188W/188Re generator

8/10/2019 188W/188Re generator

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Review Article188W/188Re Generator System and Its Therapeutic Applications

A. Boschi,1 L. Uccelli,1 M. Pasquali,1A. Duatti,1 A. Taibi,2 G. Pupillo,2 and J. Esposito3

Dipartimento di Morfologia, Chirurgia e Medicina Sperimentale, Universita di Ferrara and INFN, Sezione di Ferrara,Via Borsari , Ferrara, Italy

Dipartimento di Fisica e Scienze della erra, Universita di Ferrara and INFN, Sezione di Ferrara, Via Saragat , Ferrara, Italy INFN, Laboratori Nazionali di Legnaro (LNL), Via dellUniversita , Legnaro, Italy

Correspondence should be addressed to A. Boschi; [email protected]

Received February ; Accepted April ; Published May

Academic Editor: Joao Alberto Osso Junior

Copyright A. Boschi et al. Tis is an openaccess article distributed under the CreativeCommons AttributionLicense, whichpermits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Te 188Re radioisotope represents a useul radioisotope or the preparation o radiopharmaceuticals or therapeutic applications,particularlybecause o itsavorable nuclear properties. Te nuclide decay pattern is through theemission o a principle beta particlehaving . MeV maximum energy, which is enough to penetrate and destroy abnormal tissues, and principle gamma rays ( =

155 keV), which can efficiently be used or imaging and calculations o radiation dose. 188Re may be conveniently produced by188W/188Re generator systems. Te challenges related to the double neutron capture reaction route to provide only modest yield othe parent 188W radionuclide indeedhave been one o the major issues about the use o188Re in nuclear medicine. Since the specic

activity o188W used in the generator is relatively low (


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Journal o Chemistry

: Examples o nuclear constants or nuclides in the 188Wproduction chain.

Nuclide Decay constant,

(s1)Cross-section,

(b)Values or resonance

integral,(b)186W . 187

W 8.09 10

6

. ; 188W 1.16 107 ; ; .187Re . 188Re 1.13 105 1015 cm2s1 yields

188W with a specic activity o only GBq/g []. Use

o this relatively low specic activity 188W requires largeramounts o alumina or the generator column, thus increas-

ing the eluent volume and decreasing the 188Re concentration(activity/volume (MBq/mL)) [,]. Te increase in specicactivity using very high ux reactors is dramatically illus-

trated or the production o188W rom enriched 186W by the186W(, ) 187W(, ) 188W pathway (Figure ). Te modest186W and 187W neutron capture cross-sections (Figure ), the

competing burn-up o the 188W product [], and the signi-icant sel-shielding that has been observed [,] are actors

that decrease the 188W specic activity.At the Oak Ridge National Laboratory (ORNL, Oak

Ridge,ennessee, USA), the high ux isotope reactor (HFIR),

production o 188W rom both 186W-enriched metal andoxide tungsten targets, has been evaluated over the pastseveral years [, ]. ungsten- having adequate specic

activity suitable or the production o188W/188Re generatorscan be accomplished also in only a limited number o theresearch reactors, that is, SM Reactor, RIAR, Dimitrovgrad,Russian Federation, and BR Reactor, Belgium.

.. Availability of Enriched 186W arget Material. Ideally,188W should be produced by neutron irradiation o enriched186W targets, especially or the subsequent preparation o

high activity 188W/188Re generators. Te use o enrichedtargets is also required to minimize co-production o otherradioactive species. In addition, the use o enriched targets

reduces the target volume considerably, since the W targetsare quite large because o the modest 188W productionyields. Furthermore, because o the relatively low specic

activity o 188W produced by the double neutron captureprocess, even at very high thermal ux, the highest specic

activity188W is generally sought to minimize the amount oadsorbent required or loading o the traditional aluminiumoxide adsorption type generator. Te irradiation o highpurity natural W results in much lower specic activity andrequires even higher levels o the alumina adsorbent [].Although large electromagnetically separated quantities o

highly enriched 186W are available on the world market andmechanical-driven (i.e.,) centriuge enrichment method has

also been demonstrated on a small scale, another strategyhas been demonstrated easility, that is the recovery o

nonactivated186W rom used generators, since only a small

raction o 186W is transmuted to 188W during the reactorirradiation process. By increasing the pH o the generatoreluent, salts o tungstic acid can be readily removed []. Teuse o ammonium hydroxide with peroxide, or instance, canremove >% o the available W rom the alumina column.Subsequent precipitation with nitricacid (chloride complexeshave limited solubility), recovery by centriugation and thenheating at high temperature, readily converts the W to theoxide, which could then conceivably be used or preparationo additional targets or neutron irradiation. Although long


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Journal o Chemistry

97.8%

186W 187W 188W 189W

187Re 188Re 188Os

37.9 b 64 b 12 b

76.4 b 17.0 h

69.7 d

n, n, n,

n,

F : Scheme or reactor production o188W.

decay periods would be expected to reduce the activity othe residual radioactivity to manageable levels, this recoveredW would still be radioactive with longer lived contaminants.arget abrication with this material would thus probablyrequire special handling. Nonetheless, this approach could

represent a possible method or recovery o the 186W targetmaterial.

