Radionuclide production for the biosciences

Nucl. Med. Blol. Vol. 16, No. 4, pp. 323-336, 1989 Int. J. Radiat. Appi. Instrum. Part B Printed in Great Britain. All rights reserved

Radionuclide T. J. RUTH,’

0883-2897/89 33.00 + 0.00 Copyright 0 1989 Pergamon Press plc

Production

B. D. PATE,’

for the Biosciences

R. ROBERTSON2

and J. K. PORTER3

‘TRIUMF, University of British Columbia, Vancouver, B.C., *BeequerelLaboratories, Mississauga, Ontario, Canada and Nordion International Inc., at TRIUMF, University of British Columbia, Vancouver, B.C., Canada V6T 2A3 (Receiued

18 March

1. Introduction

to those whose favourite nuclide or reaction have been omitted, and would appreciate receiving corrective information,

For the 20 or 25 years which followed the 1939-1945 war, radionuclide production for biomedical applications was mostly centred on major nuclear reactor installations.“-3’ The last 15 years have, however, witnessed a rapid growth in the use of particle accelerators for this purpose(“) following from the favourable characteristics of accelerator-produced, neutron-deficient radionuclides in these applications. Both commercial radionuclide producers and research workers have added accelerators to their armamentarium. The machines have mostly been cyclotrons,‘O’ of compact “industrial” or “medical” design. (“,‘*’ In addition, major accelerator installations, such as BLIP’“’ and LAMPP14’ in the U.S., TRIUMF in Canada,“” and SIN in Switzerland,(16’ have significant programs for radionuclide production. The present review has been written with the aim of providing the researcher with (a) a listing of radionuclides which have been used or proposed for use in biomedical research, (b) data on their major decay modes and how the nuclides are produced, with pertinent literature references, and (c) an overview of production techniques. The data place the emphasis on accelerator-produced radionuclides, and have been organized in tabular form; what was included and in which table reflects the authors’ arbitrary choice. On production methods, it was tried, where possible, to list all proton-induced reactions (reflecting certain trends in the field) together with such different, more efficient methods as may exist. Some nuclides have been arbitrarily omitted, i.e. those which have fallen from usage or have not enjoyed wide-spread exploitation up to the present. On the other hand, others have been included (especially in the table of positron emitters) which show promise for applications in the future. The authors apologize N M.S.

lb!&*

1988)

2. Organization of Tables The data have been grouped as follows: in Table 1 are listed y-ray emitters suitable for measurement via standard y-cameras or by SPECT. Table 2 contains radionuclides which decay by positron emission. With the needs of positron emission tomography in mind, the authors have generally excluded nuclides with half-lives greater than 3 h (except for S2Fe, 76Br, and *9Zr), or with positron emission in less than 60% of their decays (except for *9Zr and 93Tc). Table 3 lists those particularly useful nuclides which are produced via generators.(‘7-‘9) Generally, data on production of the parent nuclide are included, and for relatively new generator systems references are given on how they have been implemented. Table 4 contains miscellaneous data on, for example, nuclides with very long half-lives, or which decay without y-emission. Table 5 lists the most important commercially available radionuclides, and trends in their usage over the last few years. It is worth noting the dramatic increases in the use of 3H, “‘Tl and in particular ‘*‘I. This latter increase reflects the more reliable production of ultra-pure l*‘I with relatively low energy protons (~30 MeV; see Table 1). In the tables, the yields for the acceleratorproduced radionuclides are expressed as mCi/pA at saturation where possible. Otherwise they are designated by “1,” for the integrated dose of a p A-h. For radionuclides produced by reactors, the crosssection is given in barns (b) for thermal neutrons (t) or for reactor spectrum neutrons (s). Other symbols used are e (for enriched), f.p. (for fission product), g (for generator), D (for y-transition, due to decay of a daughter radionuclide), N.D. (for no dataj, and 323

T.J. RUTH et al.

324

Table I. Radionuclides used in single photon emission studies Principal decav mode

Nuclide

es.

“Ml3

53.3 d 20.9 h

*Al “Cl

2.2 min 37.2 min

;I

‘3K

22.3 h

LJ-

‘Be

8-

E(I) [Me+%)] 0.477( 10) O/&01(36) 1.779(100) 1.642(31) 2.167(42) 0.373(88) 0.617(78)

‘%c ‘SCr

3.34 d 23.0 h

8-

e.c.

0.159(68) 0.308(99)

Wr

27.7 d

es.

0.320(10)

YMn s2Fe sFe

312d 8.3 h 44.5 d

e.c.

‘JCO

17.5 h

0.835(100) 0.169(99) 1.099(57) 1.292(43) 0.477(20) 0.931(75) 0.122(86) 0.136(11) 1.173(0.3) 1.346(0.5)

S’CO

272 d

8’ 88’ e.c.

%I %I

9.7 min 12.7 h

8’

6’Cu

61.9 h

B-

0.185(49) 0.093( 16)

8’

0.597(26) 0.548( 15) 0.439(95) 1.039(38) 0.093(37) 0.185(20)

62Zn

9.26 h

B+.B-

+ F”

69”Zn “Ga 6’Ga

13.8 h 9.4 h 78.2 h

e.c.

‘IAs

26h

8’

“As

17.8 d

P-38’

%e “Se ‘JSe ,,I%&

8.4 d 7.15 h 120d

e.c.

B’ e.c.

“Br

17.5 s 57.1 h

IT e.c.

‘R”Kr s’mKr 8h”Kr

SOS 13s 4.5h

IT

“Rb

4.6 h

fiT_,IT B’

*‘Sr ‘%r mY *Nb =Tc

64.8 d 2.8 h 16.1 s 18.8 s 2Oh

wmTc -Tc 9’Ru

89d 6.0 h 2.9 d

CC.

56 min 39.6 s 2.83 d

IT IT e.c.

1.66h 4.5h 13.6 d

IT IT IT

l13m~n

“h”In “l”Sn

e.c. IT IT IT CC.

