Journal of Nuclear and Radiochemical Sciences, Vol. 1, No. 1, pp. 15−18, 2000

15

Radiopharmaceutical Chemistry in Peking University (PKU)
Wang Xiangyun,* Wu Yonghui, Wang Yi, and Liu Yuanfang
Department of Technical Physics, Peking University, Beijing 100871, China
Received: October 13, 1999
In the past 15 years our research activities covered the following four aspects: (1) Labeling of monoclonal antibodies (McAb) with radionuclides. Both direct and indirect labeling methods by using various radionuclides werestudied. (2) Designing and synthesis of radiopharmaceuticals used for myocardial imaging. Two types of Tc
compounds were intensively studied: BATOs and complexes containing [99mTc≡N]2+ core and [99mTc=NAr]3+ core.
(3) Synthesis and screening of boron- and gadolinium-containing compounds for use in neutron capture therapy.
(4) Investigation of the coordination chemistry of Tc.

The Department of Technical Physics, Peking University consists of two specialities: nuclear physics and applied chemistry.
The applied chemistry speciality used to be radiochemistry
speciality before 1983. Now its research activities cover four
directions: radiopharmaceutical chemistry, material science,
environmental chemistry, and radiation chemistry. The
research on radiopharmaceutical chemistry began in 1983.
In the first 10 years our research was focused on labeling of
monoclonal antibodies (McAbs) with radionuclides. Bothdirect and indirect (i.e., via bifunctional conjugating agents)
labeling methods were studied. The labeled radionuclides westudied were 90Y, 99mTc, 111In, 111Ag, 169Yb, 188Re and 199Au.
Since 1992 we extended our interest to radiopharmaceuticals
used for myocardial imaging. Two types of compounds wereintensively studied: boronic acid adducts of technetium
tris(dioxime) (BATO) and complexes containing [99mTc≡N]2+
core and [99mTc=NAr]3+ core. In the meanwhile, we carried out
the investigations on relevant coordination chemistry of Tc inaqueous solution for increasing the knowledge of chemical
behavior of Tc in vivo.
In the recent five years we were involved in development ofdrugs used for neutron capture therapy (NCT). We havedesigned and synthesized some new boron compounds as well
as gadolinium compounds which have preliminarily been
proved to be concentrated in tumor cells to some extent bymeans of screening them in cellular and animal experiments.
The investigation of some subsidiary compounds, such as radiation sensitizers and p-glucoprotein inhibitors, are also being
undertaken.
1. Labeling of Monoclonal Antibodies with Radionuclides
In 1975 Kohler and Milstein1 developed a method for preparation of McAbs by fusion of an immunized spleen cell and an
osteoma cell. Their invention brought a new perspective toradioimmunodiagnosis and radioimmunotherapy. Althoughradioiodine can be easily labeled to intact McAbs, mostradioactive metal ions can not be tightly bound to them.
Two modalities for labeling of radioactive metal ions to
McAb have been developed until now. In the direct labelingmodality one or more -S-S- bonds in McAb molecule are first
reduced to -SH groups. The reduced McAbs are then incubated with a radionuclide in an appropriate oxidation state to forma metal-McAb complex via S-M bonds. In the indirect modality radionuclide ions are combined indirectly via a bifunctional
conjugating agent (BFCA). The latter uses one of its function*Corresponding author. E-mail: xywang@pku.edu.cn. FAX: +8610-6275-1873.

