Synthetic and Structural Aspects of Technetium ... - ACS Publications

6 Synthetic and Structural Aspects of Technetium Chemistry as Related to Nuclear Medicine EDWARD DEUTSCH

Downloaded by PRINCETON UNIV on November 13, 2014 | http://pubs.acs.org Publication Date: December 22, 1980 | doi: 10.1021/bk-1980-0140.ch006

Department of Chemistry, University of Cincinnati, Cincinnati, OH 45221 B. L . BARNETT Miami Valley Laboratories, Procter & Gamble Company, Cincinnati, O H 45239

The use and importance of technetium-99m in nuclear medicine has been noted many times (1-4), and is further discussed by Marzilli et al. in this symposium (5). However, realization of the full potential of technet ium-99m for diagnostic imaging of internal organs will require a much more extensive and detailed knowledge of technetium chemistry than is now available (1-5). This review covers some recent developments in the synthetic and structural aspects of technetium chemistry that may be relevant to the preparation, use, and understanding of the mode of action, of technetium radiopharmaceuticals. Synthesis Current Radiopharmaceutical Synthesis. The aqueous chemistry of technetium is dominated by the oxidizing power of soluble T c O ^ and the thermodynamic stability of insoluble T c 0 . A l l technetium-99m radiopharmaceuticals, except pertechnetate itself, are prepared by the aqueous reduction of pertechnetate in the presence of a potential ligand to prevent T c 0 deposition (2). The most commonly employed reductant is stannous chloride, although many other reductants can, and have, been used (1,2). 2

2

Tc0

4

+ L + excess reductant

T c - L complex

(1)

While widely used, this procedure is subject to several difficulties and limitations, (a) It allows introduction of only one type of ligand, or one distribution of ligands, into the technetium radiopharmaceutical, (b) It does not allow specific control over the final oxidation state, coordination number, coordination geometry, etc. of the technetium in the T c - L product, (c) The reductant, especially Sn, is often incorporated into the final product (1,6). (d) The excess reductant is injected into the patient; tin(II) has a long biological half-life (7) and causes several deleterious side effects (8). In addition, it is very unlikely for the general redox procedure described by eq. 1 to yield a single, well-defined product complex. Since 0-8412-05 88-4/ 80/47-140-103$05.00/0 © 1980 American Chemical Society In Inorganic Chemistry in Biology and Medicine; Martell, A.; ACS Symposium Series; American Chemical Society: Washington, DC, 1980.

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these preparations are conducted in dilute aqueous solution, in most cases the product radiopharmaceutical will consist of a distribution of T c - L complexes (in addition to the possible contaminants TcC>2 and T c O i+). Figure 1 shows an H P L C chromatogram (9) resulting from separation of T c ( N a B H 4 )-HEDP, a mixture obtained by NaBHi+ reduction of T c O i+~ in the presence of (l-hydroxyethylidene)diphosphonate (HEDP). It is clear from Figure 1 that T c ( N a B H i t ) - H E D P is not a single species, but rather is a complicated mixture of H E D P - T c complexes. Synthesis by Substitution Routes. Many of the limitations inherent in the redox route described above can be avoided by preparation of technetium-99m radiopharmaceuticals by a substitution route, i.e. the classical substitution of ligands onto a pre-reduced and isolated technetium center. Substitution routes allow control over the oxidation state and ligand environment of the technetium product, and permit the synthesis of complexes containing different ligands. By substitution routes it should be possible to prepare series of complexes in which some ligands are held fixed while others are varied in a systematic fashion to affect biological specificity. Recent work has focused on the use of two specific reduced technetium centers as substrates for substitution reactions: T c X and T c O X ^ ~ (X = CI, Br). The chemistry of the T c O X ^ " system has been developed principally by Davison and co-workers (10). Both of these centers are synthesized from pertechnetate, the starting material for all radiopharmaceutical preparations (2,5), by simple H X reduction: e.g., 6

Tc0 " + 9H

+

+ 9Br"