IT IT

0.834(80) 0.630(8) 0.596(60) 0.635(15) 0.046(59) 0.067(70) 0.361(97) 0.136(59) 0.265(59) 0.162(52) 0.239(24) 0.521(23)

0.130(28) 0.190(67) 0.151(75) 0.305( 14) O&6(23) 0.457(3)

0.514(99) 0.388(82) 0.909(99) 0.122(64) 0.766(94) 1.074(4) 0.096(0.3) 0.140(88) 0.216(86) 0.324(10) 0.040(0.07) 0.088(3.6) 0.171(90) 0.245(94) 0.392(64) 0.336(46) 0.159(81)

Yield (Ej . I [mCi/A (MeV)]

Reaction

‘Li (p. n)

Refs

O.l66/h(20) O.ISS/h(l40)0.3/h e O.O2i).Ci4/h&%O) See above 0.5/h (20)

86 87,88

0.1/h (25) 0.3/h(90) O.l2/h(30) See Table 4 O.O04/h(4%40)’ 0.217/h(9@-85) O.O35/h(36) 16b (t) 0.6/h(l7) O.OOl/h(15)

90-92 93

l.lb (t)

1.2

1l/h(22) 1.7/h(l2) O.O09/h(l5) O.l/h(27) e See below 4.4b (t)

98,99

O.O2/h@lO-30). O.O3/h(SOO)’ O.Ol/h(SOMeV brem. on Ig e target)* 2.3/h(22-16)

103-107

109 26,103,104,109

“Ge(P, n)

l.S/h(la-10) 4.5/h(2618) 4.7’9/h(26-i5)e 3.75/h(l66)e 2.l/h(22) lO/h(l>14) e O.l7/h(lS)

‘%%(a, 2n) “*‘Ge(a, xn)

O.O37/h(34-20) 0.22/h(26)

111,113 114

“Se@, Y)

50b (t)

“Br g “As(a, xn) m’Se(p, xn) 79Br(p, 3n) “Kr -‘Mo(p, spall) ‘%r(p, n) *‘Rb g “Kr(d, P)

See below 0.9/h(WlS) 1.2/h(20-2) 0.36/h(5&30) 0.3/min @ 175 mL/min see below 0.79(15)

119

“Br(or, 2n) ““Kr@, xn) s2Kr(p, 2n) ““Kr(p, xn) *‘Rb(p, n) *‘Rb(p, n) @Zr g wMo g %Mo(p, 2n)

2/h(30-14) 11.6/h(32-16)

121-123

26Mg(a, 2~) 27Al(~,3p) =Mg g “Cl(d, P)

40‘w%P) JIV(d, Zxpn) “Ca g WP,

W

““Ti(‘He, xn) Wr(n, i ) W(P, n) ‘*Fe(d, a) See Table 2 ‘*Fe@, a) ‘*Fe(p, 2n) “Fe(d, n) %Fe(d, n) ‘sNi(p, 2~) 62Zn g 63Cu(n, Y) @Zn(n, P) @Zn(p, 2~) 6*Zn(a, P) Wu(p, 2n) @Ga(n, P) %Zn(d, 2n) 6BZn(p,2n) %n(p, n) ‘2Ge(p, n)

89

94,95 96 1,2,97 86

77,86 100 1,2,100-103

108

110 99,111 86,111,112

11~118

120

I 5/d(22-34) i

WW9-40) O.O6/h(22) 16/h(22) See Table 4 See Table 4 7/h(2&15)*

9’.98M~(p,xn) @MOg %Ru(n, Y) M’M~(a, xn) ‘“Rh@, 013n) ““Pd g jwCd g “*Cd@, Zn)

0.01 I/h (22) See Table 4 0.25 (t) 0.069-0.075/h(30) 0.74/h(56-35) See Table 4 See Table 4 6/h(26-18)

“‘Sn g “‘Cd g “%b(p, Ipxn)

See Table 4 See Table 4 O.O15/h(6&27)

124 99 99

125 126 127,128 129

77,130-l 33

325

Radionuclide production for the biosciences Table I-continued

Nuclide “‘Sb “‘Sb ‘*‘Te ‘21rnTe ‘ZI

1112 2.8 h 3.6 min 17 d 120d 13.2 h

Principal decay mode

0. I58(86)

1.230(3) e.c.

IT cc.

8.0 d 2.3 h

mmxe

“‘Xe

’ WS

16’Tm ‘69yb

36.4 d

es.

69 s

IT

5.3 d 3.9 min 32.1 h 38.9 h 2.6 min 6.5 min 138d 3.4 min 17.3 min 8.1 h

9.2 d 32 d

E(I) [MeV(%)]

;r cc. IT IT 8’ cc. e.c. Bcc.

e.c. es.

“2LU “‘xi 18,rnW

6.7 d 9.3 min 5.2 s

e.c. e.c. IT

‘P’“Ir iwnlpt

4.9 s 4.0 d

IT IT

IPklA” 19klAu

30.5 s 7.8 s

IT IT

‘98AU

2.7 d

B_

191rnHg

23.8 h

IT

mjHg ‘941

46.6 d 7.4 h

8e.c.

‘O’Tl

73 h

es.

=“Pb

51.8 d

e.c.

*“Bi

11.2h

e.c.

lwBi

6.2 d

e.c.

0.573(80) 0.508(18) 0.159@4) 0.159(83) 0.529(l)

0.364(81) 0.637(7) 0.668(99) 0.773(76) 0.203(68) 0.172(26) 0.125(69) 0.173(38) 0.081(36) 0.443(26) 0.372(31) 0.27q18) 0.662(90) 0.605(S) 0.166(80) 1.596(0.5) 0.69q1.3) 0.326(93)

0.208-D(41) 0.063(45) 0.198(36) I .094(64) 0.09316) 0.108(18) 0.099(9) 0.129(26) 0.130(3) 0.099( 1I) 0.262(68) 0.279(71) 0.130(3) 0.41 l(96) 0.676( 1) 0.134(34) 0.279(5) 0.279(82) 0.455(12) 0.208(12) 0.167(11) 0.135(3) 0.279(80) 0.401(3) 0.899(99) 0.375(94) 0.803(99) 0.881(66)

Yield (E)

[ma/A (MeV)]

Reaction

Refs 136

“‘Sn(p, n) “*Te g ‘zWp, n) ‘*‘Sb(d, 2n) “‘Wp, n) ‘?e(p, 2n) “‘I(p, 5n)12’Xe ‘“Cs(p, spall)‘23Xe ‘*‘Xe(p, 2n)‘23Cs’23Xe ‘24Xe(p, pn) 12’Xe ‘qe(n, y)‘“Te f.p. ‘32Teg

I .q7-5). See Table 4 O.O81/h(22) 0.25/h(22) O.O18/h(22) 20/h(26.5-21). 20/h(65-50) lO/h(SoO) 27/h(30-21)e

