Production of 105Rh±EDTMP and its bone accumulation

Atsushi Andoa,*, Itsuko Andoa, Norihisa Tonamib, Seigo Kinuyab,Natsuko Okamotoa, Masami Sugimotoa, Naoko Fukudaa, Satomi Matsumotoa

aSchool of Health Sciences, Faculty of Medicine, Kanazawa University, 5-11-80, Kodatsuno, Kanazawa 920-0942, JapanbSchool of Medicine, Faculty of Medicine, Kanazawa University, 13-1, Takaramachi, Kanazawa 920-8640, Japan

Received 15 March 1999; received in revised form 20 April 1999; accepted 1 July 1999

Abstract

105Rh has favorable physical characteristics as a radiotherapeutic nuclide. Carrier-free 105Rh can be produced by

the neutron activation of 104Ru followed by beta decay of 105Ru. It was clari®ed that carrier-free 105Rh can beproduced in quantities and the purity necessary for chemical and clinical investigations of its use as a nuclide forradiotherapy. 105Rh±EDTMP was simply obtained from 105Rh3+ and EDTMP by heating for 30 min in boiling

water, giving a radiochemical yield of >99%. Dissociation of radioactivity assessed by paperchromatography wasnegligible for up to 5 days after its preparation. In animals, 105Rh±EDTMP showed rapid blood clearance andselective uptake in the bone.

Hence, 105Rh±EDTMP is thought to be a promising therapeutic agent for the treatment of pain due to bonemetastases. # 2000 Elsevier Science Ltd. All rights reserved.

Keywords: Radiotherapeutic nuclide; Rhodium-105; EDTMP; Bone metastases

1. Introduction

The use of therapeutic radionuclides which localize

at bone metastatic sites has been found to be an e�ec-

tive new method for the treatment of pain, especially

in multiple sites, for which the use of external beam ir-

radiation is impractical. Selective accumulation into

metastatic lesions as well as favorable physical charac-

teristics of the nuclide are essential to e�ectively treat

the pain. Several radiochemical compounds have been

proposed as radiopharmaceuticals for the treatment of

pain caused by disseminated bone metastases (Kutzner

et al., 1978; Mathieu et al., 1979; Ketring, 1987;Atkins et al., 1993).

Rhodium-105 is a potential radiotherapeutic nuclidein nuclear medicine: half-life, 35.4 h; bÿ, 247 keV(30%) and 560 keV (70%); g, 306 keV (5%) and 319

keV (19%). The beta particle emissions are suitable fortissue irradiation, and the g-emissions allow for stan-dard scintigraphic scanning to con®rm speci®c localiz-

ation in metastases.Rhodium-105 was produced by the following nuclear

reaction(Grazman and Troutner, 1988):

104Ru �n,g�105Ruÿÿÿ4bÿ

4:4 h

105Rh

It is known that metals such as 177Lu can be che-lated to EDTMP (ethylenediamine-tetra-methylene

phosphonic acid) producing a bone-seeking phospho-nate complex that is chemically and biologically stable,

Applied Radiation and Isotopes 52 (2000) 211±215

0969-8043/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.

PII: S0969-8043(99 )00129-3

www.elsevier.com/locate/apradiso

* Corresponding author. Tel.: +81-76-265-2527; fax: +81-

76-234-4366.

E-mail address: ando@kenroku.kanazawa-u.ac.jp (A.

Ando).

localizing in bone preferentially and concentrating inbone metastases (Ando et al., 1998). In the present

study, the production of 105Rh±EDTMP and theexamination of its chemical and biological feasibility asa therapeutic agent for painful bone metastases was

undertaken.

2. Materials and methods

2.1. Material and irradiation

Natural ruthenium metal powder (extra pure re-

agent) was purchased from Nacalai Tesque, Inc.(Kyoto, Japan). This metal powder target (25 mg) wassealed in quartz vials, which were placed in polyethy-

lene cylinders and irradiated in JRR-3M (JapanAtomic Energy Research Institute) for 3 h with ther-mal neutrons. The neutron ¯ux was 1 � 1014 n/cm2S.

2.2. Separation and puri®cation

Two days after the irradiation, the ruthenium metal

powder was dissolved by bubbling Cl2 gas through its

slurry in 2 N KOH (20 ml) for an hour at room tem-

perature. The resulting RuO4 was partly carried with

the Cl2 gas and collected in a series of CCl4 and 3 N

NaOH traps. The RuO4 remaining in the 105Rh sol-

ution was eliminated by extracting four times with

CCl4 (20 ml). The solution was then acidi®ed with 3 N

HCl, and 3 mg Fe(III) carrier and NH4OH were added

for the coprecipitation of 105Rh(OH)3 with Fe(OH)3.

