These facts show that a high labelling quality solution of clinically sufficient99mTc concentration could be achieved if the generator eluate obtained at an ‘‘early’’ elution is further
Trang 11 23
Journal of Radioanalytical and
Nuclear Chemistry
An International Journal Dealing with
All Aspects and Applications of Nuclear
Chemistry
ISSN 0236-5731
J Radioanal Nucl Chem
DOI 10.1007/s10967-014-3439-9
Development of multiple-elution cartridge-based radioisotope concentrator device
concentration and the effectiveness of
Van So Le, Nabil Morcos & Zac Bogulski
Trang 21 23
Kiadó, Budapest, Hungary This e-offprint is for personal use only and shall not be self-archived in electronic repositories If you wish
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Trang 3Development of multiple-elution cartridge-based radioisotope
Van So Le• Nabil Morcos•Zac Bogulski
Received: 4 August 2014
Ó Akade´miai Kiado´, Budapest, Hungary 2014
Abstract A self-shielded, sterile and cartridge-based
radioisotope concentrator device coupled to 99mTc/188Re
generators to increase the99mTc/188Re-concentration of the
generator eluate was developed based on new
aminoalkyl-functionalized silica sorbent which conditionally catches
and release 99mTc/188Re to concentrate the daughter
nuclide of the generator eluates The cartridge can be used
for multiple elutions with an overall concentration factor of
[100 and daughter nuclide recovery yield of [85 % This
device can be used for 10 days extension of99m
Tc-gener-ator life-time, saving about 20 % of the generTc-gener-ator activity
and for ‘‘early’’ generator-elution programs, under which
the generator is eluted at an optimized build-up time for
increasing the effectiveness of99mTc/99Mo utilisation
Keywords 99Mo/99mTc-generator
Radioisotope-concentrator188
Re
Introduction
99m
Tc is used in approximately 85 % of diagnostic imaging
procedures in nuclear medicine world-wide 188Re is
important radio-therapeutic radionuclide The expansion of
99m
Tc and 188Re application depends on the generator
availability However, the cost-effective utilisation of
99m
Tc and188Re generators and the quality of the generator
eluates are controlled by the 99mTc and 188Re generator
operation/elution management, which is determined by the
99m
Tc and188Re concentration in the generator eluate The injection dose activity of 99mTc- and 188Re-based radio-pharmaceuticals delivered in 1 mL solution (99mTc- or
188
Re- concentration, MBq/mL) is an important factor in determining the quality of 99mTc based SPECT imaging diagnosis or 188Re-based radiotherapy, respectively Gen-erally 99mTc and 188Re eluates are produced from the generators in fixed volume and the 99mTc and 188Re con-centration of the eluates decreases with the life time of the generators due to radioactive decay of parent nuclides
99
Mo and188W, respectively Consequently, the useful life time of the generator is also a function of available99mTc and188Re concentration of the eluate Moreover, the99mTc also decays to99Tc during his build-up from the decay of
99
Mo This process not only reduces the effectiveness of
99m
Tc/99Mo activity utilisation (i.e a large quantity of
99m
Tc activity is wasted and the generator is non-eco-nomically exploited), but also it makes the specific activity (SA) of 99mTc continuously decreased The low SA may cause the labelling quality of 99mTc eluate is degraded This means that the elution of the generator at a shorter buildup time of the daughter nuclide will result in its better labelling quality and more effectiveness of 99mTc/99Mo activity utilisation In contrast, the99mTc elution performed
at shorter build up time (‘‘early’’ elution) will result a lower
99m
Tc yield and thus yields an eluate of lower 99m Tc-concentration These facts show that a high labelling quality solution of clinically sufficient99mTc concentration could be achieved if the generator eluate obtained at an
‘‘early’’ elution is further concentrated by a certified radioisotope concentrator device Obviously, the radioiso-tope concentrator may not only has positive impact on the extension of useful life time of the generators, but also is capable to increase the effectiveness of 99mTc and 99Mo
V S Le N Morcos Z Bogulski
Cyclopharm Ltd, Lucas Heights, Nsw, Australia
V S Le (&)
MEDISOTEC, Gymea, Nsw, Australia
e-mail: vansole01@gmail.com
123
J Radioanal Nucl Chem
DOI 10.1007/s10967-014-3439-9
Author's personal copy
Trang 4utilisation by performing the early elutions of the generator
at any time before maximal build-up of 99mTc This fact
has been proved with the performance of the radioisotope
concentrator device developed at Cyclopharm Ltd, which is