al group in conjugation with McAb, and uses its ligatinggroups to chelate metal ion. In the past 15 years we studied
the chemistry of labeling of McAb with various metal radionuclides by both direct and indirect methods.
1.1. Direct Labeling of Monoclonal Antibodies
1.1.1. Reduction of McAb. There are two types of disulfide
bonds in an antibody molecule, one in the same peptide chain(intrachain), and the other between two peptide chains (interchain). Unless the antibody is denaturalized, intrachain disulfide bonds are not reduced because they are deeply embeddedin the tertiary structure of the protein. The interchain disulfide
bonds outside the hinge may be reduced to form -SH groups.
Various reductants have been proposed to be used for this purpose. Stannous chloride was first used by Dreyer and Munze
and modified by Rhods,2 and then so-called pretinning method
has been very popular in the reduction process. However, theeasy hydrolysis of Sn2+ ions makes the method inconvenient inuse. 2-Mercaptoethanol (2-ME) was proposed by Bremer in1986 and perfected by Schwarz and Steinstrasser3 and now hascome to be accredited. Other reductants, such as sulfite, ascorbic acid, dithiothreose, thiosulfate, dithionate, are also used byother researchers. We have made an evaluative study on these
reductants. Based on our experiments the following conclusions were drawn:(1) 2-ME is a very good reducing agent for the conversionof disulfide bond to hydrosulphonyl groups. The reduction isquite mild and the labeling efficiency is usually high (≥95%).
Since 2-ME is a quite strong complexing agent for 99mTcO3+
and 188ReO3+, any excess of 2-ME after reduction of McAbs
must be removed by gel filtration to prevent its complexation
with 99mTcO3+ or 188ReO3+ in the subsequent step. The final
McAb solution is greatly diluted and has to be concentrated
again before use.4,5(2) Ascorbic acid (AA) is also a good reducing agent. The
reduction of McAb by AA is fast and complete. The excess of
AA does not interfere in the further reaction and can act as aprotecting agent against the oxidation of McAb by air.6(3) Sodium bisulfite (NaHSO3) reduces McAb a little bit
slower than ascorbic acid. A larger excess of bisulfite is needed in order to get the same reduction percentage for McAb in
comparison with ascorbic acid.7,8
1.1.2. Direct labeling of McAb with 188Re. Perrhenate ion
188( ReO4−) in saline was reduced with SnCl2 in the presence of
citrate−tartrate (molar ratio 1:3) at pH 5.2 for 40 min. Rectal
carcinoma antibody CL3 was reduced with NaHSO3 in 1000
times excess at pH 5.2 for 40 min. Ascorbic acid (500 times of
McAb) was then added as an anti-oxidizer. The labeling reaction was initiated by mixing of the above two solutions andlasted for 1.5 h. The labeling efficiency was higher than 95%© 2000 The Japan Society of Nuclear and Radiochemical Sciences