A strategy currently used at ORNL [,] involves the

use o enriched metallic 186

W targets that are pressed intopellets and subsequently sintered at high temperature priorto neutron irradiation. Tis approach dramatically increases

the target density and thus the loading and 188W productioncapability per target, andabout g o these discs (/target)can be loaded into one HFIR hydraulic tube target assembly.Te issue o sel-shielding may need to be taken into account,as this decreases the specic activity compared with the use

o granular/powder targets []. Although the total 188Wactivity produced per target is higher with the pressed targets,since signicantly more target material can be used per target

holder, the 188W specic activity decreases as the mass o the

enriched186W increases. Although the key actors leading to

such a discrepancy are still not well understood, the specicactivity o the irradiated186W-enriched pellets is considerablyless (%) than the specic activity o the irradiated

granular/powder enriched 186W target [].

3. Processing of 188W

.. ungsten Metal and ungsten Oxide argets. Although avariety o postirradiation processing strategies are possible,

processing o188W has usually involved postirradiation basic

dissolution o 186W oxide targets and/or high temperature

oxidative processing o metallic enriched 186W targets [

]. Relatively large enriched

186

W targets are required toproduce multicurie levels o 188W. Use o granular/powderoxide targets can simpliy the processing, since dissolution insodium hydroxide solution with heating is straightorward.

Enriched 186W targets under powder orm are routinely used

or production o 188W at the SM reactor at the ResearchInstitute o Atomic Reactors (RIAR) in Dimitrovgrad, Rus-sia. However, although powder metal o oxide targets was

routinely used or 188W production in the ORNL HFIR ormany years [], transition to use o the highly enriched186W pressed and sintered targeted geometry was originally

explored as a strategy to increase the 186W mass per target[]. More recently, the pressed discs have become the target

Metal or oxide target

rapped as Na-perosmate

6N NaOH

HClStore as

stock solutionLoad to alumina

column

Air stream approx.

188W

191Os

750800C

Na2WO4 H2WO4

816 hOsO4

WO3

F : ORNL postirradiation processing scheme or pressed/sintered enriched 186W metal targets [].

o choice at ORNL because o the requirements or useo available hot cells and the need to minimize hot cellcontamination resulting rom potential release o the highlyradioactive powder. Subsequent removal o any radionuclideimpurities is possible, such as with ion exchange chro-matography as is used at RIAR []. Te purication pro-cedure is based on treating the sodium tungstate solutionin a mixture o acetic acid and hydrogen peroxide, withsubsequent passage through cation exchange resin []. operorm this procedure, the sodium tungstate basic solutionis evaporated to moist salts, and the residue is dissolved inacetic acid solution containing vol.% hydrogen peroxide.Te solution is passed through the column lled with the

KU- cation exchanger (an analogue o Dowex-). ungstenorms anionic peroxide complexesthat are notretainedby theresin, whereas many other metals, unable to produce anionicacetate or peroxide complexes, are retained in cationic ormand have distribution ratios higher than 2. Te tungstenperoxide complexes are destroyed by heating o the puriedsolution to C, with precipitation o tungstic acid. I

metallic granular/powder or pressed/sintered enriched 186Wtargets are used, as at ORNL, the irradiated target material isrst heated to C in a quartz urnace while a streamo air is passed over the target material or conversion totungsten oxide or subsequent dissolution in base, as shownin Figures and. In this case, the contaminating levels o


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Journal o Chemistry

Air in

Glass rit

Port A Port B

Stirring motor

Stirring barW target

Termocouple

10 amps

Voltagecontroller

Quartzreaction

vessel

Cell wall

Flow meter

Valveto control

owAir out

ygontubing (B)

BB

B

Bubbler/trapEmptytrap

Charcoallter unit

Cell hotOff-gas

Power line

Furnace

housing

Cell wall

40% o ull scale

750800C

F : Apparatus used at ORNL or postirradiation conversion o metallic enriched 186W targets to tungsten oxide [].

mosto the 191Os radionuclidic impurities arealso sweptawayrom the target or subsequent trapping in base. At ORNL,the resulting sodium tungstate stock solution is not puriedurther, since the possible presence o low amounts o the191Os and 192Ir impurities present in the 188Re generatoreluents used or radiopharmaceuticals preparation has beenshown to be without consequences.

