Chemistry and catalysis advances in organometallic chemistry and catalysis
ORGANOMETALLIC CHEMISTRY OF RHENIUM
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44 ORGANOMETALLIC CHEMISTRY OF RHENIUM AND TECHNETIUM FUELED BY BIOMEDICAL APPLICATIONS Ant ´onio Paulo, Goreti Ribeiro Morais, and Isabel Santos *
Metal-based compounds play an important role in the design of drugs for diagnostic or therapeutic applications, namely, anticancer agents, radiopharmaceuticals for nuclear imaging or radionuclide therapy, and contrast agents for magnetic resonance imaging (MRI). Compared to purely organic molecules, metals offer several advantages as a result of their structural diversity, varied reactivity pattern, and unique photo- and electrochemical properties. In this field, organometallic complexes play an emerging role, mainly because of the encouraging results obtained with ferrocene-tamoxifen derivatives for breast cancer therapy [1]. Since then, a variety of cyclopentadienyls or arenes of Fe, Ru, or Ti have been synthesized and their therapeutic effect explored [2]. Radiopharmaceutical chemistry is another important field in which organometallic compounds have a large potential, mainly after the introduction of the precursors fac-[M(CO) 3 (H 2 O) 3 ] + (M = Re, Tc) by Alberto et al. [3–5]. These compounds can be obtained in aqueous solution starting from the respective permetalates, [MO 4
– , which are the starting materials available to synthesize radiopharmaceuticals of 99m Tc or
186/188 Re. Since their introduction, a plethora of M(I) tricarbonyl complexes with a large variety of ligands have been synthesized and evaluated by many research groups, aiming the design of new diagnostic or therapy radiopharmaceuticals. This chapter reviews some of the results obtained in the area, giving particular attention to the more promising results for biomedical applications. This chapter will start with some basic concepts on radiopharmaceuticals, nuclear medicine imaging modalities, and radionuclide therapy. Then the research efforts of the authors’ group in the field will be presented and discussed in context with the major achievements reported by other groups worldwide. 44.2 BASIC CONCEPTS ON NUCLEAR MEDICINE AND RADIOPHARMACEUTICALS Nuclear Medicine uses radioactive compounds for in vivo imaging and therapeutic purposes. Such compounds, named radiopharmaceuticals, are used in very low concentration (10 –8 –10 –12 M), having no pharmacological effect. Depending on the intrinsic physical characteristics of the radionuclide, the radiopharmaceuticals are used for in vivo imaging or targeted radionuclide therapy (TRT). Advances in Organometallic Chemistry and Catalysis: The Silver/Gold Jubilee International Conference on Organometallic Chemistry Celebratory Book, First Edition. Edited by Armando J. L. Pombeiro. © 2014 John Wiley & Sons, Inc. Published 2014 by John Wiley & Sons, Inc.
590 ORGANOMETALLIC CHEMISTRY OF RHENIUM AND TECHNETIUM FUELED BY BIOMEDICAL APPLICATIONS TABLE 44.1 Relevant Radionuclides for Medical Applications Nuclide
Physical Half-Life Mode of Decay, % Application 99m
Tc 6.0 h
IT (100) SPECT
186 Re 3.72 d β − (92) Therapy EC (8)
188 Re 17 h β − (100) Therapy 123
I 13.2 h
EC (100) SPECT
131 I 8.02 d β − (100) Therapy 18 F 1.83 h β + (97) PET
EC (3) 11 C 20.3 min β + (100) PET
86 Y 14.7 h β + (33) PET EC (66)
90 Y 2.67 d β − (100) Therapy 111
In 2.80 d
EC (100) SPECT
67 Ga 3.26 d EC (100) SPECT
68 Ga 1.13 h β + (90) PET EC (10)
60 Cu 23.7 min β + (93) PET EC (7)
61 Cu 3.3 h β + (62) PET EC (38)
62 Cu 9.67 min β + (98) PET EC (2)
64 Cu 12.7 h β − (40), β + (19) PET/therapy EC (41)
67 Cu 2.58 d β − (100) Therapy 89 Zr 3.27 d β + (22.7) PET
EC (77) 153
Sm 46.3 d
β − (100) Therapy 166
Ho 26.8 d
β − (100) Therapy 177
Lu 6.73 d
β − (100) Therapy For in vivo imaging there are two nuclear modalities: single photon emission computed tomography (SPECT) and positron emission tomography (PET), which use γ - or β
