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Synthesis and structural characterization of the neutral indium (III) thiolate species In{(SCH2CH2)3N}
OMMUNICATIONS
ELSEVIER
Inorganic
Chemistry
Communications
I (1998) 164-166
Synthesis and structural characterization of the neutral indium( III) thiolate species In ( ( SCH,CH,) 3N) David J. Rose a, Jon Zubieta a,*, Alan J. Fischman b, Shawn Hillier b, John W. Babich b i’Department oj’Chemistr~, Syracuse University, Syracuse, NY 13244, USA h Department of Radio&J. Massachusetts General Hospital, Boston, MA 02214, USA Received 6 March 1998; accepted
16 April 1998
Abstract The neutral indium( III) thiolate species In{ (SCH,CH,) S.A. All rights reserved. Keywords: Crystal structures;
Indium complexes;
7N] was synthesized
1387.7003/98/$19.00 PIf s 1387.7003(
0 1998 Elsevier Science
Thiolate complexes
The development of brain imaging agents for use in the early detection of Alzheimer’s and Parkinson’s disease [ 1,2] is an area of significant contemporary interest. In order to cross the blood brain barrier, such agents must conform to the requirements of low molecular weight ( < 500 dalton), of lipophilicity, and of charge neutrality [ 31. Compounds of the radioisotopes of indium and gallium, 67Ga (y-emitter, t,,2=3.25 days), 68Ga (p’-emitter, t,,,=68.1 min) and “‘In ( y-emittor, t, ,2 = 2.81 days), have proved effective in PET and y-imaging [ 4-61. However, the design of radiopharmaceuticals labeled with gallium and indium is complicated by the strong affinity of both M3+ species for the plasma protein transferrin (log K for Ga( III)-transferrin, 20.3)) requiring design of ligands forming highly stable complexes to prevent exchange of metal from the radiopharmaceutical to transferrin [ 7,8]. While aminophenolate and other oxygen/nitrogen donors have been demonstrated to impart high stability to Ga( III) chelates [ 91, aminothiolate ligands are more effectiveforIn(II1) [lO,ll]. Our previous investigations [ 121 have demonstrated that neutral, stable gallium and indium thiolates may be readily prepared in good yield in aqueous solution. In an effort to design more effective thiolate ligands, the tetradentate donor tris( 2-mercaptoethyl)amine has been synthesized and its indium complex [In{ (SCH,CH,),N)] (1) isolated and structurally characterized. Tris(2-mercaptoethyl)amine was prepared in a one-pot synthesis by treating tris( chloroethyl) amine hydrochloride with thioruea in HCl, followed by addition of base [ 131: * Corresponding
and structurally characterized.
author. Tel.: + l-3 15-443 2925; Fax: + l-3 15.443 4070 0 1998 Elsevier Science S.A. All rights reserved. 98)00043-4
HCI +
A
[N{CH,CH,-
SC(NH2)
*I3 ].3Cl-
NaOH ;
[N(CHzCHzW
3 1
(NSsH3)
The reaction of N&H, with In(NO,), in water yielded [In{ ( SCH,CH,)jN}] ( 1) in 20% yield as a white solid. Ethanol/water solutions of 1 were indefinitely stable, and crystals of 1 were readily isolated as white needles ‘. The good solubility of 1 in aqueous solutions suggests that the long bridging In-S bond of the solid phase polymer structure (vide infra) is readily replaced by solvent molecules in solution. It is noteworthy that the analogous gallium complex is insoluble, suggesting that the shorter Ga-S bridge bond is not substitutionally labile with respect to solvent molecules. However, the formation of such polymeric materials on the tracer level is unlikely in view of the high dilution of the radiolabel. As shown in Fig. 1, the structure of 1 ’ consists of a onedimensional linked chain of indium centers bridged through thiolate groups of the NS3 ligands. The In sites adopt distorted trigonal bipyramidal geometry, defined by three equatorial ’Satisfactory elemental analyses. FAB ( + ) mass spectrum: m/z 309 (M, 76%). ’Crystal data for C,2H24N2ShInZ: monoclinic P2, lc, a = 8.0267(2), b=22.2692(5), c= 11.4360(2) A, /3=95.345( I)“, V=2035.28(8) A’, Z= 4, D,,,, = 2.018 g cm-‘; structure solution and refinement based on 3567 reflections converged at R, = 0.0790, wR2 = 0.1353.