^ £

Tc0 " + 6H

+

+ 6Br"

5L$

4

4

Tc

I V

Br

6

2

" + 4 H 0 + 1.5Br 2

T c O B r " + 3H 0 + Br V

4

2

2

2

2

(2) (3)

The only difference between the two preparations is the temperature at which the reduction is conducted; at low temperatures the Tc(V) species TcOX is kinetically trapped and can be isolated, whereas at higher temperatures the Tc(V) complex suffers further reduction to yield the Tc(IV) species T c X ~ (10,11). Other potential substances for radiopharmaceutical synthesis by substitution reactions include the undefined, reduced Tc-glucoheptonate complex (12) and the recently reported, lipophilic technetium(V) species Tc(HBPz~^7ci2 O ( H B P z ~ = hydrotris(l-pyrazolyDborato ligand) (13). By substituting H E D P onto T c B r " we have recently been able to generate a radiopharmaceutical with biological properties very similar to those of radiopharmaceuticals prepared by the normal redox route (14). The material prepared by substitution is designated T c - H E D P , while those prepared by N a B H i * and Sn(II) reduction of pertechnetate in the presence of H E D P are designated TcfNaBH^)-HEDP and Tc(Sn)-HEDP respectively. Figure 2 compares the biodistributions of these three agents in rats, while Figure 3 compares images of beagle dogs obtained using these agents. It is clear from these figures that all three preparations yield excellent skeletal imaging agents, thus demonstrating that synthesis of technetium radiopharmaceuticals by a substitution route is practicable. This conclusion is 4

6

2

3

6

2

In Inorganic Chemistry in Biology and Medicine; Martell, A.; ACS Symposium Series; American Chemical Society: Washington, DC, 1980.


0 '

Figure 1.

HPLC

10

20 (min)

30

separation of aqueous "Tc(NaBH,J-HEDP

TIME

mixture

40


o


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Figure 2. Comparative biodistributions of Tc-HEDP, Tc(Sn)-HEDP, Tc(NaBH )-HEDP in Sprague Dawley rats at 3 h post iv dose. Each represents the average of 5 determinations. 99m

99m

99m

/t

Figure 3.

and point

Comparative scintiphotos of beagle dogs imaged with Tc-HEDP, Tc(NaBH )-HEDP, and Tc(Sn)-HEDP at 3 h post iv dose 99ra

99m

4

99m


6.

Tc

DEUTSCH AND BARNETT

Chemistry

107

supported by a recent report (15) in which an efficacious Tc-dimercaptosuccinic acid kidney imaging agent was prepared by ligand substitution onto TcBr 6*". In summary, substitution routes have the potential of introducing hitherto unattainable flexibility and subtlety into the preparation of technetium radiopharmaceuticals. As currently being developed, these routes should lead to new classes of technetium radiopharmaceuticals, the properties of which will be considerably different and more easily controlled than those of complexes prepared by the standard Sn(II) reduction of pertechnetate.