+ -emitting radionuclides, respectively (Table 44.1). In the case of SPECT, the radionuclides decay by electron capture (EC) or isomeric transition (IT) with the emission of penetrating γ photons having energies in the range of 100–250 KeV. In PET, the β + particles emitted by the radionuclide react with the electrons from the medium releasing two photons of 511 KeV as a result of annihilation reactions. In both cases, the resulting photons (100–250 or 511 KeV) are efficiently detected outside the body leading to clinically useful medical images (Fig. 44.1). For therapy, the radiopharmaceuticals must contain radionuclides emitting ionizing particles (Auger electrons, β –
α particles). These particles have a high linear energy transfer (LET) inducing damage to targeted tumor tissues. However, their range in tissues is variable, following the order β – > α > Auger electrons. Therefore, unlike β – - or α-emitters, Auger- emitting radionuclides need to be accumulated by the nucleus of tumor cells in order to elicit significant DNA damage and therapeutic effect. The biodistribution of radiopharmaceuticals can be determined by their chemical and physical properties, perfusion radiopharmaceuticals, or by their biological interactions, target-specific radiopharmaceuticals (Fig. 44.2). The biological distribution of perfusion agents is determined by blood flow and these agents target high capacity systems, such as phagocytosis, hepatocyte clearance, and glomerular filtration. The target-specific radiopharmaceuticals target low capacity systems, and their biodistribution is determined by specific protein interactions, for example, antigen, enzymatic, or receptor- binding interactions. Based on the use of target-specific radiopharmaceuticals, SPECT and PET can determine the concentration of biomarkers in the human body in a noninvasive way, and these techniques are sensitive enough to visualize interactions between physiological targets and ligands, enabling a variety of molecular imaging applications. For molecular imaging, SPECT and PET present the advantage of high intrinsic sensitivity and unlimited depth penetration of the γ -radiation, if compared Re(I) AND Tc(I) TRICARBONYL PRECURSORS 591 (a)
(b) γ β + 511 KeV photon 511 KeV photon γ-Ray detection Figure 44.1 Examples of SPECT (a) and PET (b) images obtained after injection of a γ - or β + -emitting radiopharmaceutical. Chelator (a)
(b) Metal
BFCA Linker
Biomolecules Biomarker Figure 44.2 Schematic representation of (a) perfusion and (b) target-specific metal-based radiopharmaceuticals. with other imaging modalities, such as MRI, computed tomography (CT), ultrasound (US), bioluminescence imaging, and fluorescence imaging. PET has the additional advantage of being fully quantitative providing higher spatial resolution than SPECT. As shown in Table 44.1, of all the radionuclides relevant for medical applications, radiometals play an important role either for imaging or therapy. In particular for SPECT imaging, the overwhelming majority of radiopharmaceuticals in clinical use correspond to complexes of 99m Tc, which remains the workhorse of nuclear medicine as a result of its ideal nuclear properties, low cost, and convenient availability from commercial generators. Rhenium, the group 7 congener of technetium, has two β-emitting isotopes, 186
Re and 188
Re (Table 44.1), with nuclear properties suitable for the development of therapeutic radiopharmaceuticals. In addition, Re complexes are commonly used as surrogates for 99m Tc congeners. This approach benefits from the physicochemical similarities of these two elements and avoids the use of the long-lived β-emitter 99 Tc for the characterization of the 99m Tc complexes. Despite their differences in the kinetics of ligand exchange reactions and redox chemistry, Tc and Re can also be considered a matched pair suitable to obtain radiolabeled compounds for nuclear imaging ( 99m Tc) or radionuclide therapy ( 186/188 Re). On the basis of isostructural Re and Tc compounds, theranostic agents can be achieved, which can deliver ionizing particles ( 186
Re/ 188
Re) to treat a tumor or provide images ( 99m
Tc) for diagnosis. Such possibility overcomes undesirable differences in biodistribution and selectivity, which currently exist between distinct imaging and therapeutic tools.
