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Rhenium and technetium based radiopharmaceuticals: Development and recent advances
Journal of Organometallic Chemistry 751 (2014) 83e89
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry journal homepage: www.elsevier.com/locate/jorganchem
Review
Rhenium and technetium based radiopharmaceuticals: Development and recent advances Sophie Jürgens, Wolfgang A. Herrmann*, Fritz E. Kühn* Chair of Inorganic Chemistry/Molecular Catalysis, Catalysis Research Centre of the Technische Universität München, Ernst Otto Fischer-Str. 1, 85747 Garching bei München, Germany
a r t i c l e i n f o
a b s t r a c t
Article history: Received 31 May 2013 Received in revised form 12 July 2013 Accepted 15 July 2013
The higher homologues of group 7 transition metals, namely technetium and rhenium, offer radioisotopes suitable for the application as radiopharmaceuticals. Three generations of radiopharmaceuticals have been applied so far, with two of them reaching clinical application. While the first generation does not display a target specific functionality to bind exclusively to one (or few) targets, the second generation allows target specific binding. The synthesis, however, is more sophisticated, but allows in principle a “Lego brick” build up of a radioactive moiety, a linker and a binding moiety. The third generation aims at an “all in one approach”, an organometallic derivative of a “key”, fitting to a specific receptor that also carries the “load” of the radioactive molecule. Although most elegant from design, such molecules are most difficult to develop. With the many available organometallic and inorganic rhenium derivatives, however, at least a much larger variety of specific “second generation” radiopharmaceuticals should be available. Ó 2013 Elsevier B.V. All rights reserved.
Keywords: Rhenium Technetium Radiopharmaceuticals Molecular imaging Targeting Review
Contents 1. 2.
3. 4.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 Overview of rhenium and technetium radiopharmaceuticals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84 2.1. First generation radiopharmaceuticals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84 2.2. Second generation radiopharmaceuticals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85 2.3. Third generation radiopharmaceuticals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86 Modern approaches and recent advances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
1. Introduction Recently group 7 transition metal complexes with N-heterocyclic carbenes ligands were reviewed [1]. Numerous reviews and book articles highlighting the synthesis and application of rhenium and technetium based radiopharmaceuticals have also been published, providing good overviews on the developments preceding their publication [2e8]. However, many organometallic chemists
* Corresponding authors. Tel.: þ49 (0)89 289 13096. E-mail addresses: [email protected] [email protected] (F.E. Kühn).
(W.A.
Herrmann),
0022-328X/$ e see front matter Ó 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jorganchem.2013.07.042
are still unaware of the possibilities their newly synthesized compounds might offer for medicinal applications. The intention of this review is to compile the latest advances concerning the targeted tumor therapy based on organometallic and inorganic building blocks, especially focusing on dextran derivatives utilizing a fac[M(CO)3]þ core. Effective therapy and molecular imaging of tumors continues to be one of the most important challenges of current clinical research. Radiopharmaceuticals present thereby a noninvasive alternative for rapid detection of tumor tissue. Therapy is carried out tumor specifically and therefore at significantly lower radioactive doses as for conventional chemotherapy. A broad variety of rhenium and technetium based radiopharmaceuticals has been
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reported since the first experimental application of 99mTcO 4 for imaging of the thyroid in 1961 [9,10]. This mirrors the fact that rhenium and technetium as group 7 elements can exist in oxidation states from (þVII) to (I) and therefore display rich coordination chemistry. Radiopharmaceuticals are applied in vivo for imaging of tumors and/or radionuclide therapy. The respective utilization of a radioisotope depends on its radioactive nature; whereas g or bþ emitters are used in diagnostic nuclear medicine, b, a- or Auger electron emitters are used for tumor-specific therapy [11]. The targeted radionuclide therapy (TRT) bases thereby on the localization of tumor tissue by the ionizing radiation emitting radionuclides [12]. In contrast to chemotherapy, this radiation is specifically cytotoxic to tumor tissue cells and does