximately (92 mg; 0.28 mmol) and bis(triphenylphosphine)palladium
ꢀ
1
1
.0 TBq.mmol was estimated. This estimate was based on the dichloride (10 mg) in dry dioxane (5 ml) was heated and stirred
maximum radiochemical yield obtained directly after purification. in an oil bath at 1001C for 2 h. The reaction mixture was
1
23
ꢀ1
The SA of the [ I]iodine used was also in excess of 1 TBq.mmol
.
subsequently filtered, and the filtrate concentrated under
123
It should be noted that in this particular case the SA of the [ I]mIBG reduced pressure with heating. The oily residue was dissolved
was limited by the purity of the precursor and that a higher SA in a small amount of ethyl acetate and the solution loaded onto
should theoretically be possible, using a purer precursor.
a column filled with silica gel in hexanes. The column was eluted
with approximately 45 ml hexanes, followed by 30 ml 10% (v/v)
ethyl acetate in hexanes and finally 30 ml 20% (v/v) ethyl acetate
in hexanes (6 ꢁ 5 ml fractions). The product-containing fractions
Experimental
from the latter eluate were combined and evaporated to
)
General
1
dryness to yield 26 mg (43%) of an oily product: H NMR (CDCl
3
All reagents and chemicals were obtained from either Sigma- d: 0.27 (s, 9H), 1.35 (s, 9H), 1.49 (s, 9H), 5.17 (s, 2H), 7.18–7.42 (m,
Aldrich or Fluka. Pharmaceutical grade water was used 4H), 9.45 (br s, 2H).
www.jlcr.org
Copyright r 2009 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2009, 52 499–503

D. D. Rossouw and L. Macheli
N, N0-bis(tert-butyloxycarbonyl)-3-tributylstannylbenzylguanidine reaction was scaled up twice under optimized conditions, a
(
bis-Boc-mTBSBG) 2
two-fold increase of all chemical and radiochemical ingredients
and solvents, including the quantity of water used for Sep-Pak
elutions, was implemented. The quantity of eluant used to elute
the product, however, was not adjusted accordingly.
Bis-Boc-mIBG (35 mg; 0.07 mmol) was dissolved in dry dioxane
(
2 ml). A stream of nitrogen was bubbled through the solution
for 1 min, and tetrakis(triphenylphosphine)palladium (8 mg) and
bis(tributyltin) (172 mg; 0.3 mmol) was added. The reaction vial
was again flushed with nitrogen and the mixture was heated in
an oil bath at 1151C for 3 h. The reaction mixture was
subsequently concentrated under a stream of nitrogen with
heating. The concentrated mixture was loaded onto a column
filled with silica gel in hexanes. The column was eluted with
approximately 35 ml hexanes, followed by 25 ml 10% (v/v) ethyl
acetate in hexanes. The product-containing fractions from the
latter eluate were combined and evaporated to dryness to yield
Conclusion
The described optimized method for the production of n.c.a.
123
[
I]mIBG proved to be reliable and results appear to be
reproducible. Radiochemical yields obtained from a Boc-
protected trimethylstannyl precursor were generally higher than
those obtained from its tributylstannyl counterpart. The
described Sep-Pak purification process appears to be robust
up to activity levels of at least 5.3 GBq. Certain features of the
procedure such as the chemical degradation of the precursor
and the selective elution of the degradation products from the
Sep-Pak make a chromatographic separation of the radiola-
belled product from its precursor unnecessary. The results of this
22 mg (47%) of an impure oily product. The latter was combined
with a product from another batch (18 mg) and subjected to
further silica gel purification, using 10% (v/v) ethyl acetate in
1
petroleum ether, to obtain a semi-pure product: H NMR (CDCl )
3
d: 0.86–0.9 (m, 9H, SnBu), 1.01–1.08 (m, 6H, SnBu), 1.26–1.36
123
study suggest that n.c.a [ I]mIBG could be synthesized on a
(
m, 15H, Boc, SnBu), 1.46–1.56 (m, 15H, Boc, SnBu), 5.17 (s, 2H),
GBq scale, using a relatively simple purification procedure. This
should enable medical scientists to embark on more extensive
clinical trials.
7.2–7.45 (m, 4H), 9.45 (br s, 2H). Additional HPLC purification was
carried out by injecting a solution of semi-pure 2 (500 mg) in
methanol (50 ml) on column B and using Method C to elute the
mixture. The product fraction (RT = 16.5 min) was collected
and evaporated to dryness under a stream of nitrogen and
slight heating. The residue (approximately 450–500 mg) was
re-dissolved in methanol (50 ml).
Acknowledgement
The authors wish to thank Messrs S. Dolley and S. Buwa who
assisted with the ICP analysis.
Radiochemistry
123
No-carrier-added [ I]iodine was locally produced by means of
the I(p,5n) Xe! I route, using a 66 MeV proton beam,
and recovered in 0.01 M NaOH. The latter solution was reduced
1
27
123
123
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therefore effectively rendering
approximately 0.1M.
a NaOH concentration of
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6
1
23
A solution of I in approximately 0.1M NaOH (50 ml) was added,
followed by a solution of NCS (100–2000 mg) in glacial acetic acid
6
[
6] M. Knickmeier, P. Matheja, T. Wichter, K. P. Sch a¨ fers, P. Kies, G.
1
23
(
50 ml). When 100 ml I was used, additional acetic acid (100 ml)
was added. The mixture was stirred for 15 min at room
temperature and then quenched with a solution of Na
90–1800 mg) in water (45 ml). A small aliquot of the reaction
mixture was withdrawn for routine HPLC analysis. Neat TFA
100 ml) was then added and the mixture stirred and heated in a
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2 2 5
S O
(
[
(
[9] H. J. Verberne, K. de Bruin, J. B. A. Habraken, G. Aernout Somsen,
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sealed vial at 1101C for 15 min. Another small aliquot was taken
for HPLC analysis, and the reaction mixture subsequently
neutralized with 5 M NaOH (1.1 ml). The mixture was loaded
onto a pre-conditioned Sep-Pak cartridge (500 mg C18) and
passed through, using vacuum. The empty reaction vial was
rinsed with water (4 ml), which was subsequently passed
through the cartridge. The latter was eluted with a further
0022-1.
[
10] G. Vaidyanathan, P. C. Welsh, K. C. Vitorello, S. Snyder,
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004, 31, 1362–1370. DOI: 10.1007/s00259-004-1596-8.
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[
[
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S1:63–S1:76. DOI: 10.1016/j.nucmedbio.2008.06.002.
14 ml water, followed by a mixture of 0.1% H
3
PO
4
/absolute
ethanol = 75:25 (v/v) (1 ml). The cartridge was subsequently [13] A. C. Donovan, J. F. Valliant, Nucl. Med. Biol. 2008, 35, 741–746.
DOI: 10.1016/j.nucmedbio.2008.07.006.
eluted with a further four to five 1 ml portions of the same
[
[
14] S. M. Moerlein, H. H. Coenen, J. Chem. Soc. Perkin Trans. I 1985,
941–1947.
15] D. M. Wieland, J-L. Wu, L. E. Brown, T. J. Mangner, D. P. Swanson,
mixture. The activities in the individual fractions were counted
and those in the product-containing fractions were expressed as
percentages of the starting activity (decay-corrected). When the
1
W. H. Beierwaltes, J. Nucl. Med. 1980, 21, 349–353.
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