Structure Because of the nascent state of technetium chemistry, considerable emphasis is currently being given to the characterization of technetium complexes by single crystal x-ray structure analysis. These analyses provide a firm foundation upon which subsequent development and elaboration of technetium chemistry may be based. Approximately twenty technetium complexes have been characterized by single crystal x-ray methods (1), and several of the resulting structures have considerable relevance to radiopharmaceutical development. Structures of Tc(V) Complexes Prepared in Aqueous Media. Figure 4 shows the structure of the T c O C l i i " anion, recently determined by the combined research groups of Cotton, Davison and Day (16), while Figures 5 and 6 (17,18) show the structures of dithiolato complexes which may be prepared by ligand substitution onto the T c O C l i T center (10). These structures are dominated by the oxo ligand which induces such a strong structural trans effect (19) that the trans coordination site is vacant, and which is so sterically demanding that the other four ligating atoms are severely bent away from the Tc=0 linkage (13). Figures 4-6 also emphasize that there are three distinct types of coordination sites in five-coordinate oxo complexes: the oxo oxygen atom is tightly bound and inert to substitution, the site trans to the oxo group has only weak ligand affinity and is very labile, while the four planar sites have intermediate metalligand bond strength and intermediate substitution lability. Figure 7 shows the structure of T c ( H B P z 3 j C l 0 (13) which can be prepared by substitution of HBPZ3"" onto T c O C l i t " (11). Again, the oxo group dominates the structural description of this complex. The nitrogen atom trans to the Tc=0 linkage is 0.17A further from the technetium center than are the other two nitrogen atoms (which are trans to chloride ligands), showing that again the oxo group induces a large structural trans effect even though the tridentate H B P z " ligand suppresses five-coordination. Also, the large steric requirements of the oxo ligand cause the cis ligands to bend away from the Tc=0 linkage and towards the trans pyrazolyl ring (13). Figure 8 shows the structure of Tc(dmg)2(SnCl3)(OH) (dmg = dimethylglyoxime in unknown protonation state), which contains a seven-coordinate technetium(V) center connected to a tin(IV) center through an oxygen atom bridge (6). The observed five-, six- and seven-coordinate complexes of Figures 2

0

3


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O

Journal of the American Chemical Society Figure 5.

Figure

A perspective view of the TcO(SCH C(0)S) ~ 2

2

anion (17)

6. A perspective view of the TcO(SCH CH S) ~ anion (18; 2

2

2


DEUTSCH AND BARNETT

Tc

109

Chemistry


6.

Figure 8.

A

perspective view of Tc(dmg) (SnCl )(OH) where dmg represents dimethylglyoxime in an unknown protonation state (6) 3

3


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CHEMISTRY IN BIOLOGY A N D

MEDICINE

4-8 dramatically illustrate that reduced technetium complexes are not restricted to six-coordinate, octahedral structures as is often assumed in the radiopharmaceutical literature. A l l these complexes were prepared in aqueous, aerobic media, all contain technetium in the +5 oxidation state, and all contain either an oxo ligand or, in the case of Tc(dmg) (SnCl )(OH), a bridging oxygen atom which may reasonably be assumed to be derived from a Tc=0 linkage (6). It is therefore likely that the T c =0 moiety will be a predominant feature in the chemistry of technetium radiopharmaceuticals; the different character of the equatorial and axial ligation sites surrounding this moiety must, therefore, be taken into consideration in the design and synthesis of new radiopharmaceuticals.


3

3

Structures of Other Relevant Technetium Complexes. It was noted above that technetium(V) can exhibit five-, six-, and seven-coordination. Moreover, in 1960 Fergusson and Nyholm reported (20) the preparation, and indirect characterization, of the eight-coordinate technetium(V) complex^ [Tc(diars)2Cl i* ] , which was synthesized by oxidation of [Tc(diars) Cl ] with molecular chlorine (diars = o-pheny|enebis [dimethylarsinej ). Structural characterization of [ Tc(diars72 CI ] and [Tc(diars) CI ] (21) shows that the Tc(III) starting material has trans octahedral coordination geometry (Figure 9) and the Tc(V) product has D , dodecahedral coordination geometry (Figure 10), establishing the preparative reaction as the first known example of oxidative addition from a six-coordinate to an eightcoordinate complex (21). T h e stability of this particular eight-coordinate species, [Tc(diars) Cl ] , undoubtedly results in great part from the presence of the diars ligands which are known to promote high coordination numbers (22). However, even for those reactions in which the eightcoordinate products are metastable or unstable, oxidative addition to sixcoordinate technetium complexes has great potential as a synthetic route for the interconversion of octahedral technetium complexes and the ultimate synthesis of new technetium radiopharmaceuticals. Figure 11 shows the structure of T c C l s ~ (23) which contains a metal-metal bond and which is formed under conditions that are not remote from those used in radiopharmaceutical syntheses. This complex can undergo substitution reactions, e.g. to yield T c ( O O C C ( C H ) ) ^ C ^ shown in Figure 12 (24), and therefore, could be a precursor to a variety of components in radiopharmaceutical mixtures. Figure 13 shows the structure of t r - [ T c ( N H ) (NO)(OH ) ] determined by the research group of J . L . Hoard (25). This complex is the first characterized member (26) of what should be a large class of nitrosyltechnetium complexes analogous to the well known nitrosyl-ruthenium complexes. The NO ligand stabilizes low oxidation states and T c - N O centers should provide suitable templates for synthesis of a variety of radiopharmaceuticals. 2