.. Radionuclide Impurities. Both191Os (1/2= 15.4 d, gam-

ma emission at . KeV, %) and192Ir (1/2= 73.8 d, gam-ma emission at . KeV, %) radionuclides are producedduring irradiation o 186W targets; the levels are produceddepending upon the irradiation parameters. Although notyet documented in detail, it can be assumed that these twoimpurities are coproduced by a series o transormations

coming rom the decay o 190Os that is ormed during neu-

tron irradiation o enriched 186W []. However, at secularequilibrium, these two radionuclide impurities usually are

not detected in the gamma spectrum o188W and 188Re be-cause o the intensity o the keV gamma photon emitted

rom188

Re.Te presence o60Co in decayed samples o the 188Re elu-

ate rom188W/188Re generators probably results rom activa-

tion o the low levels o natural cobalt (59Co) present in theAl material used to construct the hydraulic tube units. It isassumed that, afer irradiation, small amounts o the Al basematerial probably accompany the irradiated 186W material,which is removed afer opening the hydraulic tube assembly.

Most o the 191Os is removed during the oxidative conversiono the metallic W target to tungsten oxide, and any remaining191Os and 192Ir is generally only detected in small amounts by

gamma spectroscopy ollowing decay o 188Re in the salineeluted bolus. Tese impurities are slowly eluted rom the

generators in only very small amounts. I the tandem cation/anion postconcentration system is used, as in the general

practice in most clinical centres, essentially all the 192Ir istrapped on the column during concentration.

ungsten- breakthrough can be also present in 188Re

eluates (with values typically in the 6 range). However, any188W breakthrough can be effectively removed by subsequent

postelution process by passage o the bolus through a small,commercially available alumina QMA Sep-Pak column [].

4. The 188W/188Re Generator System

.. Alumina Based 188W/188Re Generators. Alumina basedchromatographic generator systems,similar to those available

or 99mc, are prepared or obtaining188Re. At ORNL, active

acidicaluminium oxide is used to prepare the columns. ung-sten- with a maxima specic activity o GBq per gram

o tungsten as sodium tungstate in . mol L1 o NaOH,with a concentration o . GBq per millilitre, canbe used. Te

pH level o the Na2 188WO4solution (. mol L1 o NaOH)has to be adjusted to - with . mol L1 HCl, and therequired amount o activity is loaded onto the column undercontrolled vacuum pressure (ow rate: mL/min.). Te col-umn, placed in shielded housing and handled inside appro-priate acilities, is washed with mL o .% NaCl solution(normal saline) and, afer allowing growth o the 188Re,eluted with mL o saline.able summarizes the charac-teristics o the commercial 188W/188Re generators available inthe world market.

Rhenium- having very high radionuclidic and radio-chemical purity(>%) canbe elutedrom the alumina basedgenerator with high elution efficiency (>%). Nonetheless,


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Journal o Chemistry

: Te characteristics o the commercial188W/188Re generators.

Institution/suppliers Strength Column material Specic activity o W- Remarks

ORNL, N, USA . GBq (mCi) to GBq

( Ci) cGMP system Alumina GBq (-Ci)/g > generators since .

Dimitrovgrad, Russia .GBq (. Ci) Sterile

cGMP system

Alumina GBq (Ci)/g Regular production and supply.

IRE, Belgium Up to . GBq (. Ci) Alumina GBq ( Ci)/g Generator is available with an

automatic concentration module.

IM AG, Germany Unknown Alumina GBq ( Ci)/g Regular production and supply.

Polatom, Poland . GBq (mCi) cGMP

systemUse o99Mo/99mc

column system GBq ( Ci)/g Regular production and supply.

IDB, Holland .. G Bq ( m Ci) Alumina Unknown Regular production and supply.

most ofen the 188Re eluted rom an alumina column chro-matography generator is not suitable or the direct ormula-tion o radiopharmaceuticals; a postelution concentration o

the generator eluent solution is essential to obtain 188Re O4having radioactive concentration sufficient or radiopharma-ceutical ormulation.