not attack surrounding healthy cells. However, neither the amounts of adsorbed radiation doses needed for successful TRT, nor the tolerance doses for healthy tissues cells are exactly defined. A main point of overcoming this problem would be a full understanding of the pharmacokinetics of the therapeutical radionuclide agent [13e15]. Imaging of tumor tissue is mainly performed by single photon emission computed tomography (SPECT) and positron emission tomography (PET). These gamma imaging techniques enable a very accurate examination of the interaction between the applied radiopharmaceutical and the targeted tumor tissue. Furthermore, they offer a quantitative approach on monitoring the doses of radionuclides taken into tumor tissue [16e18]. The application of either of these high-resolution molecular imaging techniques depends on the respective isotope. While PET uses light isotopes, e.g. 18 F or 15O, SPECT demands heavy isotopes such as 131I and 67Ga. For PET most isotopes are generated via a cyclotron and subsequently incorporated into biologically active molecules. Most widely applied is fluorodeoxyglucose (18F-FDG), making up for the majority (approximately 90%) of all PET applications [19]. Moreover, PET offers a significant higher imaging sensitivity of up to three orders of magnitude than SPECT due to its higher photon detection efficiency [20]. However, with SPECT longer imaging intervals can be performed, as single photon emitters have a longer half-life time. This enables the observation of in vivo processes for several hours or even days. Plus the longer lifetime of the isotope makes SPECT a less expensive imaging technique than PET. SPECT mainly applies 99mTc for various application fields such as neurochemical or myocardial imaging [21]. In recent years the use of a hybrid technique with computed tomography (CT) has aroused interest as the imaging accuracy of SPECT and PET could be enhanced. More potent SPECT/ CT and PET/CT systems have been introduced, which incorporate multi-slice CT (up to 16 slices), allowing diagnostic CT images [22]. This stresses the fact that not only isotope tracers, but also the development of the imaging modalities are of crucial importance for the future development of radiopharmaceutical chemistry. 99m Tc is considered as the “workhorse” for radiopharmaceutical imaging. Its long-lived isotope 99Tc (half-life time 2.12 105 years) is a be emitter and is formed as a fission product in nuclear reactors. The use of 99mTc displays three major advantages: (i) a g-energy of 140 keV which penetrates tumor tissue while simultaneously presenting a relatively low radiation dose, (ii) a half-life time of 6 h, ensuring reasonable medical imaging intervals and (iii) readily availability at low costs from 99Mo/99mTc generators [23]. First introduced in 1965 for clinical application, the 99Mo/99mTc isotope generator is the main source for 99mTc (see Fig. 1) [24]. The parent isotope 99Mo, processed as molybdate [99MoO4]2, is loaded onto an alumina chromatography column and 99mTc is isolated in great quantity as pertechnetate [99mTcO4] by elution with a 0.15 M saline solution. The be emitting radionuclides 188Re (t1/2 ¼ 16.9 h, Emax ¼ 2.1 MeV) and 186Re (t1/2 ¼ 89.2 h, Emax ¼ 1.1 MeV) can be isolated in an
Fig. 1. Decay of
99
Mo in the
99
Mo/99mTc generator.
analogous fashion from a 188W generator system [25]. Both rhenium radionuclides allow an effective energy transfer to cancer tissue; however 188Re is mostly favored due to its more convenient half-life time. The isotope generators enable a preparation of the respective radiopharmaceuticals directly in hospitals, ensuring a constant availability. Those preparations are therefore carried out in saline, with the permetallate as starting material. Rhenium and technetium pharmaceuticals are organ specific; thus the demands on chemical structure and in vivo behavior can vary strongly. Through choice of ligands, the specific biological moieties and physiochemical properties of the respective radiopharmaceutical can be fine-tuned. 2. Overview of rhenium and technetium radiopharmaceuticals The rhenium and technetium based radiopharmaceuticals can be divided up into three generations, relating to their biological distribution pattern or respective synthetic approach. 