The precipitate was washed twice with distilled water,

and dissolved in 6 N HCl. Pure 105Rh was obtained by

Table 1

Yields of 105Rh and radionuclidic purities (50 h after the end

of irradiation) Natural ruthenium metal powder (25 mg) was

irradiated for 3 h with thermal neutrons. The neutron ¯ux

was 1 � 1014 n/cm2 S

No. of preparation Yields of 105Rh

(MBq)

Radionuclidic purity

(%)

1 16.5 99.4

2 15.1 99.0

3 22.0 98.3

4 20.2 99.9

Fig. 1. Actigram and autoradiogram for miniature paperchromatography with 105Rh±EDTMP and 105Rh±chloride Solvent system;

acetone±methanol±water (2:2:1).

A. Ando et al. / Applied Radiation and Isotopes 52 (2000) 211±215212

eliminating Fe(III) carrier by methylisobutyl-ketone

extraction. Small amounts of 97Ru and 103Ru may be

present in the ®nal product.

2.3. Radioactivity measurements

The radioactivities of 105Rh, 97Ru and 103Ru were

measured with Ge(Li) detectors coupled to a multi-

channel analyzer.

Table 2

Biodistribution of 105Rh±EDTMP. Uptake rates in various tissues are expressed as % of administered dose per gram tissue weight.

Tissues are normalized to a body weight (BW) of 100 g by multiplying by BW/100. Values represent the mean2S.D. of ®ve ani-

mals

1 h 3 h 24 h 48 h 96 h

Blood 0.03420.006 0.00920.001 0.00120.0001 0.000820.0002 0.000520.0001

Muscle 0.01120.003 0.00720.001 0.00420.001 0.00320.0005 0.00320.0006

Liver 0.02320.003 0.02020.003 0.01520.001 0.01120.001 0.01120.002

Spleen 0.01120.003 0.00820.003 0.00920.002 0.00820.001 0.00820.002

Kidney 0.34820.089 0.33720.156 0.13220.025 0.09320.010 0.05320.012

Lung 0.04020.006 0.02120.005 0.00820.003 0.00620.001 0.00520.002

Stomach 0.02020.004 0.01320.004 0.00520.001 0.00420.001 0.00320.001

Pancreas 0.00920.002 0.00620.003 0.00320.001 0.00320.001 0.00320.001

Heart 0.01220.002 0.01120.002 0.00320.001 0.00420.001 0.00320.001

Small intestine 0.01920.008 0.00820.001 0.00620.003 0.00520.001 0.00520.001

Brain 0.00320.001 0.00220.001 0.000320.0001 0.000620.0002 0.000420.0002

Testis 0.01320.004 0.01020.001 0.00720.002 0.00520.001 0.00520.001

Parietal bone 3.1320.35 3.1020.24 2.8220.66 2.2820.20 2.0320.57

Femur 4.5920.24 4.2020.24 3.7520.64 3.7520.32 3.2320.58

Fig. 2. Femur-to-organ uptake ratios of 105Rh±EDTMP and 99mTc±MDP.

A. Ando et al. / Applied Radiation and Isotopes 52 (2000) 211±215 213

2.4. Preparation and biodistribution of 105Rh±EDTMP

Commercially available EDTMP was obtained fromDojin Laboratories (Kumamoto, Japan). For the label-ing of EDTMP with carrier-free 105Rh, 105Rh±chloride

in 0.1 N HCl (0.45 ml, 20 MBq) was added to the 0.6ml of EDTMP in 0.1 N NaOH (10 mg/ml) and heatedfor 30 min in boiling water after adjusting pH at 8.4±

8.6 with 0.1 N NaOH. The radiochemical purity of105Rh±EDTMP was determined by miniature paper-chromatography (Sanada et al., 1986) with a solvent

mixture of acetone±methanol±water (2:2:1). Stabilityof the compound was observed by the same system upto 5 days after the preparation.Biodistribution of 105Rh±EDTMP (0.2 ml, 1 ml con-

taining 0.1±0.8 MBq of 105Rh and 0.3 mg of EDTMP)was observed in ddY mice (31.2 g22.2 g) 1, 3, 24, 48and 96 h after the intravenous injection (n= 5). The

results were expressed as a percentage of injected doseper gram tissue (% ID/g) after the normalization ofbody weight. Similarly, distribution of 99mTc±MDP

(about 4 MBq/ml 99mTc containing 167 mg/ml MDP,0.2 ml) was observed up to 24 h postinjection.