... Postelution Concentration of 188Re Perrhenate from the

Generator. Te use o low specic activity 188W and o oldgenerators results in low radioactivity concentrations o the

eluted 188Re perrhenate, which is ofen not suitable or ra-diolabelling o biomolecules. Postelution concentration is es-sential in such cases. Reports in the literature [,] oneffective postelution concentration o188Re using tandem ionexchange columns prompted an exploration o possible

means o postelution concentration o the 188Re perrhenateeluate. Postelution concentration o no-carrier-added 188Reperrhenate is based on its selective retention on a tiny anionexchange column and subsequent recovery in a small volumeo suitable eluent. Tis concentration o perrhenateis possibleonly when the 188Re eluate is ree o any other macroscopicanionic species. Tree different methods o postelution con-centration can be used, as described below.

Use of IC-Ag and Sep-Pak Accell Plus QMA Anion ExchangerColumn. Te technology developed at ORNL uses a Maxi-Clean IC-Ag; Ag+ orm cation exchanger cartridge (AlltechAssociates, USA) and a Sep-Pak Accell Plus QMA anion

exchange cartridge (Waters Corporation, Milord, USA) wasused in the rst method o postelution concentration, asreported by Guhlke et al. []. Te Maxi-Clean IC-Agcartridge was conditioned with mL o deionized water.

Rhenium- eluate obtained rom a 188W/188Re generator in mL o normal saline solution was reedo macroscopic Cl

ions as AgCl precipitate by passage through an Alltech IC-Ag+

cation exchange cartridge. Tis 188Re perrhenate eluate reeo chloride anion was then passed through the small Sep-Pak Accell Plus QMA anion exchange cartridge ( mg) toretain the perrhenate and was subsequently reeluted with a

very small volume ( mL) o normal saline. Te effluent romthe IC-Ag cartridge and a ew mL o deionized water used or

washing were measured to assess any loss o188Re activity in

the concentration process. Using this method, 188Re yield o793% was obtained, with a concentration actor o about .

Te 188W breakthrough was well below104% and at timeswas undetectable. In Figure a schematic drawn o 188Regenerator and concentration system with IC-Ag and Sep-Pak Accell Plus QMA anion exchanger column is reported.Te complete generator setup consists o an attachment orthe generator effluent or ow through an alumina QMA

SepPak, which effectively removes low levels o any 188Wbreakthrough and then through a tandem silver-cation/QMA

anion column or concentration o the 188Re eluate to usableradioactive concentration.

Use of Dowex X and AgCl Column. A Dowex X anionexchanger (Cl-orm, mesh) with a capacity o

meq/g (Sigma Chemicals) and extra pure AgCl were usedin this method o postelution concentration []. Between and mg o Dowex X resin was taken in a mL syringeand placed in a polypropylene tube ( mm mm) witha ew millilitres o water. Te other end o the tube waspacked with glass wool. Both ends o the tube were tted withminiature barbed polypropylene ttings. en millilitres onormal saline solution was passed through the resin columnand washed with mL o water ( bed volumes o the resincolumn). Between and . g o commercial AgCl salt wastaken in a glass column ( mm mm) with a sintered disc(G-), closed with a silicon rubber septum, washed with aew millilitres o deionized water, and used. Between and

mL o 188

Re eluate in normal saline obtained rom thegeneratorwas passed through the Dowex X anion exchangecolumn (placed in appropriate shielding) at a ow rate o - mL/min using controlled vacuum pressure. Te activities inthe effluent rom the Dowex column and in the subsequentwashings with a ew millilitres o deionized water weremeasured to assess the adsorption o the perrhenate. Tesewere treated as radioactive waste and appropriately disposed

o. Te no-carrier-added 188Re perrhenate adsorbed on thetiny anion exchange column was reeluted with - mL o

.moldm3 NaI solution and passed through the AgClcolumn ( g, mm mm) placed in proper shielding (-

mm o lead). Te effluent o 188Re perrhenate obtained by


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Journal o Chemistry

solution (925/1850

MBq/mL)

(elution solution)

Alumina columnis inserted in the elution lineafer the generator to trapany low levels o ungsten-188 breakthrough rom thegenerator.

Tree-way valveor water wash

and salineelution

Anionic trappingcolumn is used or

trapping theRhenium-188

ollowing passageo the bolus

through the silver-cation trapping

column

Tree-way valveor waste

Re-188collection vessel

Concentrationsystem in lead

shield

1 mL/min saline

1020 mL o elution

Silver cationic cartridge

is used or t rapping the chloride anion rom

the saline eluent using the tandem

column trapping system

>18.537 GBq/mL

Concentrated to% o 188Re generated could beeluted with .% saline solution, with high radionuclidic,radiochemical, and chemical purity and appreciably highradioactive concentration suitable or radiopharmaceuticalapplications. Application o titanium polymer prepared bythe polymerization reaction o iCl4 with isopropyl alcohol

or the preparation o a 188W/188Re generator and the elution

characteristics o188Re were studied by Venkatesh et al. [].