2.1. First generation radiopharmaceuticals The majority of all commercially established, technetium based imaging agents belongs to the first generation of radiopharmaceuticals. These complexes are perfusion agents and do not display targeting functions. The ligand system is biologically inactive without the metal center, therefore first generation radiopharmaceuticals are also referred to as “technetium/rhenium essentials” or de novo compounds [26]. Preparation of first generation radiopharmaceuticals is carried out via so-called “instant kits”, with the permetallate added directly before in vivo injection. These kits contain the ligand system, a reducing agent (typically a Sn(II) salt), buffer to adjust the pH to labeling conditions, stabilizers and catalysts [27,28]. The ligand system stabilizes thereby the lower oxidation state of the Lewis acidic metal center and determines its biological distribution. The field of application for first generation pharmaceuticals is mainly determined by their physiochemical properties such as hydrophilicity, charge and size of the complex. These properties are believed to determine the biological distribution of the radiopharmaceutical between tissues [29]. A full explanation for the biological distribution and pharmacokinetic path of first generation radiopharmaceuticals has yet to be found. One of the first technetium-based radiopharmaceuticals were 99m Tc-gluconates and 99mTc-glucoheptonates [30]. They were introduced for renal clearing studies, as they display the high hydrophilicity, which is mandatory for renal imaging in order scans the delivery of fluid into the kidneys via the bloodstream concentration [6]. Yet the excretion through the kidneys is too slow do to
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their high plasma protein binding affinity. Therefore 99mTc-gluconates and 99mTc-glucoheptonates are no longer used for renal clearing studies, but for skeleton scintigraphy, which does not demand a fast clearing. These complexes were shown to contain Tc(V) in form of a [TcO]3þ core, which is a classical building block for radiopharmaceuticals [31]. However, their structures are not completely defined, most likely due to multiple stable species at carrier-added level. Another important class of first generation pharmaceuticals is the aminoacetic acid derived complexones [32]. Depending on the complexone, the physicochemical properties of these negatively charged complexes vary strongly. The EHIDA (N-(2,6diethylacetanilido)iminodiacetic acid)technetium complex is a lipophilic complexone and established in liver scintigraphy, which, due to the excretion through the hepatobiliary tract, demands lower hydrophilicity than renal imaging. The highly hydrophilic technetium complex with DTPA (diethylenetriamine pentaacetic acid) has been found as an ideal replacement for 99mTc-gluconate in renal imaging. 188Re labeled DTPA is a radiopharmaceutical for intravascular radiation therapy [33]. The use of DTPA labeled rhenium and technetium compounds is a perfect example for the desired “matched-pair strategy” for technetium and rhenium based radiopharmaceuticals. This strategy aims at same synthetic approaches with different applications for rhenium and technetium based radiopharmaceuticals. So far, none of the prior mentioned complexes could fully be structural characterized. It has been suspected that either a polymeric species is formed, or mixed oxidation states are presented after the intake of the complexone-based radiopharmaceuticals [4]. In contrast to that, the structures of the three todays most widely applied technetium radiopharmaceuticals are well defined (see Fig. 2). One of the most prominent examples is probably the cationic hexa(methoxyisobutylisonitrile)technetium complex [99mTc(CNR)6]þ[(R ¼ CH2Ce(CH3)2OCH3)] (A) [34,35]. It is also known as “sestamibi” (MIBI ¼ methoxyisobutylisonitrile) or under its trade name CardioliteÒ and is applied for myocardial imaging. Due to the d6 configuration of the technetium center, the cationic complex is highly stable towards ligand loss or oxidation. The low oxidation state of the Tc(I) center is stabilized by the high reducing potential of the isonitrile ligands. Bearing a HMPAO (hexamethylpropyleneamineoxime) ligand, the neutral complex CeretecÒ (B) contains a [Tc]O]3þ core [36]. CeretecÒ is lipophilic and is used for imaging of the cerebral blood flow, as it is able to pass the blood brain Barrier (BBB). The stereochemistry is extremely important for CeretecÒ; while the D,Lisomers pass the braineblood-barrier, the meso form is not cerebrally extracted. Tc-MAG3 (mag ¼ mercaptoacetyltriglycine) (C), also called TechnescanÒ, is the agent of choice for renal clearing studies
Fig. 2. Prominent
99m
85