D.J. Rose et 01. /Itzorgunic Chemistry Comnunications
165
I (1998) 1644166
Fig. I, (a) A view of the asymmetric unit of [In{ ( SCHICH2),N )I, showing 50% thermal ellipsoids and the atom-labeling scheme. Selected bond lengths (A) and angles (“): Inl-Nl. 2.39(l); Inl-Sl, 2.429(3); Inl-S2, 2.424(3); InlLS3, 2.517(3); Inl-S4, 2.649(3); In2-N2, 2.41 (I); In2S4. 2.526(3); In2-SS, 2.43613); In2-S6, 2.430(3); In2-S3. 2.636(3); Inl-S3-In2, 120.0( I ): Inl-S4-In2, 122.1( I ). (b) A view of the puckered one-dimensional chain achieved through bridging at thiolates S3 and S4.
Blood
Liver
Kidnev
51
5
30
60
5
Muscle
GI tract
30
5
50
60
Bone 2.5-
0.5 0.4 0.3 09 0.1 0
6i
30
Time (Min.) In-OAc
0
In-NS3
h9 Ga-OAc
W Ga-NS3
and “Ga-NS1 Fig. 2. Biodistrihution data in rats as c/c dose per gram for “‘In-acetate. “‘In-NS,, “Ga-acetate hone at 5, 30, and 60 min. Additional data in tabular form is available, see Supplementary material.
thiolate donors and by nitrogen and sulfur donors in the axial positions. Thus, the NS, ligand adopts a capping geometry with the nitrogen donor at the apex and the three sulfur ligands in the equatorial plane. One sulfur from each NS3 ligand
1
in blood, kidney, liver, GI tract, muscle and
bridges to a neighboring In site to complete the coordination geometry and to link the In sites into the one-dimensional chain structure. Compound 1 exhibits three distinct In-S bond distances, reflecting the different bonding modes adopted by
166
D.J. Rose et al. /Inorganic
Chemists
the thiolate donors: (i) In-S(av.) of 2.429(8) A for the terminally coordinated thiolates in the equatorial plane, (ii) In-S (av.) of 2.522(7) A for the bridging thiolate in the equatorial plane, and (iii) In-S (av.) of 2.642( 6) A for the axial bridging thiolate. The unusual trigonal bipyramidal geometry adopted by In in 1 reflects the constraints imposed by the tripodal NS3 ligand, whose Re and Tc complexes also exhibit trigonal bipyramidal geometries [ 141. In order to assess the potential of N&-coordinated 67Ga and ” ‘In for diagnostic applications, the biodistributions of ” ‘In-acetate, ” ‘In-N&, 67Ga-acetate and 67Ga-NS, were studied. The results are given in Fig. 2, expressed as percent injected dose per gram. In genera1 the NS3 chelate complexes of Ga and In demonstrate unique biological distributions which are significantly different from their corresponding acetate complexes. The tissue distributions of the Ga- and In-NS, complexes are qualitatively similar in many tissues with major differences found in blood (In-N& > Ga-NS,), liver (In-N& < Ga-NS,) and kidney (In-N& > Ga-NS,). For most other tissues there is less than a factor of two between the peak activity of the metal complexes. The rapid accumulation of In-N& in the kidney may be due to the larger radius of the In allowing access to solvent ions. This may impart a more polar and, hence, hydrophilic character to the compound that would facilitate renal excretion. In contrast, the smaller ionic radius of Ga may allow the chelate to shield the metal from such solvent ions, imparting a more lipophilic character. This may explain the greater accumulation of Ga-NS, in the liver. The low blood levels of Ga-NS, suggest that the complex is relatively stable in vivo to transchelation by transferrin, an iron binding protein which plays a major role in the distribution of weaker Ga complexes such as the Ga-acetate studied here. The NS3 Iigand system presented here represents a novel approach to the development of neutral Ga and In complexes. Structural derivatives of this ligand system should allow further exploitation of medically useful isotopes of Ga and In,
Cornrnunicutions I (1998) 164-166
especially 6XGa, a generator produced positron emitting radionuclide with a half-life of 68 min. Further ligand development is underway which should lead to complexes with unique and useful properties for diagnostic evaluation, such as myocardial and cerebra1 blood flow.
Supplementary
material
Additional biodistribution data in tabular form is available from the authors on request.