Wang

16 J. Nucl. Radiochem. Sci., Vol. 1, No. 1, 2000
99m

188

with colloidal Tc less than 3%. The Re-labeled CL3 wasstable in vitro to DTPA, but was not to cysteine. The
immunoactivity of 188Re-labeled CL3 was substantially maintained.8
Similar results were obtained by using ascorbic acid insteadof NaHSO 3 and citrate alone instead of citrate−tartrate
mixture.6
We feel that the intermediate complexing agent is important.
Its complexing ability towards 188ReO3+ should be stronger
than the weak (non-specific) binding sites of McAb, but weaker than –SH groups. It can prevent the formation of colloidal
SnO2 and Re(V). The strong complexing ability of it will slow
down the reduction of 188ReO4− and decrease the labeling efficiency.
1.1.3. Direct Labeling of McAb with 99mTc. Since the reduction of TcO4− is easier than ReO4− and TcO3+ is more labile
than ReO 3+ in respect to ligand substitution reactions, thereduction of 99mTcO4− and the labeling of McAb with 99mTcO3+
are usually combined to a single step. Stannous chloride(SnCl2) is nearly exclusively used for the reduction of 99mTcO4−
to 99mTcO3+. Various hydroxycarboxylic acids, such as citricacid, tartaric acid, glucoheptonic acid, etc. can be used as theintermediate complexing agent. The reduction-labeling reaction completes at pH ≈7 within 1.5 h. A labeling efficiency
higher than 95% can be achieved without difficulties.4, 5
1.1.4. Direct Labeling of McAb with 199Au. Tetrachloroaurateion (199AuCl4−) was converted to 199AuClS(CH2CH2OH)2 or
199
Au(SO3)23− and then labeled to reduced McAbs. The 199AuMcAb was quite stable towards thiourea in the absence of oxygen.7
1.2. Indirect Labeling of Monoclonal Antibodies.
Indirect labeling of McAbs with radionuclides was comprehensively reviewed.9,10
1.2.1. 111In. We used DTPA as a bifunctional conjugating
agent for labeling of McAb with 111In and obtained a labeled
McAb with a very high specific activity of 1.1×109 Bq/mg
antibody (30 mCi/mg antibody). The 111In-labeled McAb wasused for the diagnosis of colon carcinoma. Among 15 colon
carcinoma-bearing patients whose disease had been confirmed
by other diagnostic methods, 14 patients gave a positive reaction. The 111In was produced by bombardment of Cd target
with proton beam. A special separation and purification procedure was developed. The 111In product was proved in ultrahigh purity. Our experiment evidenced that only ultra highpure 111In could ensure a satisfactory 111In-labeled McAb. The
presence of any isotopic and non-isotopic impurity greatly
deteriorated the labeling quality.11−21
1.2.2. 99mTc. A new bifunctional conjugating agent N, N'-bis(L-cysteinyl) -L-lysine (BCL) was synthesized. It was conjugated to McAb (or its fragment Fab) and biotin by condensationof it with an ε-NH2 group on lysine residue. The functionalized McAb was then labeled with 99mTcO3+. In vitro and invivo experiments showed that 99mTc-BCL-McAb, 99mTc-BCLFab and 99mTc-BCL-biotin were quite stable.22,23
Metallothionein (MT) was also used as a bifunctional conjugating agent with satisfactory results. The conjugation of MT
to antibody was accomplished by condensation with glutaric
dialdehyde followed by the reduction of imine with NaBH4.24−26
N, N'-ethylene-bis-L-cysteine (EC) was used as a bifunctional chelating agent for 99m Tc labeling of McAbs. A new
conjugating agent N-hydroxyl-1,4-epoxy-cyclohex-5-ene-2,3di-carboxylimide (HONCE) and a water-soluble dehydrating
agent 1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide (EDC)
were used to accomplish the conjugation of EC with McAb.27,28
1.2.3. 188Re. Four new bifuctional conjugating agents weresynthesized: Bz-MA-Ala-Ala-EACA, Bz-MA-Ala-Gly-EACA,
Bz-MA-Gly-Ala-EACA, and Bz-MAG3-EACA (Bz=benzoyl,
MA= mercaptoacetyl, EACA=ε-aminocaproic acid). Our
strategy was simultaneous removal of protective group Bz andlabeling of the de-protected bifuctional conjugating agent with
188
Re followed by conjugation of 188 Re-MAG 3 -EACA to
McAb. The labeling efficiency was roughly 50%. The sixcarbon-atom EACA acted as a spacer between the McAb andthe 188ReOS2N2 moiety and thus ensured a relatively high labeling efficiency and a good immunoactivity of the antibody as
well. Both the in vitro and in vivo stability of 188Re-MAG3EACA-McAb were experimentally proved very high.29,30
1.2.4. 111Ag and 199Au. We found that 111Ag could be indirectly labeled to McAbs via metallothionein24 and 199Au via
thiomalic acid.31
1.2.5. 90Y and 169Yb. Yttrium-90 is a very good radionuclide
for therapy of tumor. 1,4,7,10-tetraaza-dodecane-1,4,7,10tetraacetic acid (DOTA) was tentatively used as a bifunctional
conjugating agent. The effort was frustrated by the slow reaction kinetics of DOTA with 90Y3+. If one lets 90Y3+ chelated by
DOTA first, then no active group can be used for formation a
peptide bond with McAb. Alternatively, if DOTA is first conjugated to McAb, the labeling with 90Y3+ will proceed painfully
slow at 37 oC. It was observed that the completion of the formation of Y3+-DOTA complex could be achieved by boilingfor 2h at pH ∼8.32,33
Ytterbium-169 can be labeled to IgG and McAbs throughTTHA.34
2. Myocardial Imaging Agents
2.1. Boronic Acid Adducts of Technetium Tris(dioxime)(BATO).35−39 We synthesized several new BATOs and determined the crystal structure of one of them. 35,36 The animal
experiments showed that none of these 99m Tc-BATOs was
superior to 99m Tc-CDO-MeB in myocardial imaging. 37,38
Similar rhenium compounds (BAROs) were also synthesized.
We developed a new method for preparation of BATOs byusing [99Tc (thiourea)6] Cl3⋅4H2O as the starting material. The
overall yield of 99Tc was about 60%.39
2.2. Complexes Containing [Tc≡N]2+ or [Tc=NAr] 3+. We
synthesized new complexes containing [Tc≡N]2+ core. The
ligands that we designed and synthesized include derivativesof xanthate,40 dithiocarbamate, dialkyl dithiophosphate, anddialkyl dithiophosphonates. Few of these complexes displayed
a good myocardial uptake (>1% ID) or cerebral uptake (>0.6%ID), and are worthy of further study. Complexes of[Tc=NAr]3+ showed a poor biodistribution, probably due totheir in vivo instability.41
3. Production of 186/188Re, 111Ag and 199Au
3.1. New Process for Separation of Radiorhenium fromProton-bombarded Tungsten Target. An Al2(WO4)3 target
bombarded with proton beam was dissolved in aqueous NaOH
solution, and then acidified to precipitate the bulk of
Al2(WO4)3 and leave the radiorhenium as *ReO4− in the solution. After filtration the *ReO4− was further purified by alumina gel chromatography. The process is simple and fast.42,43
3.2. Preparation of 186/188Re with High Specific Activity
by Szilard−Chalmers Effect. Rhenium-186 and -188 are
regarded as the best radionuclides used for radiotherapy andradioimmunotherapy. We prepared 186Re and 188Re with highspecific activity by the Szilard−Chalmers effect. A series ofrhenium complexes was synthesized and then irradiated withthermal neutrons (neutron flux: 1012 n/sec/cm2) for 1 h. The
recoiled radioactive rhenium atoms were separated by strippingthem from the dichloromethane solution of irradiated rhenium
compound with an aqueous solution. Various aqueous stripping
agents were tested. In the case of ReN(S2CNEt2)2, an enrichment factor of 210 and a chemical yield of 36% were achieved.
The product was in pure perrhenate form with specific activityof 0.72 GBq/mg Re (19.5 mCi /mg Re). Radiorhenium with