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Journal o Chemistry

For the synthesis o the polymeric titaniumadsorbent, tita-nium tetrachloride was mixed with isopropyl alcohol in theratio o : in a beaker with vigorous stirring. Te materialobtained was water soluble. o make this into an insolublepolymer, itwas heatedor h atC. Tisproduct wasinsol-uble in water and in most o the mineral acids and alkaline.

Tedried cake was ground to a ne powder and sieved witha mesh sieve. Te distribution ratio () o

188W in. mol dm3 HNO3 was determined at different time inter-

vals and the results indicated that about min is requiredto reach the equilibration. In all subsequent experiments,the polymer was adsorbed with the 188W activity or min.

It was observed that the maximum adsorption o 188W astungstate on thetitanium polymer occurred at pH -. While

both 188W-tungstate and 188Re asperrhenate were adsorbed,when eluted with saline, perrhenate exhibited arless affinity(approximately -old lower) or the matrix. In order toestimate the saturation capacity o the titanium polymer and

the concentration at which breakthrough begins, adsorptiono 188W on the titanium polymer was determined underdynamic conditions using an ion exchange chromatographiccolumn in the presence o different carrier concentrationso tungsten in the eed. Te breakthrough capacity andsaturation capacity o tungsten were ound to be and mg/g, respectively, indicatingthatapproximately mg otungsten per gram o titanium polymer canbe loaded withoutany breakthrough being observed. A process demonstration

run was carried out with this adsorbent using mCi o188W,

and the elution behavior o the 188Re was studied. It wasobserved that only about % o the 188Re on the columncould be eluted with saline, but that approximately% o this

was eluted in the rst mL. Further study o this materialis needed and will be done as the next step in generatordevelopment.

Monroy-Guzman et al. [] prepared 188W/188Re gener-

ators based on188W-tungstates and hydroxyapatite. Te tita-nium tungstate gels were synthesized rom tetrabutyl orthoti-

tanate and sodium 188W-tungstate solutions. Gels were pre-

pared using 188W-tungstate solutions o our different pHvalues (in the range o .) at a i : W molar ratioo : . Te gels were stirred and dried or . h at Cand then placed on polyethylene columns. Te zirconiumtungstate gels were prepared rom zirconium ethoxide solu-

tions and sodium

188

W-tungstate solutions ollowing theprocess described above. Gels were prepared using 188W-tungstate solutions o our different pH values at a Zr : Wmolar ratio o : . Te columns were washed with mLo .% NaCl and were eluted every three days or a period

o three months. Tey ound that the pH level o the 188W-tungstate solution used or the preparation o the titanium

and zirconium 188W-tungstate based generators inuence

the efficiency and the 188W breakthrough o the generators.Both parameters decreased when the gels were synthesized

with more acidic 188W-tungstate solutions. Te best 188Reelution efficiency (%) was obtained rom the titanium188W-tungstate based generators; however, the lowest 188W

6 7 8 9 10 11 12

0

100

200

300

400

500

pH

o188W/188Re with HAP-PO4

F : Separation actors o tungsten and rhenium (W/Re) onhydroxyapatite [].

breakthrough (.%) was obtained rom the zirconium 188W-

tungstate based generators. Te 188Re radiochemical purityobtained rom both types o generator is less in the gels

prepared with basic 188W-tungstate solutions (%) than

in those prepared with acidic 188W-tungstate solution, which

had a 188Re radiochemical purity o %.

TeW/Reseparation actors shown inFigure indicatethat tungsten andrhenium canbe readily separatedwith .%NaCl solutions at pH levels below .. Based on these data,hydroxyapatite based generators were constructed using our.% NaClsolutions at pH ., ., ., and . (series A), andusinghydroxyapatite particles o threesizes (series B). Resultson the perormance o these generators are shown in Figures

and. For all the 188Re eluates obtained in both series, thepH was ., the phosphate concentration was greater than ppm, and the radiochemical purity was greater than

%. Te lowest 188W breakthrough and highest averageelution volumes were obtained in the generators eluted with.% NaCl solution at pH . and with hydroxyapatite

particles between and m in size. Te efficiency o the188W/188Re generators decreased with the pH value o theNaCl solution, but the particle size o the hydroxyapatiteappeared to have no signicant effect. Te mean efficienciesobtained were about %, whereas the elution volumes and188W breakthrough values decreased with a decrease o thehydroxyapatite particle size and with an increase o the pH

value o the NaCl solution. Te generators in series A and Bshowed that phosphate ions are released during the elution

o188Re, leading to the proposal to wash the generators afer

elution with .% NaCl solutions, using . mol dm3 CaCl2or . mol dm3 NaH2PO4solutions, in order to avoid thedissolution o hydroxyapatite.