2

2

2

h

2

+

2

z+

2

3

2

3

3

2 +

3

1+

2

Structures of Diphosphonate Complexes. Diphosphonate ligands are widely used to prepare Tc-99m skeletal imaging agents and Tc-99m myocardial infarct imaging agents (1,2). The constitutions, and associated acronyms, of several diphosphonates are shown below along with that of the related ligand pyrophosphate:



6.

DEUTSCH AND BARNETT

Tc

111

Chemistry

Figure 9. A perspective view of the [Tc(diars) >Cl Y cation where diars represents o-phenylenebis(dimethylarsine) (21) 2

C4

Figure 10. A perspective view of the [Tc(diars) Cl,X cation where diars represents o-phenylenebis(dimethylarsine (21) 2


INORGANIC


112

Figure 12. A perspective view of Tc (OOCC(CH ) ) Cl (24)


2

3 3 Jt

2

Nouveau Journal De Chemie

Figure 13. A perspective view of the [Tc(NH ),,(NO)(OH )T cation (25); "O > represents the oxygen atom of the coordinated water 3

2

w


6.

Tc

DEUTSCH AND BARNETT

PP

O3P-OPO3

MDP

0 P-CH -P0 3

2

Chemistry

pyrophosphate 3

4

m ethy lenediphosphonate

-

dichloromethylenediphosphonate

O P-C(CI) -PO "


3

2

3

4

4-

HMDP

0 P-CH(OH)-P0

HEDP

0 P-C(OH)-PO ~

3

Q

113

Q

hy droxy m ethy lenediphosphonate

3

(l-hydroxyethylidene)diphosphonate

4

Clinical applications have focused largely on H E D P and MDP, although considerable attention is currently being given to H M D P . It is generally assumed that technetium complexes of all of these agents are avid bond seekers, and reasonably effective myocardial infarct imaging agents, because the coordinated phosphonate or phosphate ligand retains much of the calcium affinity characteristic of the free ligand. Both bone and myocardial infarcts provide sites of high calcium concentration, and in this context the diphosphonate radiopharmaceuticals are probably best referred to as calcium seeking agents. However, the chemistry of these systems is very complex and no coherent theory explaining the in vivo mechanism(s) of action of technetium diphosphonate radiopharmaceuticals has yet been developed. The evolution of such a theory will require firm structural data as to the possible modes of bonding and interaction between diphosphonate ligands and metal centers. To acquire such data we have conducted structural investigations of several diphosphonate sodium(I) salts (27) (sodium(I) and calcium(II) have similar ionic radii), and of a technetiumMDP complex prepared by substitution of MDP onto TcBr "(28). fi

2

The solid state structure of the technetium-MDP complex consists of infinite polymeric chains. Each MDP ligand (Figure 14) bridges two symmetry related technetium atoms (Figure 15), and each technetium atom is bound to two symmetry related MDP ligands (Figure 16) — the MDP/Tc ratio within the polymer is therefore 1/1. The polymeric repeat unit is completed by an oxygen atom (presumably in the form of a hydroxyl ion) that bridges two symmetry related technetium atoms (Figure 15) and by a hydrated lithium cation which neutralizes the charge associated with each repeat unit. In addition, there is a single oxygen atom (presumably in the form of a disordered water molecule) on the three-fold axis of the space group. The molecular formula of the polvmeric technetium-MDP complex may thus be represented as {[Li(H 0 ) ] [Tc (OH)(MDP)]-l- H 0 } where the indicated protonation states of the bridging and non-coordinated oxygen atoms are chemically reasonable and consistent with an assumed Tc(IV) oxidation state, but are not definitively established by the x-ray diffraction data. One of the most important structural features of the diphosphonate ligands is the orientation of the - P O 3 groups with respect to the P - C - P plane. The "W" configuration, wherein the atoms 02-P1-C-P2-04 form a planar "W", can easily be seen in Figures 14 and 15. This configuration allows MDP to be doubly bidentate with 01 and 06 on one side of the "W" 2