“‘Cs (p, spall) “‘I(P, n) “‘Cs(p, 2pSn) 1*‘I(P,n)

O.O7/h(500) O.O7/h(20) 0.1 l/h(l74-77) 0.4/min @ 250 mL/min

145

Cp. “*Ba g ‘*‘I(a, 2n) “‘Cs(d, 2n) ws g ‘39Ceg “WP, n) ‘“Nb g ‘&Ce a Y) ‘?b(p, 3n) “‘Gd(a, 2n) ‘“Er(p, 2n) ‘6+fm(p, n)

38b (t) See Table 4 0.7/h(45) l.l/h(16) See Table 4 See Table 4 O.O06/h(l5) See Table 4 See Table 4 36b (t) O.O23/h(30) O.O8/h(30) 0.3/h(22) O.O8/h(22)

146,147

“‘Hf g ‘“W g la3Ta g

See Table 4 See Table 4 See Table 4

‘9’0sg 19’Au(p, 3n) ‘vt(li-, y) ‘9smHgg 19”“Hgg

See Table 4 N.D. 1.2b (t) See Table 4 See below

‘“Au@, y)

IOOb (t)

“‘Au(p, n) ‘%Hg(n. Y) 2”Hg(n, Y) *“Hg(p. 2n)

0.23/h(l8) 500b (1)

““Tl(p, 3n)Pb 20’Pb(p, 7n) 703Tl(p,n) 2”w(P, 3w ‘wPb(p, 3n)

1.5/h(29-21)e 5.14(65-52) e 0.22/h(22) 3.5/h(28) 2/h(32)

158,159 151

m’Pb(P, 2n) M’Pb(p, xn)

0.7/h(22) 1.7/h(42-20)

161 162

‘56Dy~,

+ (for yields calculated by the authors from crosssection data in the literature). Some of the references in the tables are not directly connected with the tabulated physical production data, but rather with potentially useful radiochemical separations. 3. Production Techniques (a) General The researcher seldom has direct interest in radionuclide production via reactors, since most of the

0.2b It) 17b(ij See Table 4

137 99.137 138-142

143-144,245 245 1.2

148 149

86

15&152

99 99

5b(0 6.6/h(22)

products are available from commercial suppliers. On the other hand, techniques reviewed below for production via accelerators will be of interest to research staff with their own in-house cyclotron. A cyclotron for radionuclide production may be chosen with low projectile energy (typically 10-16 MeV protons and deuterons of about half that energy) if a limited range of positron emitters at low cost is the objective, or be chosen to produce higher energy projectiles (proton energies (say) from 26 to 65 MeV) if the objective is a wider range of medical radionuclides. All such cyclotrons, however, share

326

T. J. RUTHet al. Table 2. Positron emitting radionuclida,

Nuclide “C

‘I/Z 20.4 min

“N

9.96 min

‘0 ISO

70.8 s 2.03 min

‘OF

‘We

Mp

109.8 min

17.2 s

2.50 min

Branch %+

E(I) [MeV(%)]

99.8

No

99.8

No

loo 100

96.9

2.3 13(99) No

No

100

No

100

2.235(0.06)

*Cl

32.0 min

55.5

2.127(43)

“K

7.6 min

99.5

2.168(99)

‘qi ‘PCr “Mn

3.08 h 42.0 min 462 min

;: 97.2

0.720(0.2) 0.091(54) 0.749(26)

sb”Mn

21.1 min

98.5

1.434(98)

8.3 h

56.5

0.169(99)

wu WI

23.2 min 3.4 h

91.7 62.2

1.332(88) 0.283(13)

Ql *Zn 68Ga ‘JBr

9.8 min 38.1 min 68.1 min 97 min

97.8 93 89.1 72

1.173(0.33) 0.67q8.4) 1.077(2.9) 0.285(92)

Yield (E) [mCi/A(MeV)]

Reaction “B(d, “Wp, “N(P, “C(d, “C(P,

n) n) 01) n) n)

:$$

“n;

“N(d: n) “N(P, n) ‘Q(P, pn) ‘tiCHe, p) ‘6G(K,pn) ‘*O(P, n) ‘?Je(d, K) ““Ne(p, x) ‘“G@, n) 19F(p,n) *e(d, dn) “Al(a, n) “P(p, pn) “P(a, n) "WP, pn)

JzFe

“Cl(Or, n) “‘Ar(p, pn) ‘WP, n) "V(p,W MWd,n)

5”Cr(p, 2n) >‘Fe g “Cr(p, n) %(K, 2n) “Mn(p, 4n) -‘Ni(p, spall) @Wp, n) *‘Ni(p, n) 6*Zn(p,a)

‘6Br “Kr “Rb s’Zr aZr

19

0.559(72) 0.13q80) 0.77ql3) 1.228(3) 0.909(99) 1.5lqlOO) 1.36(66) 0.871(100) 0.658(98)

1.35 h

81

0.560(73)

3.6 min

76

0.564(18)

92TC TC VC "OIn

16h 1.24h 1.25 min 1.6h 78.5 h 4.44 min 2.7 h 52 min 69 min

'=l ltq

57 87 95.5 ;9 94 13

@Zn g WU(P, n) @&g “As(K, 4n) ‘5As(3He, 3n) ‘WP, 2n) “WP, 3n) ““Br(d, xn)“Kr nBr(p, 5n) “Kr ‘*Kr(p, a) ‘6Se(p, n) “Br(p, 3n) 82Srg *Wp, 3n) *V(P, n) P2Mo(~,n) 92Mo(d, n) %Mo(P, 3n) ““Cd(d, 2n) “‘Cd(d, 3n) IwAg@, 3n) “‘I(p, 811)‘~xe ’Ws(p,spall) ‘20Xe ‘22Xeg

one characteristic which sets them apart from the previous generation of accelerators built for physics research, namely production of much higher beam intensities (in the range from 50 to 200pA). This high beam intensity, coupled with the substantial reaction cross-sections characteristic of lowenergy nuclear reactions, leads to the radionuclide production capacity necessary for biomedical applications; it does so at the expense of the high target power-densities and attendant problems described below.