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Journal o Chemistry

5.4 5.6 5.8 6.0 6.2 6.4 6.6

0.1

1

10

100

1000

NaCl solution pH

Eluate volume (mL)

Eluate pH188

Re elution efficiency (%)188W breakthrough (%)

188Re radiochemical purity (%)

188Re elution phosphates (g/cm3)

F : Perormance o the hydroxyapatite based 188W/188Regenerators as a unction o the .% NaCl solution pH (series A)[].

20 40 60 80 100 120 140

0.1

1

10

100

1000

160

Hydroxyapatite particle size (m)

Eluate volume (mL)Eluate pH188Re elution efficiency (%)

188W breakthrough (%)

188Re radiochemical purity (%)

188Re elution phosphates (g/cm3)

F : Perormance o the hydroxyapatite based 188W/188Regenerators as a unction o the hydroxyapatite particle size (seriesB) [].

A third series o generators (series C) was then abri-cated and evaluated using the method previously described.Te perormance o these generators as a unction o theeluent is shown in Figure . Washing the generators with

. mol dm3 CaCl2or . mol dm3 NaH2PO4 solutions

100

0.1

1

10

0.01

Eluent

Eluate volume (mL)188Re elution efficiency (%)

188Re radiochemical purity (%)Eluate pH

NaCl0.9%CaCl20.01 M NaH2PO40.01 MNaCl0.9% NaCl0.9%

188W breakthrough (%)in CaCl20.01 M

188W breakthrough (%)in NaCl0.9%

Hydroxyapatite based188 W/188Re generators

F : Perormance o the hydroxyapatite based 188W/188Regenerators as a unction o the eluent (series C) [].

afer elution with .% NaCl solutions caused an increase othe 188W breakthrough in the 188Re eluate.

However, there wasno apparent effect on the188Re elutionefficiency, the eluate pH, or the radiochemical purity. Te

presence o phosphate ions in the 188Re eluates shows that thehydroxyapatite continues to dissolve.

5. 188 Re-Radiopharmaceuticals

.. Reduction of the etraoxo Rhenium- Anion. Rhenium- is a-emitting nuclide that is currently attracting muchinterest as a potential candidate or therapeutic applica-tions because o its useul nuclear properties and avail-ability. Another important advantage o employing 188Re-radiopharmaceuticals comes rom the easy availability othis radionuclide, which is produced through a transportablegenerator system under the chemical orm o the tetraoxo

perrhenate anion [188ReO4] in physiological solution. Tis

situation, thereore, parallels completely that o the nuclide99mc, which is obtained through the 99Mo/

99mc generator

system in the orm o [mc O]

, which always consti-

tutes the starting compound or preparing 99mc-radio-

pharmaceuticals. Likewise [188ReO4] is the ubiquitous start-

ing compound or the preparation o 188Re-radiophar-maceuticals. However, since technetium and rhenium belongto the same group o the transition series, the similarities

between 99mc and 188Re radiopharmaceuticals are evenmore pronounced. In act, owing to lanthanide contraction,technetium and rhenium have almost identical ionic radii.Tis indicates that, when these two elements orm analogouscomplexes having exactly the same chemical structure andstability and differ only in the metal center, these species


9/15


10/15

Journal o Chemistry

Collecting vial

SCE

V4 V5 V6

A B

C

R

Alumina Sep-Pak

Waste

FilterSonde 1

Sonde 2

V3V2V1

188W/188Re generator

P1

QMA

C18

P2Maniold

V7

Filter

F : Flowchart illustrating the automated system or the preparation o188Re-lipiodol [].