3

2


INORGANIC



114

Figure 16. A perspective view of a portion of the \Tc(MDP)(OH)~] showing one technetium center bridging two MDP ligands (2%)

n


polymer


DEUTSCH AND BARNETT

Tc

1

Chemistry

Figure 17. A perspective view of a portion of the polymeric structure of Na H HEDP showing one sodium center bridging two HEDP ligands (21); "08W" represents the oxygen atom of a water molecule coordinated to the sodium center u

MDP,

PP ond C l M D P g

z

Multifunctional Diphosphonate HEDP and HMDP (possibly others)

Additional Bidentate Binding by Terminal - P 0

3

Figure 18. A summary of the established modes by which diphosphonate ligands bridge metal centers. The perspective views are obtained from structural analyses of the respective sodium salts (21), and are interpreted with respect to the hypothesized bridging of technetium to hydroxy apatite (HAP).



19. A molecular model showing tridentate binding of HMDP trigonal face of a calcium center at the surface of hydroxyapatite


to

DEUTSCH AND BARNETT

6.

Tc

Chemistry

117

coordinating to one metal center, and 03 and 05 on the other side of the W coordinating to another metal center (Figure 15). This doubly bidentate character of MDP allows it to bridge metal centers, e.g. T c - t o Tc in the technetium-MDP polymer, Na-to-Na in N a 2 H 2 M D P , and T c - t o - C a in the presumed biological mechanism of action. If the diphosphonate ligand contains a hydroxyl group on the central carbon atom (as in H E D P and HMDP), then the diphosphonate can function as a mixed bidentatetridentate bridge. Figure 17 shows a portion of the polymeric structure of Na2 H H E D P (27) in which each H E D P ligand functions as a bidentate ligand to one sodium center and as a tridentate ligand to another sodium center. This figure illustrates the coordination about one sodium ion, the tridentate and bidentate modes of H E D P coordination being readily apparent. It is therefore clear that by virtue of the extra hydroxyl group, HMDP and H E D P are distinct from those diphosphonates that cannot form mixed bidentate-tridentate bridges (MDP, C I 2 M D P , PP, etc.), and different chemical and biological properties are expected for the two classes of diphosphonate ligands. Figure 18 illustrates the possible modes of bridging between technetium and hydroxyapatite (HAP, the form of calcium most likely encountered in biological systems) by bidentate-bidentate and b i dentate-tridentate diphosphonate ligands. The mode wherein tridentate HMDP or H E D P binds to hydroxyapatite is especially intriguing since such tridentate ligation nicely completes the trigonal antiprismatic coordination of calcium at the fastest growing H A P crystal axis. This hypothesized bonding is illustrated more dramatically in Figure 19. These structural studies emphasize the central role of polymeric metal-diphosphonate complexes in the chemistry of technetium-diphosphonate calcium seeking agents. It is clearly the ability of diphosphonates to bridge metal centers that provides the mechanism for the initial sorption of the radiopharmaceutical onto bone. Mixed metal (technetium, tin, and calcium) diphosphonate polymeric complexes are likely to be the dominant chemical species in clinically used skeletal and myocardial infarct imaging agents. A n understanding of the chemistry of these polymeric species will be crucial to an understanding of the mechanisms of action of diphosphonate radiopharmaceuticals and to the development of more efficacious imaging agents. TT

n


2

Acknowledgments Financial support for this work was provided by the National Institutes of Health (Grant No. HL-21276) and the Procter

Synthetic and Structural Aspects of Technetium ... - ACS Publications

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