reported in this article
Experimental
Materials and methods
99m
Tc-generator was supplied from ANSTO (Australia)
Functional sorbent and strong cation exchange in silver
form were provided by MEDISOTEC and IC-Ag resin was
purchased from ALTECH Associates Aust Pty Ltd
Radioactivity of 99Mo and 99mTc was measured using
Capintec radioisotope dose calibrator Gamma-ray
spec-trometric assays were performed using an Ortec
gamma-ray spectrometer coupled with HpGe detector, which was
calibrated using a standard152Eu radioisotope solution
Radioisotope concentration process
A multi-elution, radioisotope concentrator device [1 3],
in-line eluted via evacuated-vial and through disposable
sterile filters was developed to increase the concentration
of 99mTc in the elution of aged commercial 99mTc
gener-ators A self-shielded radioisotope concentrator device
(Fig.1) was created based on a newly developed sorbent/
concentrator column which selectively retains 99mTcO4
-ions.99mTc concentration is performed in two steps First, a
standard elution of the generator through a tandem of: (1) a
competitive ion-selective (CIS) column (Silver-form of
strong cation exchange resin or IC-Ag resin) and (2) a
sorbent (Isosorb-FS-01) concentration column of the
con-centrator is performed with 5 or 10 mL saline The Cl
-and MoO42- ions are retained on CIS column by forming a
stable AgCl and Ag2MoO4 precipitates, while 99mTcO4
-ions retained on the Isosorb-FS-01 sorbent by an anion
exchange reaction 99mTc is then eluted from the
concen-trator column with \1.0 mL saline into an evacuated vial
through a Millipore filter and is ready for injection The
design of the device in form of a disposable cartridge was
optimised to make elution process effective, simple, sterile
and radiation safe Disposable cartridge was designed for
5–10 elutions
The early elutions were also performed at the 6 h
build-up times to evaluate the effective utilisation of 99mTc
generator achieved with an early elution regime, for which
the99mTc-yield ratio (Ry) factor was used as described in
the following sections Gentech 99mTc generators of
110 GBq activities eluted with 10 mL saline was chosen to
test our radioisotope concentrator device
Design of Concentrator Device [4,5]
In general, the performance of the concentration process is characterized with the concentration factor n,
n¼ c2=c1
For a concentration process of solute recovery yield (k), the following mass balance is established:
V2 c2¼ k c1 V1
Relating the above equations, the following is derived:
n¼c2
c1¼ k V1
V2 where, V1and V2are the solution volumes before and after concentration, respectively c1is the solute concentration in the solution before the concentration and c2is the solute concentration in the solution after the concentration using a given concentration process In individual case of 99mTc concentration, c1is the99mTc radioactivity concentration in the eluate eluted from the 99mTc generator and c2 is the
99m
Tc radioactivity concentration in the 99mTc solution concentrated using a given concentration process
All the chromatographic column concentration pro-cesses are described by the following basic equations
V1 ¼ Vmþ KS S where S¼ mc S and KS¼ KW= S
If V2 is given as a designed value, the concentration factor (n) is evaluated based on the above equations Assuming the dead volume of the concentration column
Vm V2), the concentration factor (n) is assessed for the designing of the concentrator column as follows:
Fig 1 Radioisotope concentrator device with standard accessories
a and the radioisotope concentrator device coupled with 99mTc generator for in-line elution/concentration of 99m Tc eluate b
Trang 5n¼ k V1
V2¼ k Vm
V2 þ KS S
V2
¼ k KS S
V2
where, KS(mL/m2) and KW(mL/g) are the area and weight
distribution coefficients of the solute (99mTcO4
-) in a given sorbent-solution system, respectively; S is the surface area
of the sorbent loaded in the column (m2); mcis the weight
of sorbent loaded in the column (g); S is the specific
sur-face area of the sorbent (m2/g)
Results and discussion
Use of radioisotope concentrator for increasing
the generator life time
As a result obtained from our project, the 99mTc eluate
was concentrated more than 10-fold with a 99mTc
recovery yield of [85 % using this radioisotope concen-trator device The increase in 99mTc concentration in the eluate enhances the utilisation of technetium in Technegas generator-based lung perfusion (3.7–9.25 GBq/mL) and other SPECT (740–1,110 MBq/mL) imaging studies 10