[37,38]. TechnescanÒ contains likewise to CeretecÒ a [Tc]O]3þ core. The tetradentate mercaptoacetyltriglycine ligand acts as a N3S donor. The carboxyl groups of TechnescanÒ are four times deprotonated upon coordination at physiological pH, therefore a high hydrophilicity of the resulting monoanionic complex is presented. The interaction of TechnescanÒ with renal receptors is believed to rely on the polarity of the complex, given by the deprotonated carboxyl group and the [Tcv]O]3þ core [2,39]. CeretecÒ and TechnescanÒ both comprise high complex stability as pseudo ring closing of the oxime ligands occurs due to hydrogen bridges. First generation radiopharmaceuticals base on an easy, one-step preparation which can be executed directly at hospitals. Due to the convenient synthesis and relatively low costs, first generation radiopharmaceuticals account for the majority of todays radiopharmaceuticals in clinical use [4,35,40]. However, the first generation of pharmaceuticals has been found mainly through “trial and error” approaches. The second generation pharmaceuticals emanate from a more sophisticated synthetic approach, aiming at specifically designed radiopharmaceuticals. 2.2. Second generation radiopharmaceuticals Second generation radiopharmaceuticals are target-specific, meaning that they are designed to bind to a particular receptor. Preparation of second generation radiopharmaceuticals is carried out via bifunctional chelators (BFC) [41]. These ligands exhibit two functions: covalent binding to the radioactive precursor and conjugation to a biovector. Possible target biovectors are amongst others peptides, proteins or pharmacophores. This preparation displays the challenge of tightly binding the radioactive precursor while not influencing the in vivo behavior of the biovector. The biodistribution of the radiopharmaceutical can be influenced by the use of linker between the chelated metal center and the biovector. This was for instance demonstrated by Novak-Hofer et al. for liver metabolism and improved tumor targeting of 67Cu labeled antibody fragments [42]. First generation radiopharmaceuticals can also be utilized as building blocks for the synthesis of second generation radiopharmaceuticals. The carboxylic ligands of TechnescanÒ for example are an ideal position for further linking to biomolecules [43]. Most commonly, the carboxylate and/or amine functions of polyaminopolycarboxylic acids are used as for chelating. Throughout the last decades, a vast number of cyclic and acyclic polyaminopolycarboxylic chelating ligands for second (and respectively first) generation radiopharmaceuticals has been reported. Fig. 3 gives an exemplary overview of the most common ones. Diethylenetriaminepentacetic acid (DTPA), 1,4,7,10-tetraazac yclododecane-1,4,7,10-tetraacetic acid (DOTA) and the cross-bridged tetraazamocycle derivative 3,6,10,13,15,18-hexaazabicyclo[6.6.4]
Tc radiopharmaceuticals in clinical use: (A) CardioliteÒ; (B) CeretecÒ; (C) TechnescanÒ.
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Fig. 3. Chelate ligands.
octadecane (SAR) are three of the most broadly evaluated BFCs. The activation of the respective connecting functional group is achieved by common organic synthesis methods [32]. Neuroreceptor targeting is one important subject of current research and development of second generation radiopharmaceuticals. Applicable radiopharmaceuticals need to possess: (i) low molecular weight (Mw 600 Da), (ii) moderate lipophilicity, (iii) neutral charge and (iv) high specificity and selectivity for one receptor [44,45]. These factors are important for the molecules in order to pass the braineblood-barrier and can be met efficiently by means of precise drug design. However, many challenges, mainly concerning synthesis and related high costs, still need to be overcome. 99m Tc labeled tropane systems have shown to target brain receptors with high affinity and have been evaluated for neurodegenerative and psychiatric diseases such as Alzheimer, Parkinson disease or schizophrenia [46e48]. The DADS chelated [Tc]O]3þ core for instance is an excellent imaging agent for the dopamine transporter (DAT) in the brain. The DADS system comprises of an ethylenedicysteine (ECD) framework with two ester functionalities in the backbone. One promising DADS candidate is 99mTc-TRODAT-1 (Fig. 4) which exhibits excellent binding affinity to the dopamine receptor and has successfully passed all preclinical test phases and was clinically accepted in 2007 [49]. In general, high yields and good selectivities are extremely important for the preparation of second generation radiopharmaceuticals. As the labeled and unlabeled biovectors are both active, competitive binding to the targeted receptor occurs otherwise in a significant degree. Therefore ratios for clinical application are generally desired to be at 95 or above [2]. 2.3. Third generation radiopharmaceuticals Third generation radiopharmaceuticals apply the so-called integrated labeling concept. Essential structure parts of biomolecules, mostly hormones, are mimicked and the metalorganic complex is incorporated into the carbon skeleton. In contrast to second generation radiopharmaceuticals, binding to an intrinsic receptor occur, rather than coupling to a receptor-binding biovector. These
Rhe
Fig. 4. Tc-TRODAT-1.