For the majority of metals studied in radiopharmaceutical chemistry, for example, lanthanides, gallium, indium, or copper, the most relevant compounds are coordination complexes [6–9]. However, for Tc and Re, as a result of their rich chemistry, organometallic complexes have recently assumed a growing importance through the possibility of preparing the precursors fac-[M(CO) 3 (H 2 O) 3 ] + (M = Re, Tc) in aqueous solution, as already mentioned in the introductory part [3–5]. The availability of these precursors brought renewed interest on the design of Tc(I) organometallic radiopharmaceuticals as an alternative to classical strategies based on the [ 99m
Tc(O)] 3 + , trans-[ 99m
TcO 2 ] + , [
99m Tc(N)]
2 + , or [ 99m Tc-HYNIC] (HYNIC = 6-hydrazinonicotinic acid) cores [10–12].
592 ORGANOMETALLIC CHEMISTRY OF RHENIUM AND TECHNETIUM FUELED BY BIOMEDICAL APPLICATIONS K 2
3 BCO
2 ], Na
2 (tartarate), Na 2 B
O 7 , Na 2 CO 3 , 98 °C, 20 min, pH > 11 H 3
4 conc, K
2 [H 3 BCO 2 ], BH 3 ·NH
3 , 15 min, 60 °C M
2 OH 2 OC OH 2 OC CO + 3a M = 99m
Tc 4a M = 188
Re − 188 Re O O O O 99m Tc O O O O − 1 2 Scheme 44.1 Aqueous synthesis of fac-[M(CO) 3 (H
O) 3 ] + (M = 99m Tc (3a), 188 Re (4a)). As referred earlier, for 99m
Tc and 188
Re, the synthesis of the compounds starts always from pertechnetate or perrhenate in saline, obtained by elution of 99 Mo/
99m Tc and
188 W/ 188 Re generators, respectively. Initially, Alberto et al. showed that the halide (NEt 4 )
[ 99 TcCl 3 (CO)
3 ] could be obtained directly from [ 99 TcO
4 ] – by reduction with BH 3 in refluxing tetrahydrofuran (THF) saturated with CO [3]. It was also shown that the halides in (NEt 4 ) 2 [MCl
3 (CO)
3 ] are readily replaceable by water, affording the corresponding aquo-tricarbonyl precursors fac-[M(CO) 3 (H 2 O) 3 ] + (M = 99 Tc (3), Re (4)). Later, it was also shown that fac-[ 99m
Tc(CO) 3 (H 2 O) 3 ] + (3a) could be obtained by treating [ 99m TcO
4 ] – (1) with NaBH 4 in the presence of CO [4]. However, CO is a toxic gas, unsuitable for use in hospitals and in commercial radiopharmaceutical kits, a problem that was overcome by the use of boranocarbonate, K 2 [H
BCO 2 ]. This compound reduces the Tc(VII) and acts as a CO source, through mechanisms not yet fully understood (Scheme 44.1) [13]. As shown in Scheme 44.1, the synthesis of fac- [ 188 Re(CO) 3 (H 2 O) 3 ] + (4a) is only possible by reducing 2 with a combination of K 2 [H 3 BCO 2 ] and amine borane (BH 3 .NH
3 ), reflecting the different redox chemistry of Tc and Re [5]. 44.4 ORGANOMETALLIC BUILDING BLOCKS FOR THE DESIGN OF RADIOPHARMACEUTICALS Using the precursors fac-[M(CO) 3 (H
O) 3 ] + (M = 99 Tc (3), 99m Tc (3a), Re (4), 188 Re(4a)), a multitude of building blocks bearing the fac-[M(CO) 3 ] + unit have been synthesized in the last few years. The d 6 low spin electronic configuration of the metal in 3/3a and 4/4a leads to highly stable M–C bonds and to weakly bound water molecules, easily replaceable by chelators with different donor atoms sets and denticity. Under physiological conditions, a variety of classical bi- or tridentate chelators have been studied with these metal moieties [14–26]. From all the studies undertaken, it has been shown that, in general, the complexes based on tridentate chelators presented a more favorable biodistribution profile and pharmacokinetics to be further used as building blocks in the design of radiopharmaceuticals. Some examples of stable buildings blocks containing the tricarbonyl core and tridentate chelators are shown in Fig. 44.3. Other typically organometallic ligands explored in this area were cyclopentadienyls, carboranes, and bridging hydrides [27–29]. All these ligands allowed the synthesis in aqueous medium of Re and Tc tricarbonyl complexes (Fig. 44.4). Alberto et al. have shown that complexes of the type fac-[ 99m
Tc( η 5 -Cp-R)(CO) 3 ] can be synthesized in aqueous conditions starting from fac-[ 99m