or 20 repeated elutions were successfully performed with each cartridge coupled to the 10 or 5 mL saline solution-eluted generators, respectively So, each cartridge can be effectively used for 10 days in the hospital environment for radiopharmaceutical formulation This fact also shows that when a bolus 99mTc-solution is needed to be con-centrated, the concentration factor n =50 can be achieved The useful lifetime of the 99mTc generator (Table1) was significantly extended from 10 to 20 days for the generators of 11.1–111 GBq activity, respectively This means that about 20 % of the generator activity is saved by extending the life time of the generator as
Fig 2 Gamma-ray spectra of
99m Tc-solutions: a, Spectrum of
unprocessed99mTc-generator
eluate; b, Spectrum of
concentrated99mTc-eluate
Table 1 Effect of radioisotope concentrator on 99m Tc-generator useful life
Radioactivity
of generator, GBq
Life time of generator useful for clinical SPECT imaging (days)
Life time of generator useful for the Cyclomedica Technegas Generator (days)
Without99mTc concentration
With post-elution concentration of99mTc
Without99mTc concentration With post-elution
concentration of99mTc
J Radioanal Nucl Chem
123
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Trang 6shown in Fig.4b The 99Mo impurity in the 99mTc
solu-tion eluted from the Gentech generator was totally
elim-inated by this radioisotope concentrator device (Fig.2)
Use of radioisotope concentrator in optimisation
of the generator elution to increase99mTc-activity yield
and effectiveness of99Mo utilisation [5,6]
The radioisotope concentration process not only has
posi-tive impact on the extension of useful life time of the
generators, but also is capable to increase the effectiveness
of 99mTc and 99Mo utilisation by performing the early
elutions of the generator at any time before maximal
build-up of99mTc
The 99mTc activity yield of the generator can be
increased by performing an optimal regime of multiple
‘‘early’’ elutions (the generator is more frequently eluted)
combined with a process of 99mTc-eluate concentration
The method for evaluation of the effectiveness of early
elution regime in comparison with a single elution
performed at maximal build-up time of the generator is described as follows For this evaluation,99mTc-yield ratio (Ry) is set up and calculated based on quotient of the total
of eluted99mTc-elution yields (or99mTc-activity produced/ used for scans) in all i elutions (Eiis the index for the ith elution) divcan be increased by performing an optimal ided
by the maximal99mTc-activity (A99mTcðMaxÞwhich would be eluted from the generator at maximal build-up time tMax:
Ry ¼X
i ¼n
i ¼1
A99mTcðE
i Þ
,
A99mTcðMaxÞ ð1Þ
Starting from the basic equations of radioactivity build-up/yield A99m Tc Max ð Þand time (maximal build-up time,
tMax) for attaining the maximal activity build-up yield of daughter nuclide radioactivity growth-in in the radionu-clide generator system, the equation for calculation of the
99m
Tc-yield ratio (Ry) is derived as follows:
The decay scheme of 99Mo/99mTc system used in the calculation processes is present as follows
Fig 3 Kinetics of radioactive
decay/99mTc-activity build-up in
the generator eluted with an
early elution regime: a,99
Mo-activity; b,99mTc-activity
build-up from beginning; c,99m
Tc-activity growth after first
elution; d, 99m Tc-activity
growth/eluted at 6-h elutions; e,
99m Tc-SA in the system of
99m Tc-radioactivity build-up
from beginning
Fig 4 a, Effectiveness of
99m Tc activity utilisation of the
generator eluted with an early
elution program compared with
that normally eluted at the time
point of maximal 99m
Tc-build-up (The dashed line is
calculated using Eq 8 and the
solid black circles are
experimental results); b,
Recovery of residual99m
Tc-activity of expired generators
versus their originally calibrated
activities
Trang 7Radioactivity of99mTc nuclides in the generator:
A99mTc¼ k99m Tc N0; Mo b1 kMo
k99m Tc kMo
ðek Mot ek99m Tct
Þ
ð2Þ
The maximal build-up time (at which the maximal
99m
Tc-activity build-up/yield in 99Mo/99mTc generator
system is available):
tMax¼ ½lnðk99m Tc=k99 MoÞ=ðk99m Tc k99 MoÞ ð3Þ
Numbers of Tc atoms at build-up time t:
NTc ¼ N99 Tcþ N99m Tc¼ N0;Mo NMo
¼ N0;Mo ð1 ek MotÞ ð4Þ
Specific activity of carrier-included99mTc in the 99mTc
generator system or 99mTc-eluate is calculated by
combi-nation of Eqs.2and4as follows:
SA99mTc¼A99mTc
NTc
¼ 6:02213 108
k99mTcb1 e
k Mot ek 99mTct k99mTc
kMo 1
1 eð k MotÞ ðGBq=lmolÞ ð5Þ
99m
Tc-yield ratio (Ry) calculation for multiple early elution
regimes
The Ry value is calculated based on quotient of the
total 99mTc-elution yields eluted (or 99mTc-activity
pro-duced/used for scans) in all i elution numbers (Ei is the
index for the ith elution) divided by the maximal 99m
Tc-activity A99m Tc Max ð Þ