References I ‘I S.K. Meegalla, K. Plassl, M.-P. Kung, S. Chumpradit,
D.A. Stevenson, S.A. Kushner, W.T. McElgin, P.D. Mozley, H.F. Kung, J. Med. Chem. 40 ( 1997) 9 and Refs. therein. 121 J.J. Frost, A.J. Rosier, S.G. Reich, J.S. Smith, M.D. Ehlers, S.H. Snyder, H.T. Ravert, R.F. Dannals, Ann. Neural. 34 ( 1993) 423. 131 J.E. Bollinger, J.T. Mague, C.J. O’Connor, W.A. Banks, D.M. Roundhill, J. Chem. Sot. Dalton Trans. ( 1995) 1677 and Refs. therein. 141 V.L. Alvarez, M.L. Wen, C. Lee, A.D. Lopes, J.D. Rodwell, T.J. McKearn, Nucl. Med. Biol. 13 ( 1986) 347. [51 C. Loc’h, B. Maziere, D. Comar, J. Nucl. Med. 21 ( 1980) 171, [61 M. Koiaumi, K. Endo, M. Kunimatsa, H. Sakahara, T. Nakashima, Y. Kawamura, Y. Watanabe, Y. Ohmomo, Y. Arano, J. lmmunol. Methods 104 (1987) 93. 171 S.M. Moerlein, M.J. Welch, Int. J. Nucl. Med. Biol. 8 ( 1981) 277. 181 W.R. Harris, Y.C. Chen, K. Wein, Inorg. Chem. 33 ( 1994) 4991, 191 P. Caravan, C. Orwig, Inorg. Chem. 36 ( 1997) 236. I101 Y. Li, A.E. Martell, R.D. Hancock, J.H. Reibenspies, C.J. Anderson, M.J. Welch, Inorg. Chem. 35 ( 1996) 404. [Ill R. Ma, M.J. Welch, J. Reibenspies, A.E. Martell, Inorg. Chim. Acta 236 (1995) 75. 1121 D.J. Rose, Y.-D. Chang, Q. Chen, P.B. Kettler, J. Zubieta, Inorg. Chem. 34 ( 1995) 3973. It31 P. Barbaro, C. Bianchini, G. Scapacci, D. Masi, P. Zanello, Inorg. Chem. 33 (1994) 3180. 1141 H. Spies, M. Glaser, H.-J. Pietrsch, F.E. Hahn, G. Kintrel, T. Liigger, Angew. Chem., Int. Ed. Engl. 33 ( 1994) 1354.
ELSEVIER
Inorganic
Chemistry
Communications
I (1998) 164-166
Synthesis and structural characterization of the neutral indium( III) thiolate species In ( ( SCH,CH,) 3N) David J. Rose a, Jon Zubieta a,*, Alan J. Fischman b, Shawn Hillier b, John W. Babich b i’Department oj’Chemistr~, Syracuse University, Syracuse, NY 13244, USA h Department of Radio&J. Massachusetts General Hospital, Boston, MA 02214, USA Received 6 March 1998; accepted
16 April 1998
Abstract The neutral indium( III) thiolate species In{ (SCH,CH,) S.A. All rights reserved. Keywords: Crystal structures;
Indium complexes;
7N] was synthesized
1387.7003/98/$19.00 PIf s 1387.7003(
0 1998 Elsevier Science
Thiolate complexes
The development of brain imaging agents for use in the early detection of Alzheimer’s and Parkinson’s disease [ 1,2] is an area of significant contemporary interest. In order to cross the blood brain barrier, such agents must conform to the requirements of low molecular weight ( < 500 dalton), of lipophilicity, and of charge neutrality [ 31. Compounds of the radioisotopes of indium and gallium, 67Ga (y-emitter, t,,2=3.25 days), 68Ga (p’-emitter, t,,,=68.1 min) and “‘In ( y-emittor, t, ,2 = 2.81 days), have proved effective in PET and y-imaging [ 4-61. However, the design of radiopharmaceuticals labeled with gallium and indium is complicated by the strong affinity of both M3+ species for the plasma protein transferrin (log K for Ga( III)-transferrin, 20.3)) requiring design of ligands forming highly stable complexes to prevent exchange of metal from the radiopharmaceutical to transferrin [ 7,8]. While aminophenolate and other oxygen/nitrogen donors have been demonstrated to impart high stability to Ga( III) chelates [ 91, aminothiolate ligands are more effectiveforIn(II1) [lO,ll]. Our previous investigations [ 121 have demonstrated that neutral, stable gallium and indium thiolates may be readily prepared in good yield in aqueous solution. In an effort to design more effective thiolate ligands, the tetradentate donor tris( 2-mercaptoethyl)amine has been synthesized and its indium complex [In{ (SCH,CH,),N)] (1) isolated and structurally characterized. Tris(2-mercaptoethyl)amine was prepared in a one-pot synthesis by treating tris( chloroethyl) amine hydrochloride with thioruea in HCl, followed by addition of base [ 131: * Corresponding
and structurally characterized.