Refs

lo(7.0)

163-167

50(7) 155(15) 65(23) 2.4(10-7) 27w) 47(8-6) 25(26.s25) 105(30-26) 6/h(23) 27w 180(1l-4) 82(14-2) 8q40-34) I .2/min @ 2L/min 0.6/min @ 0.8L/min l/min @ lLjmin(l49) 4.74(28-10) 18.7(3>19) N.D. 0.9/h(20) 0.58(15-6) 4.4(32-29.8) 48( 11J-9.0) 37(45-3oy N.D. 35/h(26) see below 50/h(12.3)e O.O03/h(30) O.l6/h(65) 8.3 Ci (0.5 sat) (800, 1 mA) 16(12-IO)* 25(12-IO)* 10(18-12). See Table 1 125(15-4)* See Table 4 7.5(6&54) 6(34-24) 118(28-22) e 50(38-28) e 0.21(90-68) N.D. 2(15_12)e 8/h(l6-10) e 48-75(45-25) See Table 4’ 50(45-35)’ Uh(13)

167-170

46(35-27)’ 29(2&l 1)* io(28-21 j* 1.5(40-30). N.D.( > 100 MeV) N.D. See Table 4

171,172 40,167,171,173-176 177 38,178,179 18 177 181,182 183 184

185,186 187 94 39,186 186,188 107,188-190

84 84,85 100 100,191 192,193 194

195 7,183 5-118 196 197 198 198 125 199 200 201 202,203

The four major intermediate-energy accelerator installations, referred to above, also have the characteristics of high beam intensity. At their proton beam energies (ranging from 200 to 8OOMeV) the reaction cross-sections are smaller by about an order of magnitude; however, this is more than compensated for by the larger thickness of target material which can be penetrated by the beam, and hence from which radionuclide production takes place. Thus, these accelerators are, in principle, copious sources of radionuclides, via the spallation

321

Radionuclide production for the biosciences Table 3. Generator svstems Daughter nuclide

_.

412

Priocipal decay mode

-21

2.2min 37.2min

/?b-

“SC

3.3 d

8’ b-

2’Al

S2mMn 21.1min 62CU ‘Ga

9.7min 68.1 min

fl+ 8’

“AS

26 h

8’

17.5s 13s 1.86h 1.25min

IT IT IT j?+

2.80 h 16.1 s

IT IT

18.8 6.0 hs 56 min 39.6 s 48.6min

:T IT IT IT

1.66 h 4.49 h 3.6min

IT IT fi+

3.6min

fl+

2.30 h

8-

3.9 min

8’

2.55min 6.5min

IT fi*

3.4min

fi+

122,

WS

‘OPr ‘“Pr

l7.3min

“jLU

6.7 d

“‘At 2,'Bi

bC.C.

9.3 min 5.2 s 4.9 s 30.6 s 7.8 s

KC.

7.2 h 60.5 min

01,cc. a, B-

IT IT IT IT

E(I) [MeV(%)] 1.78(100) 2.17(42). l&(32) 0.159(68) 0.511(193) 1.43(98) 0.511(196) 0.511(178) 1.08(3) 0.511(175) 0.834(80) 0.162(52) 0.190(67) 0.009(5) 0.511(191) 0.777(13.4) 0.388(82) 0.909(99) 0.122(64) 0.140(88) 0.040(0.07) 0.088(3.6) 0.151(30) 0.245(94) 0.392(64) 0.336(46) 0.511(148) 1.23(3) 0.511(152) 0.564(18) 0.668(99) 0.773(76) 0.511(137) O&43(26) 0.662(90) O.SIl(l26) 0.605(s) 0.511(102) 1.60(0.5) 0.69q1.3) 2.18qO.7) 1.094(69) 0.901(33) 0.093(7) 0.108(18) 0.129(26) 0.261(68) 0.130(3) 0.279(71) 0.569(0.3) 0.5830(32)

reaction. They do, though, produce a wider spectrum of product (and hence impurity) nuclides, distributed through a larger target mass. To cope with this, the separation and purification chemistry tends to be complex, large scale and slow. The total beam power from these machines is an order of magnitude greater than that from the low-energy cyclotrons described above. On the other hand, this power is distributed at lower density through the larger mass of target material, and this is reflected in the details of the target engineering. (‘3*20~2’) Radionuclide production at these machines is generally parasitic on the physics program for which they were built. This often leads to scheduling, reliability and other problems for routine supply. They do, however, provide access to a wider range of radionuclides of demonstrated and potential usefulness in biomedical research.

Reaction PaEttt **Mg

$2

(see Tabk)

Refs

20.9 h 2.8 h

I 4

‘*Fe

4.56 8.3 h

4 2

62Zn “Ge

9.3 h 271 d

1 4

108,204

‘2Se

8.4 d

1

113

“Br *‘Rb *?Rb 82Sr

57 h 4.6 h 83d 26d

I I

205,206

4 4

206 207-2 I 1

8’Y s9Zr wMo “MO ‘OsPd ‘“Cd “‘In

3.3 d 78.5 h 5.7 h 2.75 d 17.0 d 462 d 2.83 d

4 4 4 4 4 4

212-214

“‘Sn “*Cd “*Te

115d 53.5 h 6.0 d

4 4 4

206 215

l”Xe

20.1 h

4

202

38,s -

%a

188

206 206

I

“‘Te

3.26 d

4

216

12*Ba

2.43 d

4

216,217

4 4

216

“‘CS ‘“Ce ‘“Nd ‘We “2Hf

2”Rn “‘Pb

30Y 73 h 3.4 d

4 4

218

4

219

21.7d 5.1 d 15.4 d 41.6h 23.8 d

4 4 4 4 1

220

14.6 h (10.6 h)

4 4

223 224,225

285 d 1.87 y

221 206,222 216

(b) Target design problems

In principle, the beam from a cyclotron is available in two locations. The circulating beam is available to targets inserted into the vacuum tank of the cyclotron itself, while the external beam is available following its extraction into an external beam line system. Utilization of the circulating beam poses a number of difficulties. In addition to the obvious ones of producing a target system which can be introduced through a vacuum lock and which can withstand irradiation without degrading the machine vacuum, strategies must be adopted to reduce the power density deposited in the target material to a value that the target structure can dissipate. Rotating target systems or targets which are oriented so that the beam strikes them at an oblique angle may be employed.02,23)

328

T. J. RUTH er al. Table 4. Miscellaneous radionuclides Principal decay mode

Nuclide ‘H

1%

*Na “Na

12.3 y 5730 y 2.6 y 1Sh

‘ZP “S “S

14.3 d 87.2 d 2.84 h

“Cl “Ca

3 x IOJy 4.54 d

“Fe =co

2.7 y 70.9 d

MC0 65Zn we

5.3 y 2444 271 d

E(I) meV(%)J

No

b8-

;’ $1 88-98’ 8-

1.27$0) 1.368(100) 2.75(W) No 1.942:)

1.297;) 0.808(7)

e.c.