analogs are biologically inactive without the radioactive metal complex [50,51]. Mostly steroid analogs, such as progesterone and testosterone, have been synthesized and tested for application [48,52]. The radioactive metal is incorporated into the carbon skeleton structure by binding over bidentate or tetradentate chelate ligands (for example carboxylate or aminethiol groups). The metal center and its ligands are generally insulated by metal oxygen double bonds in order to mimic the electronical structure of the respective hormone. Numerous complexes with bis-bidentate ligands were prepared and tested for their in vivo stability, amongst other S2 (ethane-l,2dithiol [53]) or OS (2-mercaptoethanol [54]) ligands. However, the use of bidentate chelators displays several disadvantages in comparison to tetradentate ligands: (i) introduction of substituents onto the carbon atom backbone of the bidentate ligand creates a significantly higher number of possible stereoisomers, (ii) onesided complex modifications are extremely difficult as the bisbidentate complex is symmetrical and (iii) insufficient in vivo stability occurs due to higher ligand exchange lability than for tetradentate ligands [55]. Therefore preparation is mainly based on tetradentate ligands. The synthetic routes were first introduced by Katzenellenbogen and coworkers, giving straight forward access to rhenium and technetium labeled steroid analogs [56]. They described the synthesis of a tetradentate oxorhenium(V) complex with an amino amido thioether thiol (AATT) ligand, in which the metal complex replaced the CD ring portion of the estradiol (see Fig. 5). The rhenium estradiol template B is a close steric congener, displaying the same molecular volume and reasonable in vivo complex stability. However, only minor binding affinity to the receptor in comparison to estradiol was exhibited. This highlights the fact that metal complexes must be in accordance with the mimicked biomolecule concerning electronic complementarity, as well as structural properties. Although synthetic routes and structural information have been known for over 20 years [55,57], no clinical application for therapy or imaging has been established so far. This stresses that it is extremely difficult to mimic the original physiochemical and stereochemical properties of the hormone with a metalorganic complex incorporated into the analog. Research and development is further carried out for tetradentate ligands.
Fig. 5. Estradiol (A) and rhenium estradiol template (B).
S. Jürgens et al. / Journal of Organometallic Chemistry 751 (2014) 83e89
87
Fig. 6. Preparation of the [M(H2O)3(CO)3] complex.
Fig. 7. LymphoseekÒ.
A research field of high interest throughout the last years has been the prostate specific membrane antigen (PSMA) targeting compounds developed by Zubieta et al. [58]. These complexes base on the application of single amino acid chelate (SAAC) systems for the complexation of metal precursors. The chelators derive from amino acids or amino acid analogs and possess a tridentate chelating moiety which is ideal for the complexation of the fac-[M(CO)3]þ core. It could be demonstrated that an exclusive binding to PSMA molecules, exposing the surface of living prostate cancer cells, occurs [59]. Currently Phase II clinical trials are being run; these complexes may therefore become the first third generation pharmaceuticals approved for medical application to humans. 3. Modern approaches and recent advances Recent research focus has mainly been set on designing new second generation radiopharmaceuticals for improved receptor targeting. Numerous complexes labeled with technetium or rhenium cores have been published within the last decades. The applied cores range from more “classical” cores, such as the former mentioned [Tc]O]3þ, to more recent cores like [Tc]3þ and [Tc] N]2þ [32,44,60,61]. Special interest has been drawn to the usage of fac-[M(CO)3]þ labeled complexes, due to convenient properties concerning preparation and feasible ligands. First introduced by Alberto et al. in 1998 [62,63], [M(CO)3(H2O)3]þ has proven to be a convenient
precursor for the preparation of fac-[M(CO)3]þ complexes [64] Fig. 6. A major advantage of the [M(CO)3]þ core is the variety of possible, well coordinating ligands, which can bind in a mono-, bior tridentate fashion. Most fac-[M(CO)3]þ complexes show high stability in serum or in vivo due to the kinetically inert d6 low spin system. The CO ligands are tightly bound due to back bonding, whereas the H2O ligands are labile and easily replaced in ligand exchange reactions. A broad number of complexes obtained by ligand exchange reactions have therefore been reported since 1998 [65e67]. Fac-[M(CO)3]þ based complexes have been synthesized and tested for several application fields and various metal cores [68,69]. An important and relatively new research field is thereby sentinel lymph node detection (SLND), as it enables the early detection of metastases for different cancer types such as breast or prostate cancer. The sentinel lymph nodes have the highest probability to contain tumor metastases prior to subsequent nodes. Lymphatic mapping of the sentinel lymph nodes has been confirmed to have a false negative rate of less than 5% for the prediction of axillary nodal status in breast cancer [59,70,71]. SLND is commonly carried out via a colloidal technique with injection of a technetium radiolabeled colloid and a blue dye. The blue dye is herein applied for improved visualization of the lymphatic drainage. The most commonly used technetium colloids are 99mTc-human serum albumin colloids (HSA) and filtered 99mTc-sulfur colloids (fTcSC). However, these colloids exhibit disadvantages concerning persistent retention and their clearance rate from the injection site [72e74]. Therefore
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Fig. 8. Mannosylated dextran derivatives for sentinel lymph node targeting.