author. Tel.: + l-3 15-443 2925; Fax: + l-3 15.443 4070 0 1998 Elsevier Science S.A. All rights reserved. 98)00043-4
HCI +
A
[N{CH,CH,-
SC(NH2)
*I3 ].3Cl-
NaOH ;
[N(CHzCHzW
3 1
(NSsH3)
The reaction of N&H, with In(NO,), in water yielded [In{ ( SCH,CH,)jN}] ( 1) in 20% yield as a white solid. Ethanol/water solutions of 1 were indefinitely stable, and crystals of 1 were readily isolated as white needles ‘. The good solubility of 1 in aqueous solutions suggests that the long bridging In-S bond of the solid phase polymer structure (vide infra) is readily replaced by solvent molecules in solution. It is noteworthy that the analogous gallium complex is insoluble, suggesting that the shorter Ga-S bridge bond is not substitutionally labile with respect to solvent molecules. However, the formation of such polymeric materials on the tracer level is unlikely in view of the high dilution of the radiolabel. As shown in Fig. 1, the structure of 1 ’ consists of a onedimensional linked chain of indium centers bridged through thiolate groups of the NS3 ligands. The In sites adopt distorted trigonal bipyramidal geometry, defined by three equatorial ’Satisfactory elemental analyses. FAB ( + ) mass spectrum: m/z 309 (M, 76%). ’Crystal data for C,2H24N2ShInZ: monoclinic P2, lc, a = 8.0267(2), b=22.2692(5), c= 11.4360(2) A, /3=95.345( I)“, V=2035.28(8) A’, Z= 4, D,,,, = 2.018 g cm-‘; structure solution and refinement based on 3567 reflections converged at R, = 0.0790, wR2 = 0.1353.
D.J. Rose et 01. /Itzorgunic Chemistry Comnunications
165
I (1998) 1644166
Fig. I, (a) A view of the asymmetric unit of [In{ ( SCHICH2),N )I, showing 50% thermal ellipsoids and the atom-labeling scheme. Selected bond lengths (A) and angles (“): Inl-Nl. 2.39(l); Inl-Sl, 2.429(3); Inl-S2, 2.424(3); InlLS3, 2.517(3); Inl-S4, 2.649(3); In2-N2, 2.41 (I); In2S4. 2.526(3); In2-SS, 2.43613); In2-S6, 2.430(3); In2-S3. 2.636(3); Inl-S3-In2, 120.0( I ): Inl-S4-In2, 122.1( I ). (b) A view of the puckered one-dimensional chain achieved through bridging at thiolates S3 and S4.
Blood
Liver
Kidnev
51
5
30
60
5
Muscle
GI tract
30
5
50
60
Bone 2.5-
0.5 0.4 0.3 09 0.1 0
6i
30
Time (Min.) In-OAc
0
In-NS3
h9 Ga-OAc
W Ga-NS3
and “Ga-NS1 Fig. 2. Biodistrihution data in rats as c/c dose per gram for “‘In-acetate. “‘In-NS,, “Ga-acetate hone at 5, 30, and 60 min. Additional data in tabular form is available, see Supplementary material.