4-

0.811:)

8-

1.173(100) 1.332(100) 1.115(51) 1.077-D(3)

e.c. C.C.

Reaction 6Li(n, a) “NW, P) “M&d, a) “Na(n, Y)

940b (t) 1.8b(s) O.O02/h(lS) 0.43b (t)

“S(n,P)

0.07b (s) 0.49b (t) N.D. N.D. 43b (t) 0.7b (t)

Wl(n, “‘Cl(a, aAr(~. ‘5Cl(n,

P) 3p) 3~) yj

%h

Y)

8’ B-

“Rb

86d

cc.

?k

25.6 d

cc.

0.261(12.7) 0.776(83) O.SS4(71) 0.521(46) 0.530(30) 0.776-D(13)

s’Y

3.3 d

es.

0.485(92)

9oy @Zr

2.67 d 78.5 h 5.7 h

cc.

2.75 d

B-

9oMO

*MO llllrn~

‘@I’d “‘Pd

’QCd

’ “Cd “)Sn

’ ‘sTe ““Te ‘%I

4.34 d 3.63 d 17.0d 462 d

53.5 h IlSd 6.0 d 3.26 d 4.2 d 6Od 25 min 20.1 h

“‘CS ,*sga ‘“Ce ‘&‘ce ““Nd ‘6SEr ‘“Hf ‘7pTa ‘s’Ta

30Y 2.43 d 73 h 285 d 3.4 d 10.4 h 1.87~ 1.82~ 5.1 d 21.7 d 121 d 90.7 h 15.4d 41.6h 7.2 h 14.6 h

“‘Pb

10.6 h

5.

0.307(86) O.O84(lGu) o&40-D(O.07) 0.088-D(3.6)

c..c. cc. e.c. C.C.

Be.c. cc. 8C.C.

z; 8CC. CC.

BCC. CC. CC. CC. I!-

CC. CC. 88-

IT, CC. 8-

0.909&9) 0.257(78) 0.203(6) 0.140-D(91)

C.C.

0.336-D(S0) 0.392~D(64) 0.255(2) 1.229-D(3) 0.228(88) 0.603(61) 1.691(11) 0.035(7) O&3(16) 0.564-D(18) 0.350(8) O&2(85) 0.273(15) 0.605-D(S) 0.134(11) 1.596-D(O.5) 0.182$23) 0.246;;) 0.354(11) 0.093-D(7) Ta x-rays 0.137(9) 0.129-D(26) 0.262(33) 0.569(0.3) 0.674(46) I .363(33) 0.239(e))

Refs 226 99

1,2 1.2

‘sMn@, n) “Co(p, pn) @Wp, 2pn) J9Co(n, Y)

O.O14/h(ZO) O.O66/h(3&20)* O.O28/h(40-30). 37b (t)

wu(p,

O.OlS/h(20) O.O12/h(19) O.O28/h(26) O.O09/h(SS-10) O.O04/h(sOO) O.O02/h(SOO) O.O48/h(6.+28) 14.9/h(4S-O) 2.7b (1)

86 229

““Kr(p, xn)

O.O07/h(22)

231

“‘Mo(p, spall) ““Rb@, xn) “‘Rb@, spall) *‘Sr(p, n) +WP, 2n) NLRbftx.xnl *Sr gj*(n, y) WP, o) 9wP, 4n)

O.O6O/h(SOO) O.l8/h(60) 0.3/h(84-51) O.O08/h(23) 2.7/h(26-20) O.O59/h(35) 1.3b (t) 0.8/h(21-IO)* N.D.

206-209

%Wn, Y1

0.14b (t) 3Sb (t) 2.28(56-55) 0.89(35-23) 0.52/h(22) 1.2b (1) O.O08/h(16) O.O18/h(SOO) O.O2S/h(20&177) 0.3b (t) lb(t)

192

n)

69Ga(p,2n) Gab, xn)

35.0 h 35.3 h

Yield (E) [mCi/A(MeV)]

As(P, spall) RbBr (p, spall) nWe@. pxn) “Wp, *‘Br(n,

xn) Y)

f .PRh(p, 3@‘Pd lo Wh(p, 4n) ‘O’Rh(P, a) lwCd(n, y) e ‘OpAg(d,2n) In@, spall) “‘In(p, 2pSn) “‘Cd@, y ) “‘Sn(n, y)

;:7,228

230 119

211, 232, 233 212,213 214 234 235

129 129 235 236

1,2

“‘Sb(p, 4n) f.p. ‘Wp, n)

N.D O.O93/h(2612)

139

“‘Xe(n, y)12$Xe ‘271(n,Y 1 12’I(p, 6n)

120b (t) 6b (t) l/h(70-53) 3.7/h(6S-43)

132

f.g I3 Cs(p, 6n) ‘39La(p, 6n) f.p. “‘Pr(p, 2n) ‘6JHo(p, n) “‘Ta(p, spall) ‘“Hf(p, 2n) “‘Ta(nn, y) “‘Ta(p, 4n) “‘Ta(d, 2n) 18’Re(n, y) ‘“WP, n) ‘wWb

Y)

“‘Au(p, 3n) 20PBi(a,2n) z09Bi(Li,Sn) *Ra (decay-f.p.) z8Th (decay-f.p.)

202 203

3.1/h(67-54) N.D.

217,235

3.4/h(33-12) N.D.