Radiopharmaceutical Chemistry in Peking Univ.
higher specific activity (>37 GBq/mg Re) could be obtained byirradiation with 1×1014 n/sec/cm2 neutron flux for 1 h.44
3.3. Preparation of Carrier-free 199Au. Gold-199 (Eβmax =0.30, 0.46 MeV, Eγ=0.158, 0.208 MeV, T1/2=3.15 d) is a potential radionuclide for medical use. It was produced by reaction198
Pt (n,γ) 199Pt (β−) and separated by ion exchange.45
3.4. Preparation of Carrier-free 111Ag. Silver-111 (Eβmax=1.035 MeV (92%), 0.69 MeV (6.80%), E γ =0.245 MeV(1.35%), 0.342 MeV(6.55%), T1/2 =7.45 d) was produced by
110
Pd(n, γ)111Pd(β−) and separated by anionic exchange resin.46
This radionuclide may be used for radiotherapy or radioimmunotherapy.
4. Neutron Capture Therapy Drugs47
4.1. Liposome-Encapsulated Gadolinium Complexes. 48
Liposome is an effective drug delivery agent for neutron capture therapy. Most of the publications are dedicated to thedelivery of boron compounds. We explored its feasibility for
gadolinium complexes. Liposome encapsulating gadolinium
complex (LGd) was prepared and characterized. The influenceof formulation factors, such as pH, ionic strength, buffer composition, and storage temperature and medium, upon the stability of the LGd was investigated. The rate constant of cellular
uptake and its dependence upon the concentration were comparatively studied in vitro for LGd and free gadolinium complex that was not encapsulated into liposome micelle. The
results indicate that transmembrane delivery of LGd is more
efficient than that of the free gadolinium complex. The uptake
in both cases follows a first-order kinetics. The kinetics ofeffluxion after cellular uptake was also studied for both LGd
and free gadolinium complex.
4.2. Boronated Glucosides.49,50 Two boronated methylglucosides, cesium bis(6-deoxo-2,3,4-tri-O-acetyl-α-D-methylglucoside-6-)sulfido-undecahydro-closo-dodecaborate(1-) andtetrabutyl ammonium 6-deoxo-2,3,4-tri-O-acetyl-α-D-methylglucoside-6-oxo-undecahydro-closo-dodecaborate(2-), weresynthesized and characterized by IR, 1HNMR and elemental
analysis. After removal of the acetyl groups by basic hydrolysis, their biodistribution was studied with mice bearing
hepatoma H22. The results show that they can be concentrated
in tumor to some degree (ca. 10 µgB/g tumor for an injection
dose of 45mg B/kg body weight). The concentration of boronin blood is relatively low (T/B≈2, where T and B denote theconcentration of boron in tumor and in blood, respectively).
Its clearance is quite fast.
4.3. Monovalent Organoboron Cations.51 Monovalentcations such as 201Tl+, 99mTc-MIBI, and 99mTc-tetrofosmin are
not only the most popular myocardial imaging agents but also
the tumor imaging agents because they are accumulated intumors to various degrees. Following this fact we synthesizeda new boron compound 1-(4-methylphenyl)-4-methyl-4dimethylamino-1-boron-2,6,dioxo-cyclohexane, which could
be protonated to an ammonium cation MeC6 H 4 B(OCH 2 ) 2
C(Me)NMe2H+ (compound a) at a biological pH, and threebis(ligand)dihydroborane (1+) cations [BH2D1D2]+ : D1=NEt3,
D2=4-methylpyridine (compound b); D1=D2=4-methylpyridine(compound c); D1=D2=2,6-dimethylpyridine (compound d).
We studied their biodistribution in Kunming mice bearing
sarcoma S180 and found that these compounds could be concentrated in tumor to some extent. The T/N (the ratio of theconcentration of boron in tumor tissue to that in normal tissue)
and T/B were 1.3−1.8 and 1.0−1.5, respectively. The maximum boron concentration was 2.1−3.2 µg/g (injected dose: 5
mg B/kg body weight). We found these compounds werehighly toxic, probably due to their in vivo instabilities.
Therefore, only very low dose could be used.
4.4. Boronated Porphyrins. 52 We synthesized a simple
boronated porphyrin, 5,10,15,20-tetrakis(4-(4,4-dimethyl-1,5-