thiolate donors and by nitrogen and sulfur donors in the axial positions. Thus, the NS, ligand adopts a capping geometry with the nitrogen donor at the apex and the three sulfur ligands in the equatorial plane. One sulfur from each NS3 ligand
1
in blood, kidney, liver, GI tract, muscle and
bridges to a neighboring In site to complete the coordination geometry and to link the In sites into the one-dimensional chain structure. Compound 1 exhibits three distinct In-S bond distances, reflecting the different bonding modes adopted by
166
D.J. Rose et al. /Inorganic
Chemists
the thiolate donors: (i) In-S(av.) of 2.429(8) A for the terminally coordinated thiolates in the equatorial plane, (ii) In-S (av.) of 2.522(7) A for the bridging thiolate in the equatorial plane, and (iii) In-S (av.) of 2.642( 6) A for the axial bridging thiolate. The unusual trigonal bipyramidal geometry adopted by In in 1 reflects the constraints imposed by the tripodal NS3 ligand, whose Re and Tc complexes also exhibit trigonal bipyramidal geometries [ 141. In order to assess the potential of N&-coordinated 67Ga and ” ‘In for diagnostic applications, the biodistributions of ” ‘In-acetate, ” ‘In-N&, 67Ga-acetate and 67Ga-NS, were studied. The results are given in Fig. 2, expressed as percent injected dose per gram. In genera1 the NS3 chelate complexes of Ga and In demonstrate unique biological distributions which are significantly different from their corresponding acetate complexes. The tissue distributions of the Ga- and In-NS, complexes are qualitatively similar in many tissues with major differences found in blood (In-N& > Ga-NS,), liver (In-N& < Ga-NS,) and kidney (In-N& > Ga-NS,). For most other tissues there is less than a factor of two between the peak activity of the metal complexes. The rapid accumulation of In-N& in the kidney may be due to the larger radius of the In allowing access to solvent ions. This may impart a more polar and, hence, hydrophilic character to the compound that would facilitate renal excretion. In contrast, the smaller ionic radius of Ga may allow the chelate to shield the metal from such solvent ions, imparting a more lipophilic character. This may explain the greater accumulation of Ga-NS, in the liver. The low blood levels of Ga-NS, suggest that the complex is relatively stable in vivo to transchelation by transferrin, an iron binding protein which plays a major role in the distribution of weaker Ga complexes such as the Ga-acetate studied here. The NS3 Iigand system presented here represents a novel approach to the development of neutral Ga and In complexes. Structural derivatives of this ligand system should allow further exploitation of medically useful isotopes of Ga and In,
Cornrnunicutions I (1998) 164-166
especially 6XGa, a generator produced positron emitting radionuclide with a half-life of 68 min. Further ligand development is underway which should lead to complexes with unique and useful properties for diagnostic evaluation, such as myocardial and cerebra1 blood flow.
Supplementary
material
Additional biodistribution data in tabular form is available from the authors on request.
References I ‘I S.K. Meegalla, K. Plassl, M.-P. Kung, S. Chumpradit,
D.A. Stevenson, S.A. Kushner, W.T. McElgin, P.D. Mozley, H.F. Kung, J. Med. Chem. 40 ( 1997) 9 and Refs. therein. 121 J.J. Frost, A.J. Rosier, S.G. Reich, J.S. Smith, M.D. Ehlers, S.H. Snyder, H.T. Ravert, R.F. Dannals, Ann. Neural. 34 ( 1993) 423. 131 J.E. Bollinger, J.T. Mague, C.J. O’Connor, W.A. Banks, D.M. Roundhill, J. Chem. Sot. Dalton Trans. ( 1995) 1677 and Refs. therein. 141 V.L. Alvarez, M.L. Wen, C. Lee, A.D. Lopes, J.D. Rodwell, T.J. McKearn, Nucl. Med. Biol. 13 ( 1986) 347. [51 C. Loc’h, B. Maziere, D. Comar, J. Nucl. Med. 21 ( 1980) 171, [61 M. Koiaumi, K. Endo, M. Kunimatsa, H. Sakahara, T. Nakashima, Y. Kawamura, Y. Watanabe, Y. Ohmomo, Y. Arano, J. lmmunol. Methods 104 (1987) 93. 171 S.M. Moerlein, M.J. Welch, Int. J. Nucl. Med. Biol. 8 ( 1981) 277. 181 W.R. Harris, Y.C. Chen, K. Wein, Inorg. Chem. 33 ( 1994) 4991, 191 P. Caravan, C. Orwig, Inorg. Chem. 36 ( 1997) 236. I101 Y. Li, A.E. Martell, R.D. Hancock, J.H. Reibenspies, C.J. Anderson, M.J. Welch, Inorg. Chem. 35 ( 1996) 404. [Ill R. Ma, M.J. Welch, J. Reibenspies, A.E. Martell, Inorg. Chim. Acta 236 (1995) 75. 1121 D.J. Rose, Y.-D. Chang, Q. Chen, P.B. Kettler, J. Zubieta, Inorg. Chem. 34 ( 1995) 3973. It31 P. Barbaro, C. Bianchini, G. Scapacci, D. Masi, P. Zanello, Inorg. Chem. 33 (1994) 3180. 1141 H. Spies, M. Glaser, H.-J. Pietrsch, F.E. Hahn, G. Kintrel, T. Liigger, Angew. Chem., Int. Ed. Engl. 33 ( 1994) 1354.