Tc(CO) 3 (H 2 O) 3 ] + (3a) and using carboxylic and amide derivatives of cyclopentadienyls with a keto group in α position. They further extended the scope of the aqueous chemistry of cyclopentadienyls, showing that Diels–Alder dimerized CpH derivatives also react directly with 3a affording the same type of half-sandwich complexes [27, 30, 31]. Valliant et al. [32–34] studied the aqueous chemistry of carborane 99m Tc tricarbonyl complexes and confirmed their relevance for the design of target-specific radiopharmaceuticals, despite the initial difficulties that have been found in the synthesis of this type of complexes using 3a as the starting material. The first examples of Re(I) and Tc(I) complexes containing coordinated hydrides stable in aqueous medium have been reported by our group. These complexes were obtained by reacting dihydrobis(2-mercaptoimidazolyl)borates and trihydro(2- mercaptoimidazolyl)borates with fac-[M(CO) 3 (H 2 O) 3 ] + (M = Re, 99 Tc, 99m Tc), as for example complexes 5 and 6 (Schemes PERFUSION AGENTS 593 Carbon
Rhenium Nitrogen
Oxygen Sulphur
Figure 44.3 Selected examples of Re(I) tricarbonyl complexes with tridentate Werner-type ligands [14–18]. (See insert for color representation of the figure.) Carbon
Technetium Nitrogen
Oxygen Sulphur
Boron Figure 44.4 Selected examples of 99 Tc(I) tricarbonyl complexes stabilized by a cyclopentadienyl, a carborane, and a dihydro- bis(mercaptoimidazolyl)borate [27–29]. 44.2 and 44.3). The coordination mode of the respective boron-containing ligands ( κ 3
κ 3 -S,H,H) was assessed by X-ray structural analysis, multinuclear NMR and IR spectroscopy of the 99 Tc and Re complexes [29, 35, 36]. At tracer level ( 99m
Tc), the complexes are formed at room temperature with low ligand concentrations, and are remarkably stable under physiologic conditions. The water and the ∼10 5
– present in solution does not compete with the bridging hydrides. Biodistribution in mice of the 99m
Tc congener of 5 has shown that this class of complexes cross the blood–brain barrier (BBB). Such in vivo behavior motivated their use as building blocks to design target-specific complexes for imaging of brain receptors [37]. The B–H
· · ·M bonds in complexes 5 and 6 (Schemes 44.2 and 44.3) resist to physiologic conditions, but are cleaved by neutral and unidentate substrates (L), such as pyridine, isonitriles, and phosphines, yielding monomeric mixed-ligand complexes (e.g., 8 and 9) of the type fac-[Re {κ 2 -(R)H 2 B(tim Me ) }(CO) 3 (L)] (R
= H, tim Me ) (Schemes 44.2 and 44.3) [38–40]. The reaction of 5 with 1,2-ethylenediamine (en) led to the replacement of both B–H · · ·Re bonds with the formation of complex 7, stabilized by a κ 1 -S-scorpionate [38]. Reactions of 6 with different azoles, such as mercaptoimidazoles, mercaptobenzothiazoles, and pyrazoles, were also studied (Scheme 44.3). These reactions gave complexes anchored by tridentate poly(azolyl)borates generated in situ most probably by metal-assisted processes [41]. For pyrazoles, these reactivity studies allowed the synthesis of complexes anchored by unprecedented hybrid poly(azolyl)borates (10 and 11). The 99m Tc
by reacting precursor 3a with the sodium salt of the corresponding dihydrobis(azolyl)borate [42]. 44.5 PERFUSION AGENTS To replace some established 99m Tc-perfusion agents in clinical use, several research groups worldwide have recently investigated 99m
Tc tricarbonyl complexes as perfusion agents for kidney or myocardium imaging, with encouraging in vivo results [43–52]. For myocardial imaging, several research groups have searched for lipophilic and cationic 99m
Tc complexes of greater efficiency than those in clinical use [ 99m Tc-Sestamibi and 99m Tc-Tetrofosmin (Fig. 44.5)] [47–52]. 594 ORGANOMETALLIC CHEMISTRY OF RHENIUM AND TECHNETIUM FUELED BY BIOMEDICAL APPLICATIONS H 2
2 ) 2 NH 2
8 5 NC Carbon Rhenium Nitrogen
Oxygen Sulphur
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