which would be eluted from the generator at maximal build-up time tMax The total99m
Tc-elution yields eluted in all i Tc-elutions is the sum of99m Tc-radioactivities at different elution number i A99m Tc E ð Þ i This amount is described as follows
X
i ¼n
i ¼1
A99m
TcðE i Þ¼ k99m Tc X
x ¼i1
x ¼0
h
N0;Mo ek Moxtb b1
kMo
k99m Tc kMo
ðekMotb ek99m TctbÞi
ð6Þ The maximal 99mTc-activity build-up/yield in
99
Mo/99mTc generator system described using Eqs.2and3
is as follows
A99m
TcðMaxÞ¼ k99m Tc N0; Mo b1 kMo
k99m Tc kMo
ðek MotMax ek99m TctMax
99m
Tc-yield ratio (Ry) is derived from the above Eqs.6,
7 as follows
Ry ¼
P
i ¼n
i ¼1
A99mTcðE
i Þ
A99mTcðMaxÞ ¼
P
x ¼i1
x ¼0
½ek Moxtb ðek Motb ek99m TctbÞ
ðek MotMax ek99m TctMaxÞ
ð8Þ
i is the number of the early elutions needed for a practical schedule of SPECT scans The build-up time (tb) for each elution is determined as tb=(tMax/i) x is the number of the elution which have been performed before starting a 99mTc-build-up process for each con-secutive elution At this starting time point no residual
Tc atoms left in the generator from a preceding elution
is assumed (i.e 99mTc-elution yield of the preceding elution is assumed 100 %)
The results of the evaluation based on the Eqs.2,5, and
8are described in Figs.3and4a As shown in Fig.4a, the
99m
Tc yield of the generator eluted with a early elution regime of build-up/elution time \6 h increases by a factor [2
Table 2 Effectiveness of 99m Tc elution performed with an early elution regime compared with that normally eluted at the time point of maximal 99m Tc-build-up
Early elution regime of
6 h99mTc-buid-up time
(4 elutions/day)
99m Tc-concentration (MBq/mL) 15,170.0 7,400.0–5,735.0 4,440.0–3,515.0 2,109.0–1,628.0 Total yield of generator elutions
per day (MBq)
15,358.7 25,289.5 15,540.0 7,292.7
Elution at maximal99m
Tc-build-up time (tMax= 22.86 h)
(One elution/day)
99m Tc-concentration (MBq/mL) 3,071.0 2,331.0 1,435.6 673.4 Total yield of generator elution
per day (MBq)
15,358.7 11,655.0 7,178.0 3,370.7
Generator activity at calibration day (day 1, 8:00 AM) is 19.425 GBq 99 Mo or 17.0 GBq 99m Tc; Solvent is 5 mL saline; Generator is coupled with Ultralute concentrator device; Final concentrated 99m Tc solution volume is 1.0 mL
J Radioanal Nucl Chem
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Trang 8With the utilization of99mTc concentrator device which
give a final99mTc-solution of 1.0 mL volume, the
experi-mental results reported in Table2 using a *20 GBq
generator as an example confirmed that the concentration
and the yield of99mTc solution eluted with a 6-h
elution-regime is much better than that achieved with the elution
regime performed at the maximal build up time (22.86 h)
The effectiveness of this early elution mode was also
confirmed experimentally in the prior-of-art of68Ga/68Ge
generator [7]
Conclusions
We conclude that the radioisotope concentrator device
functioned well and is robust in operation This device will,
to some extent, mitigate the global 99mTc crisis The
extension of the99mTc-generator life time can save about
20 % of the generator activity.99mTc concentrator device
also allows performing an optimal regime of multiple
‘‘early’’ elutions, under which the generator will be eluted
at the time before establishment of radioactive decay
equilibrium in the99mTc/99Mo system This elution regime
will increase the99mTc activity use and specific activity of
the99mTc eluate by a factor of [2 All these features of the
99m
Tc concentrator device benefit the economic use of the
generator for users, the improved quality of labelling/scan for radiopharmacies, the reduced residual radiation dose of
99
Tc for patients, and the lowered cost of scan for patients Thus there is an increase in the effectiveness of 99Mo utilisation
References
1 Le VS, McBrayer J, Morcos N (2014) A radioisotope concentrator, PCT International Publication Number WO2014/063198A1, http:// patentscope.wipo.int/search/en/detail.jsf?docId=WO2014063198& recNum=1&office=&queryString=ALLNAMES%3A%28Le%2C
?Van?So%29&prevFilter=&sortOption=Pub?Date?Desc&max Rec=7 Accessed 8 August 2014
2 Le VS, Morcos N, McBrayer J, Bogulski Z, Buttigieg C, Phillips G (2013) J Label Compd Radiopharm 56(Suppl 1):S190
3 Le VS, Morcos N (2013) J Nucl Med 54(S2):609
4 Le VS, Le MK (2013) Australian Patent AU2013903629, 20 September 2013
5 Le VS, Do ZH, Le MK, Le V, Le NT (2014) Molecules doi:10 3390/molecules19067714
6 Le VS (2014)99mTc Generator Development: up-to-date 99m Tc-recovery technologies for increasing the effectiveness of 99Mo utilization Sci Technol Nuclear Installations doi:10.1155/2014/ 345252
7 Le VS (2013) Rec Res Can Res 194:43–75