237 238 219 99

?&,h(22) N.D O.O4S/h(38-3 I) O.OOS/h(lS) 1lob(t) 0.05/h@-10) I I b (1) 4/h(28-17) 0.4/h(28-26) 0.26/h(6&38)

220 86,239 240 244 222 241-243 223 224 225

Radionuclide production for the biosciences Table 5. Main commercial radioouclides Life-science retail consumption (_ Ci/ycar, time of cod-use) Nuciide

$2

‘H “C ‘IF Wr “Ga %gppmTc

12.3 y 5730 y 14.3 d 27.7 d 78.3 h 66h/6h 68h “3Sn/“3mIn 115 d/99 min ,231 13.2h 1251 6Od ,,‘I 8.0 d “‘Xe 36.4 d 5.2d ‘33Xe w‘Tl 73h

see Table 4 4 4 I : 1 4 1 4 I I 1

1

1982

1987

>lOOQ 600 700 150 800 100,000 ~Mo) 150 40 Q’fSo) 75 1500 10,000 100 25,000

> 10,000 600 700 75 800 l20,Ooa 160 40 1250

so0

2500 10,000 too 25,000

2500

In the case of irradiation with an external beam, the power density can be manipulated by beam defocusing or scanning. An external beam is easier to steer and generally much more convenient to work with. These advantages may, however, be offset by a lower available external beam intensity, at least from a cyclotron accelerating positive ions. In the case of a linear accelerator or of a negative ion cyclotron, the efficiency with which a beam can be brought out of the machine into an external beam line is close to 100°%?.(u”*bl Thus, there is no advantage in using the internal beam, and irradiations for isotope production are generally conducted external to the accelerator. (c) Power dissipation Beam energies of tens of MeV, coupled with beam intensities of the order of 100 PA, lead to power dissipations in target structures of several kilowatts. Even with a defocused beam incident on a few square centimeters of target surface, the power dissipation will take place in a few cubic centimeters. Thus, elaborate target cooling is required to avoid melting of target structures. In addition, the target material must be chosen to resist radiolytic decomposition, evaporation and other processes leading to gas evolution or target disintegration. For safety, the target material may be separated from the machine or beam line vacuum by means of a “window”, consisting of a metal foil thick enough to resist the pressure differentials which may arise (for example) during target recovery. The passage of the beam through such a window also leads to heat deposition, and measures may be needed to remove this heat. At the highest beam currents, two windows with a helium gas coolant flow between them may be required.(25a) (d) Solid targets

Target materials are most commonly irradiated as solids and all or a major part of the target structure needs to be subsequently transported to the radiochemistry laboratory, to permit extraction and purification of the product radionuclide.

329

Many metals, particularly of intermediate melting point, are electroplated onto a copper backing providing good heat contact to the cooling system.tM) The front surface of a metallic target material, such as Tl, Cd or Zn, may be exposed directly to the beam within the accelerator vacuum system. This system is convenient, since no target de-encapsulation is subsequently required, and there is no beam energy loss in target windows. Glassy materials (such as TeO) can likewise be fused to a backing,‘*‘) while salts and powders are commonly compressed to pellet form and irradiated within appropriate metallic encapsulation.“‘) Alloys such as Cu,As sometimes offer particular advantages. oR)If the target material is of natural isotopic composition, economy of material during target preparation and recovery during the processing of an irradiated target is not a problem. The reverse is true if expensive isotopically-enriched material is being used. (e) Liquid targets Liquids can be irradiated by charged particle cyclotron beams, to the limit permitted by power dissipation and radiolytic decomposition. Currents of up to 25 PA of 10 MeV protons can be delivered to (e.g.) water volumes of a fraction of a millilitre(29j without boiling becoming a problem. Water of natural isotopic composition is a source of *‘N via the i60(p, a) reaction,(30) while water enriched in ‘*O is a source of “F by means of the (p, n) reaction, the radiofluorine being recovered as fluoride.(29*3i)Molten metals, inorganic and organic compounds have also been used as radionuclide production targets, sometimes in special systems permitting a vertical target orientation.(32) For example, molten NaI has been used in the production of ‘23Ivia 123Xeproduced by the 1271(p,Sn) reaction,(33j while iodine mixed with diiodomethane is used in a similar application at Harwell.(34) Likewise, molten cesium metal in a heat-pipe target system has been used in the production of 123Iand 12’Xevia the spallation reaction. (“) In each case, the reaction product activity is conveniently recovered by sparging the voiume above the liquid target material with a suitable sweep gas, usually helium. The use of a slurry of a target powder in a water medium has also been found effective for the production of i3N with 10 MeV protons.t3@ (J) Gus targets Perhaps the most extensive use of gaseous target materials has been in the production of radionuclides of carbon, nitrogen, oxygen and fluorine for positron emission tomography. Centres well known for work on this topic are Hammersmith Hospital in the U.K. (which produced a textbook, Ref. 37), Washington University in St Louis,(51 Brookhaven National Laboratory(‘Q and the University of Wisconsin,‘39) all in the U.S. Gas target systems have certain unique advantages and disadvantages to the chemist. The loading and

330

T. J. RUTH et ul.

unloading of target materials are easily accomplished under remote control, and the recovered material may be subjected to gas chemistry processing en route to the laboratory. Thus, radioactivity in a desired chemical form may be available very shortly after the end of bombardment.(qO’ Manipulation of the target gas mixture itself also permits some control over the radionuclide product chemistry.(4’) There are, however, two significant problems. First, in order to have enough target material in the beam to produce enough radionuclide product, it is often necessary to use long target chambers or elevated gas pressures. The latter in turn necessitate windows strong enough to withstand the pressure differentials with some reliability, in the face of beam irradiation. Increased window thickness increases power deposition in the window material, with degradation and straggling of the beam energy reaching the target material. Secondly, there is the phenomenon of the reduction of the gas density in the target region traversed by the beam, due to “beam heating”.‘42’ In a sealed target of fixed volume, the heat deposited causes a general increase in target gas pressure; however, there are also generated gas density inhomogeneities, and a gas target thick enough to stop a beam completely at low beam currents may fail to do so at higher beam currents, even though the beam energy remains unchanged. (‘j) Such effects reduce product yields below those calculated, or extrapolated from low current values. However, careful target design can promote recoveries up to 85% of theoretical values, even at beam currents above 20pA.@‘9”)

the desired product) being present only in minor proportions, if the incident projectile energy is properly controlled. This is particularly true if halflife differences or parent-daughter activity relationships can be exploited, in addition, to minimize the yield of such impurities. On the other hand, the products of the spallation reaction at intermediate energies will produce larger quantities of a wider range of impurity nuclides, for all except the lightest target nuclides. The procedures used for the separation and purification of radionuclides are generally adaptations of classical techniques. Thorough, useful compilations have been published.(‘,2*57-T9)

4.

Acknowledgements-The authors wish to thank June Lively and Diane Mellor for their tireless efforts in producing many versions of this review.