3. Results

The yield and radionuclidic purity of 105Rh areshown in Table 1. 15.1±22.0 MBq of 105Rh wereobtained in the four preparations. The average radio-

nuclidic purity of the four preparations determined bycounting with Ge(Li) detector coupled to a multi-channel analyzer was 99.2%. Impurities (97Ru and103Ru) were negligible.Figure 1 shows the actigram and autoradiogram for

the paper chromatography. 105Rh±EDTMP remainedat the origin and 105Rh±chloride moved to the solvent

front with Rf=0.42±0.48. The reaction with EDTMPgave no other products than 105Rh±EDTMP, with alabeling e�ciency always over 99%. Dissociation of105Rh was not observed for up to 5 days in the injec-tate stored at room temperature.In animals, the radioactivity of 105Rh±EDTMP was

found primarily in the bones: 4.59% ID/g for thefemur and 3.13% ID/g for the parietal bone at 1 hdecreasing gradually with time (Table 2). Renal uptakewas 0.348 and 0.337% ID/g, respectively, at 1 h and 3

h, and clear thereafter. Uptake into other organs wasnegligible when compared with bone uptake.Cumulative urinary excretion of 105Rh±EDTMP at 1

and 3 h after administration was 57.5210.3 and61.025.9%, respectively. As shown in Fig. 2, bone-to-organ uptake ratios of 105Rh±EDTMP were extremely

high, with the femur-to-organ ratio being 138±6327 forblood, 429±1311 for muscle, 206±351 for liver, 429±571 for spleen, 14±64 for kidney and 118±651 for lung.

Bone uptake of 105Rh±EDTMP was comparable to

that of 99mTc±MDP (Tables 2 and 3). Furthermore,105Rh±EDTMP was cleared from the circulation faster

than 99mTc±MDP, and the bone-to-tissue ratios of105Rh±EDTMP were signi®cantly higher than those of99mTc±MDP (Fig. 2).

4. Discussion

It is clearly evident that 105Rh has favorable physical

characteristics as a radiotherapeutic nuclide. Moreover,

dose estimation can be performed using the infor-

mation from the resultant images. A relatively short

physical half-life (35.4 h) of 105Rh permits the delivery

of radiation doses at high dose rates presenting the

possibility of fractionated dosing, and also reduces the

problems of radioactive waste handling and storage.

Since carrier-free 105Rh is produced by the neutron

activation of 104Ru followed by its beta decay, the

radiotherapeutic agent (105Rh±EDTMP) can be

obtained with high speci®c activity. It was clari®ed

that carrier-free 105Rh can be produced in large quan-

tities and adequate purity for chemical and clinical in-

vestigation for its use as a nuclide for radiotherapy.

Also, the preparation of 105Rh±EDTMP is very

simple and the chelate is very stable. In animal studies,105Rh±EDTMP shows suitable characteristics for the

treatment of palliative pain of bone metastases.

Minimal uptake and rapid elimination in irrelevant tis-

sues avoid ambient radiation to patients.

In conclusion, 105Rh±EDTMP seems to be a promis-

ing therapeutic agent for the treatment of pain due to

bone metastases because of its favorable physical and

biological characteristics.

Table 3

Biodistribution of 99mTc±MDP. Uptake rates in various tis-

sues are expressed as % of administered dose per gram tissue

weight. Tissues are normalized to a body weight (BW) of 100

g by multiplying by BW/100. Values represent the

mean2S.D. of ®ve animals

1 h 3 h 24 h

Blood 0.11720.016 0.07820.017 0.02120.003

Muscle 0.03220.006 0.02220.005 0.00820.001

Liver 0.71620.177 0.37320.117 0.13120.015

Spleen 0.24520.113 0.69820.225 0.70220.228

Kidney 2.8721.56 1.3620.76 0.20120.035

Lung 0.12220.025 0.24520.096 0.06220.019

Parietal bone 3.8920.29 4.6821.08 3.3020.33

Femur 4.9120.32 6.2421.24 5.3720.48

A. Ando et al. / Applied Radiation and Isotopes 52 (2000) 211±215214

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