J. Nucl. Radiochem. Sci., Vol. 1, No. 1, 2000 17
dioxo-1-boro-cyclohexyl) phenyl) porphyrin (TBPP). Since
the removal of the four protective groups (2,2-dimethyl-1,3propanediol) is extremely difficult, we directly used it for cellular and animal experiments. The ingestion of TBPP byosteoma cell SP20 from a 144 µmol/L TBPP culture solution
was 45 µgB/g cell. Approximately a half of the ingested TBPP
was excreted in 3 h in a TBPP-free culture solution. The
biodistribution of TBPP was studied with mice bearing
Hepatocarcinoma BALB/C. When the injection dose was 2.5
mg/kg body weight, the concentration of TBPP in tumor,
blood, liver, and brain were 0.51, 0.34, 2.9 and 0.80 µg/g,
respectively, at 6 h after injection. Since this compound issparely soluble in water, 2-hydroxypropyl-β-cyclodextrin wasadded.
4.5. Subsidiary Compounds
4.5.1. p-Glucoprotein Inhibitors. In some tumor cells themultidrug resistance gene (MDR) may be overexpressed,
resulting in high level p-glucoprotein on the cellular surface.
We are trying to develop an assay procedure based on 99mTcMIBI or 99mTc-tetrofosmin radionuclide imaging. We expect
to use this method to screen p-glucoprotein inhibitors. The
aim of this study is to predict the drug action in chemotherapy
for a given cancer and a given patient, and to improve theuptake of anti-tumor drugs.
4.5.2. Radiation Sensitizers. In 1989 Prof. J. L. Sessler(University of Texas at Austin) discovered “Texas-sized”
expanded porphyrins (Texaphyrins). The Gd 3+-Texaphyrin
complex revealed very good tumor-seeking and radiationsensitizing properties. It may remarkably improve the effect of
X- or γ-ray radiotherapy for cancer. We expect that such compounds will also magnify the relative biological effectiveness(RBE) of NCT. We therefore tried to design compounds otherthan Texaphyrins but possessing similar properties by using
quantum chemical and molecular mechanical calculations.
The synthesis is in progress.
5. Conclusion
In the past 15 years we tried to follow the new trend inradiopharmaceutical chemistry. Unfortunately, we have notbeen engaged in PET pharmaceuticals study due to the lack ofboth a PET machine and a cyclotron suitable for production of
β+-emitters. Our unremitting efforts have led to the publication of some 50 papers, and growing up a number of M.Sc. and
Ph.D. students.
Acknowledgement. We thank the National Natural Science
Foundation of China and the National Ministry of Science andTechnology of China for their financial support.
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