References Manual of RadioisotopeProduction.Technical

(g) Chemical separations The variety of radiochemical procedures employed to separate the product nuclide from the residual target material is as wide as the diversity of chemical species dealt with. The procedures do, however, have some characteristics in common. (i) Shielding and some degree of remote control are often needed.“**) The production of patient doses of 10mCi and more at the end of synthetic organic chemistry and radiopharmaceutical procedures may necessitate the separation of radionuclide quantities ranging from 100 mCi to 1 Ci or more from the irradiated target. Quantities at the lower end of this activity scale may be handled in a radiochemical fume hood with demountable lead brick shielding. In general, quantities more than about 1 Ci require proper hot cell facilities with substantial shielding, and remote manipulation facilities.@@ Semi-automated or automated (“robotics”) chemical systems for the production of radiogases in particular chemical forms, or for the synthesis of routine scanning agents, continue to be developed.‘47-56’ (ii) The radionuclide mixture produced by low energy nuclear reactions generally will contain the desired product as the dominant component, with impurity nuclides (particularly those isotopic with

Other Data

For further data on nuclear reactions, the interested reader is referred to the BNL compilation,(@‘) and for more data on radioisotope production to the compilation by Christman and Karlstrom.@‘) References (6,7,25 [a, b, c] and 62-83) contain information on nuclear decay data, medical cyclotrons, reaction compilations, and other information that may prove useful to the researcher on medical isotopes.

5.

6.

7.

8.

9. 10. 11. 12.

Report Series No. 63. Vienna: IAEA; 1966. RadioisotopeProductionand QualityControl. Technical Report Series No. 128. Vienna: IAEA; 1971. Poggenburg, J. K. The nuclear reactor and its products. Semin. Nucl. Med. 4: 229-243; 1974. Silvester, D. J.; Waters, S. L. Radionuclide Production. Radiopharmaceuticals II: Proc. Second. Int. Symp. Radiopharm., Seattle, Wash. Society of Nuclear Medicine; 1979: 727-744. Welch, M. J.; Ter-Pogossian, M. M. Preparation of short half-lived radioactive gases for medical studies. Radial. Res. 36: 580-587: 1968. Qaim, S. M. Nuclear dara relevant to cyclotron produced short-lived medical radioisotopes. JZudiochim. Acta 30: 147-162; 1982. Qaim, S. M.; Stocklin, G. Production of some medically important short-lived neutron-deficient radioisotopes of halogens. Radiochim.Acta 34: 25-40,1983. Vandecasteele, C.; Strijckmans, K. Targetry for the cyclotron production of short-lived radionuclides for medical use. Nucl. Instrum. Meth. Phys. Res. A236: 558-562; 1985. Crouxel, C.; Comar, D. Carbon-11, nitrogen-13 and oxygen-15-labelled molecules. Nucl. Med. Eiol. 13: 119-126; 1986. Martin, J. A. Cyclotrons-1978. Proc. Eighth Int. Conf. on Cyclotrons -and their Applications- IEEE Trans. Nucl. Sci. NS-26: 2443-2651: 1979. Wolf, A. P.; Jones, W. B. Cyclotrons for biomedical radioisotope production. Radiochim. Acta 34: l-7; 1983. Wolf, A. P. Cyclotrons, radionuclides, precursors, and demands for routine versus research compounds. Ann. Neural. 15 (Suppl.): Sl9-S24; 1984.

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Radionuclide production for the biosciences 13. Mausner, L. F.; Mirxadeh, S.; Srivastava, S. C. BLIP II: A new spallation radionuclide research and production facility. J. Labelled Compd. Radiopharm. 23: 1386-1388; 1986. 14. Grant, P. M.; Miller, D. A.; Gilmore, J. S.; O’Brien, H. A. Jr. Medium-energy spallation cross sections. I. RbBr irradiation with 800-MeV protons. Int. J. Appl. Radiat. Isot. 33: 415-417;

1982.

15. Pate, B. D. Medical Radioisotope Production at TRIUMF. Proc. 27th Conf on Remote Systems Tech., Am. Nucl. Sot.; 1979: 283-284. 16. Huszar, I.; Loepfe, E. Production of Cyclotron Isotopes for Medical Purposes at SINIEIR. SIN Physics Report No. 3 (April 1981). 5234 Villigen, Switzerland: Swiss Inst. for Nuclear Research. 17. Lambrecht, R. M. Radionuclide generators. Radiochim. Acta 34: _~ 924, _..

1983. -_

_

18. Guillaume, M.; Brihaye, C. Generators for short-lived gamma and positron emitting radionuclides: current status and prospects. Nucl. Med. Biol. 13: 89-100, 1986. 19. Radionuclide Generator Technology. Special Issue. Radiochim. Acta 41: 57-130; 1987. 20. Cummings, C. E.; Ogard, A. E.; Shaw, R. H. Target insertion and handling system for the LAMPF isotope production facility. Proc. 26th Conf on Remote Systems Tech. Am. Nucl. Sot.; 1978: 210-206. 21. Burgerjon, J. J.; Pate, B. D.; Blaby, R. E.; Page, E. G.; Lenz, J.; Trevitt, B. T.; Wilson, A. D. The TRIUMF 500-MeV, IOO-Microampere Isotope Production Facilitv. Proc. 27th Conf. on Remote Svstems Tech. Am. I&cl. Sot.; 1979: 285-291. ’ 22. Krasnov, N. N.; Dmitriyev, P. P.; Konrtantinov, I. 0.; Konjakin, N. A.; Ponomarev, A. A.; Ognev, A. A.; Romanchenkov, A. E.; Tuyev, V. M. Radioisotope Production in the 1.Ph.P.E. Cyclotron. Proc. Conf. on the Uses of Cyclotrons in Chemistry, Metallurgy and Biology. London: Butterworths; 1970: 159-167.

23. Pinto, G.; Straatmann, M.; Schlyer, D.; Currin, J.; Hendry, G. Target systems for radioisotope production. IEEE NS-30: 1797-1800, 1983. 24. (a) Rickey, M. E.; Smythe, R.; The acceleration and extraction of negative hydrogen ions in the C.U. cyclotron. Nucl. Instrum. Metho& 18-19: 66-69; 1962. (b) Burgerjon, J. J. H- Cyclotrons for radioisotope production. Nucl. Instrum. Methods Phvs. Res. BlO/ll: 951-956; 1985. 25. (a) Helus, F., editor. Radionuclide Production. Boca Raton. Fla.: CRC Press: 1983: Vols I and II. (b) Ruth, T.; Helus, F., editors. Proc. First Workshop on Targetry and Target Chemistry. Heidelberg, F.R.D.: DKFZ Press; 1987. (c) Helus, F.; McQuarrie, S.; Ruth, T., editors. Proc. Second Workshop on Targetry and Target Chemistry.