yieldwas low and the 188Re complex wasnot stablyretained in

hepatoma. Tis result reects the difficulty in obtaining 188Recomplexes in satisactory yield and the intrinsic instability

o oxo-rhenium complexes. Following the same labellingstrategy, an efficient procedure or labelling lipiodol with188Re, at tracer level and under sterile and pyrogen-reeconditions was developed, and the resulting radiolabelledproduct has been successully employed in the treatment oa number o HCC patients []. Tis labelling procedure wasbased on the preliminary preparation o the highly lipophilic

complex bis(diethyldithiocarbamato) nitrido [188Re] rhe-

nium (188ReN-DEDC) carried out using a two-vial, reeze-dried kit ormulation. Tis complex was, subsequently,mixed with lipiodol to yield the nal radiopharmaceutical.Te whole preparation involves different steps and com-plex manipulation o high-activity samples that dramatically

increases radiation exposure o the operator, particularlyin routine treatment o HCC patients. o overcome thisproblem, an automated system or the remote controlled

preparation o 188Re-lipiodol using this labeling methodhad been developed. Tis synthesis module [] (Figure )was designed to accommodate the two-vial kit ormulationdeveloped previously or manually conducting the prepara-

tion o188Re-lipiodol in a hospital radiopharmacy. Troughthis procedure, the hydrophobic lipiodol was used as asolvent or solubilising the highly lipophilic radiocompound188ReN-DEDC that, in turn, remained strongly trapped intothe organic phase. Specically, the two-vial kit ormula-

tion allowed the high-activity preparation o188ReN-DEDC.

Te reeze-dried kit was, successively, produced at the Insti-tute o Isotopes in Budapest, Hungary, ollowing currentregulatory requirements. Te preparation o the complex188

ReN-DEDC was relatively simple as it involved mixing o[188ReO4] with reagents in vial A and glacial acetic acid

to yield the intermediate [188ReN]2+ core. Tis group was,

then, converted into the nal complex 188ReN-DEDC byaddition o the content o vial B to vial A. Results showedthat this preparation afforded 188ReN-DEDC in high yield(>%). However, the critical step exposing the operatorto the highest radiation burden is when withdrawal o thesupernatant aqueous layer was perormed by means o asyringe. As this operation had to be carriedout afer labelling,it required the manipulation o highly radioactive samples. Itwas ound that the automated process was an ideal solutionto overcome this important drawback. In the automated

system, the content o reconstituted vials A and B weretranserred to a reactor vial (R) where the preparation othe nal complex 188ReN-DEDC was obtained by heating atC. Most importantly, the manual separation was replacedby a chromatographic procedure carried out by passing thereaction solution pumped out o vial A through a C Sep-

Pak cartridge onto which the complex 188ReN-DEDC wasquantitatively retained. Tis allowed the elimination o the

aqueous solvent and o any residual [188Re] perrhenate. Since

[188ReO4] is a highly hydrophilic substance that cannot be

dissolved by nonpolar solvents, it constitutes an undesiredcontaminant in the nal radiopharmaceutical that may causerelease o activity rom the target and uptake in other


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Journal o Chemistry

O

P

O

N

O

P

O

O

PNP3

O

P

O

N

O

P

O

O

PNP5

S

N

DEDC

SNaO

O

N

S

BDODC

N

S

SNa

BDPC

H2N

N

S

Me

SMe

DCZ

HS

O OH

H2OS

HS

O

OH NHAc

H2cysNAc

HS NHHNS

SNa

F : Chemical structure o PNP, L, and B ligands [].

nontarget organs, particularly in the thyroid gland. Even

i the complex 188ReN-DEDC ormed with high RCP, thepurication step always ensures that all polar radioactiveimpuritiescan be efficiently separated rom the reaction bulk.Tus, their complete removal appears as a sharp improve-ment with respect to the nonautomated preparation. Te

lipophilic complex was, subsequently, recovered by elutingthe cartridge with absolute ethanol and then sterilized bypassing the resulting solution through a . m lter beorecollecting it into the nal recovering vial C. Lipiodol wasnally introduced into vial C afer evaporating ethanolby short heating under a nitrogen stream, thus causingthe complete dissolution o the radioactive complex. Teradiochemical yield and chemical identity o188ReN-DEDCwere checked by HPLC chromatography afer preparationin the reactor vial R, and afer evaporation o ethanol rom

vial C (Figure ). Results showed that the complex wasproduced in high yield (>%) and that it was recovered

unaltered rom vial C. Current advantages include a reducedoperator assistance during the production process with aconcomitant dramatic reduction o radiation exposure, andthepossibility to affordhigh activity samples o188Re-lipiodol(> GBq), thus allowing the daily treatment o a relativelylarge number o HCC patients. Whole-body -imaging oHCC patients within h o intrahepatic arterial admin-istration o 188Re-labeled lipiodol demonstrated excellentuptake in the lesion without signicant activity in the gutand lungs []. Stable retention o activity in hepatomawas revealed at h afer administration with minimalincrease in colonic activity and some uptake in the spleen.In particular, no lung activity was observed in any patient

as opposed to treatment o hepatocellular carcinoma with131I-lipiodol where lung uptake approaches % o adminis-trated activity.