Heidelberg, F.R.D: DKFZ Press; 1988. 26. Neirinckx, R. D. High-yield production method of gallium-67 using an electroplated natural zinc or enriched zinc-66 target. Int. J. Appl. Radiat. Isot. 27: 1-4; 1976. 27. Assmus, K.;

Jager, K.; Schutz, R.; Schulz, F.; Schweickert, H. Routine production of iodine-123 at the karlsruhe isochronous cyclotron. IEEE Trans.

Nuci. Sci. NS-26: 2265-2268; 1979. 28. Blessing, G.; Qaim, S. M. An improved

internal Cu,As-alloy cyclotron target for the production of 75Br and “Br and separation of the by-product “Ga from the matrix activity. Int. J. Appi. Radiat. Isot. 35:

927-931; 1984. 29. Wieland, B. W.; Hendry,

G. 0.; Schmidt, D. G.; Bida, G.; Ruth, T. J. Efficient small-volume O-18 water targets for producing F-18 fluoride with low energy protons. J. Labelled Compd. Radiopharm. 23: 1205-1207;

1986.

30. Tilbury, R. S.; Dahl, J. R. “N Species formed by proton irradiation of water. Radiat. Res. 79: 22-33; 1979. 31. Kilboum, M. R.; Jerabek, P. A.; Welch, M. J. An improved [‘*O]water target for [‘*Flfluoride production. In; J.-Appl. Bad&. Isof. 36: 327-328; 1985. 32. Helus. F.: Wolber. G.: Mahtmka. I.: Laver. K.: MaierBorst,’ W. Vertical target syst& ‘for- the cyclotron production of positron emitters from melted targets. J. Labelled Compd. Radiopharm. 23: 1193-l 194; 1986. 33. Jungerman, J. A.; Lagunas-Solar, M. C. Cyclotron production of high-purity iodine-123 for medical applications. J. Radioanal. Chem. 65: 3145; 1981. 34. Cuninghame, J. G.; Morris, B.; Nichols, A. L.; Taylor, N. K. Large scale production of ‘u1 from a flowing liquid target using the (p, Sn) reaction. Int. J. Appl. Radial. Isot. 27: 597-603;

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35. Vincent, J. S.; Dougan, A. H.; Lyster, D. M.; Blue, J. W. A facility for the production of iodine-123 by the spallation of caesium. J. Radioanal. Chem. 65: 17-29; 1981. 36. Bida, G.; Wieland, B. W.; Ruth, T. J.; Schmidt, D. G.; Hendry, G. 0.; Keen, R. E. An economical target for nitrogen-13 production by proton bombardment of a slurry of C-13 powder in 16-O water. J. Labelled Cornid. Radioph&m. 23: 1217-1218; 1986. 37. Clark. J. C.: Buckinaham. P. D. Short-Lived Radioactive’ Gases’for C&al Gse. London: Buttenvorths; 1975. 38. Casella, V.; Ido, T.; Wolf, A. P.; Fowler, J. S.; MacGregor, R. R.; Ruth, T. J. Anhydrous F-18 labelled elemental fluorine for radiopharmaceutical preparation. J. Nucl. Med. 21: 750-757; 1980. 39. Hichwa, R. D.; Nickles, R. J. Targetry for the production of medical isotopes. IEEE NS-28: 1924-1927; 1981. 40. Beaver, J. E.; Finn, R. D.; Hupf, H. B. A new method for the production of high concentration oxygen-15 labelled carbon dioxide with protons. Znt. J. Appl. Radiat. Isot. 27: 195-197;

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41. Christman, D. R.; Finn, R. D.; Karlstrom, K. J.; Wolf, A. P. The production of ultra high activity “C-1abelled hydrogen cyanide, carbon dioxide, carbon monoxide and methane via the “N(p, a)“C reaction (XV). Int. J. Appl. Radial. Isot. 26: 435-442;

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42. Heselius, S-J.; Malmborg, P.; Solin, 0.; Langstrom, B. Studies of proton beam penetration in nitrogen-gas targets with respect to production and specific radioactivity of carbon-11. Appl. Radiat. Isot. 38: 49-57; 1987.

43. Wieland, B. W.; Schlyer, D. J.; Wolf, A. P. Charged particle penetration in gas targets designed for accelerator production of radionuclides used in nuclear medicine. Int. J. Appl. Radiat. Isot. 35: 387-396; 1984. 44. Vandervalle, T.; Vandecasteele, C. Optimisation of the production of “CO, by proton irradiation of nitrogen gas. Int. J. Appl. Rhdiat. Isot. 34: 1459-1464; 1983. 45. Wieland, B. W.; Hendry, G. 0.; Schmidt, D. G. Design and performance of targets for producing C- 11, N- 13, O-15 and F-18 with 11 MeV protons. J. Labelled Compd. Radiopharm. 23: 1187-1189; 1986. 46. Fowler. J. S.: Karlstrom. K.: Koehler. C.: Lambrecht. R. M.; ‘MacGregor, R. R.; Ruth, T. J.; Sceviour, W.; Wolf, A. P. A hot cell for the synthesis of lab&d organic compounds. Proc. 27th. C&f. Remote Systems Tech. Am. Nucl. Sot.; 1979: 310-313. 47. Fowler, J. S.; MacGregor, R. R.; Wolf, A. P.; Farrell. A. A.: Karlstrom. K. I.: Ruth. T. J. A shielded synthesis system for production of i-deoxy-2[‘*FJfluoro-D-glucose. J. Nucl. Med. 22: 376380; 1981. 48. Berger, G.; Maxiere, M.; Knipper, R.; Prenant, C.; Comar, D. Automated synthesis of “C-1abelled radiopharmaceuticals: imipramine, chlorpromazine,

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1979.

49. Barrio, J. R.; MacDonald,

N. S.; Robinson, G. D. Jr; Najafi, A; Cook, J. S.; Kuhl, D. E. Remote, semiautomated production of F-l&labelled 2deoxy-2-

flUOrO-D-ghCOSe.J. Nucl. Med. 22: 372-375; 1981. 50. Roeda, D.; Crouzel, C.; van der Jagt, P. J.; van Zanten,

51.

52.

53.

54.

55.

56.

57.

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