.. New Methods for the Preparation of Rhenium- Nitride

Radiopharmaceuticals. Recently a novel procedure or thepreparation o nitride 188ReN radiopharmaceuticals was re-ported []. Te novel HO2C-PEG-DCZ nitrido nitro-gen atom donor or the preparation o 188Re radiophar-maceuticals containing a metal nitrogen-multiple bond HO2C-PEG-DCZ was obtained by conjugation oN-methyl-S-methyl dithiocarbazate [H2NN (CH3)C(=S)SCH3,HDCZ] with polyethylene glycol (PEG). Asym-

metrical heterocomplexes o the type [188Re(N)(PNP)(B)]0/+

(PNP = diphosphine ligands, B = DBODC, DEDC, NSH,HOS, CysNAc, HDCZ) and symmetrical nitride com-

pounds o the type [188Re (N)(L)] (L = DEDC, DPDC) havebeen prepared in high yield by using the newly designed

nitride nitrogen atom donor HO2C-PEG-DCZ. InFigure is reported the chemical structure o PNP, L, andB ligands. A two-step procedure was applied or preparingthe above symmetrical and asymmetrical complexes. Terst step involved the preliminary ormation o a mixture o

nitride 188Re precursors, which contained the [188ReN]2+

core, through reduction o generator eluted 188Re-perrhenatewith tin(II) chloride in the presence o HO2C-PEG-DCZ. In the second step, the intermediate mixture wasconverted in either the nal mixed asymmetrical complexby the simultaneous addition o diphosphine ligand and thesuitable bidentate ligand B, or in the nal symmetricalcomplex by the only addition o the bidentate ligand L.


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Journal o Chemistry

N

MY

N

X

H

S

F : Schematic drawing o the molecular structure o 3 + 1nitrido complexes (X = S, N; Y = monodentate ligand; M = 99mc,188Re) [].

It was also demonstrated that the novel water soluble nitridenitrogen atom donor HO2C-PEG-DCZ did not show

coordinating properties toward the 188ReN core.More recently [] a new molecular metallic ragment or

labeling biologically active molecules with 99mc and 188Re is

described. Tis system is composed o a combination o tri-dentate -donor and monodentate -acceptor ligands bound

to a [MN]2+ group (M = 99mc, 188Re) in a pseudo square-

pyramidal geometry (Figure ). A simple structural model othenew metallic ragment wasobtainedby reacting theligand,-iminodiethanethiol [H2NS2 = NH (CH2CH2SH)2] andmonodentate tertiary phosphines with the [MN]2+ group

(M= 99mc,188Re). In the resulting complexes (dubbed 3 +

1 complexes), the tridentate ligand binds the [MN]2+

core through the two deprotonated, negatively charged, thiolsulur atoms, and the neutral, protonated, amine nitrogenatom. Te residual ourth position o the ve-coordinatedarrangement is occupied by a phosphine ligand. Te chem-

ical identity o these models 99mc and 188Re compoundswas established by comparison with the chromatographicproperties o the corresponding complexes obtained at the

macroscopic level with the long-lived

99g

c and natural Reisotopes. Te investigation was urther extended to comprisea series o ligands ormed by simple combinations o twobasic amino acids or pseudoamino acids to yield potentialtridentate chelating systems having [S, N, S] and [N, N, S]as sets o-donor atoms. Labeling yields and in vitro sta-bility were investigated using different ancillary ligands [].Results showed that SNS-type ligands afforded the highestlabeling yields and the most robust + nitrido complexes

with both 99mc and 188Re. Tus, this new chelating system

can be conveniently employed or labeling peptides and other

biomolecules with the [MN]2+ group.

6. Conclusion

Te availability o188W/188Re generators and the use o high

specic activity 188Re or a variety o important therapeuticapplications in nuclear medicine and oncology still continuesto be o widespread interest. Te attractive radionuclidic andchemical properties o188Re, and the possibility o obtaining188Re in-house and on demand make this generator systemideal or many applications. Tereore the development onew chemical strategies allows to obtain in very high yield

and in physiological condition 188Re-radiopharmaceuticalwhich gives a new attractive prospective to the developmento new Radiopharmaceuticals or therapy.

Conflict of Interests

Te authors declare that they have no conict o interests.

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188W/188Re generator

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