alternatives to the more conventional colloids would be preferred for clinical application. An ideal lymph node targeting compound would have to meet the following criteria: (i) rapid clearance from the injection site, (ii) rapid uptake in the sentinel lymph nodes, (iii) high in vivo stability and (iv) high and prior retention in the sentinel lymph nodes [75,76]. This approach is conducted for the recently (by the US Food and Drug Administration (FDA)) approved 99mTc tilmanocept, also called LymphoseekÒ due to its specificity for lymph node targeting. LymphoseekÒ is the first new drug for lymph node mapping to be approved for clinical application since isosulfan blue in 1981 [77] Fig. 7. The compound consists of a dextran backbone, which is modified with a mannose unit. By introducing mannose into the dextran backbone, a specific targeting of the lymph node mannose receptors is intended [78]. The receptor displayed by sentinel lymph nodes is mannose specific and binds carbohydrates that terminate with a mannose glycoside [79]. Coordination of 99mTc is achieved via the classical bifunctional chelator DTPA. Its relatively small size (molecular weight z19 kDa, mean molecular diameter 7.1 nm) enables LymphoseekÒ to exit the injection site rapidly and to quickly accumulate in first-echelon nodes [80,81]. Santos and coworkers introduced the first fully characterized fac-[99mTc(CO)3]þ mannosylated dextran derivative for sentinel lymph node targeting in 2011 [78]. Fig. 8 shows the synthesized complex. The dextran backbone (molecular weight z10 kDa) was functionalized with pyrazolyl-diamine or cysteine for stabilization of the fac-[M(CO)3]þ core. S-Derivatized cysteines are efficient SNO chelators for the fac-[99mTc(CO)3]þ core and are suitable for the attachment of mannose units at the same time. These complexes display higher in vivo stability than those that apply classical BFCs for coordination of the 99mTc [82,83]. SPECT/CT studies confirmed a high uptake and retention in the sentinel lymph nodes, as well as fast injection site clearance [84]. As a simple “one pot” synthesis at high yields is possible, the fac-[99mTc(CO)3]þ mannosylated dextran derivatives stand exemplarily for new second generation radiopharmaceuticals for improved receptor targeting. 4. Conclusions A variety of inorganic and organometallic derivatives of Tc and Re are applied in radiopharmaceuticals. The clinically applied
compounds, however, are quite far behind the possibilities modern synthetic chemistry would allow. Particularly a “Lego brick” approach for synthesizing second generation radiopharmaceuticals appears quite promising. Limiting factors are the time of synthesis (in comparison to the half-life of the radioactive nuclei), the sophistication of synthesis (to allow a post-generator synthesis in hospitals) and the toxicity of the organometallic/inorganic moieties and their degradation/decomposition products in the body. Much more research and chemistry/biology/medicine cooperation will be needed in this area to transform both biologic constraints and requirements and synthetic inorganic and organometallic knowledge into useful medicinal applications.
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Contents lists available at ScienceDirect
Journal of Organometallic Chemistry journal homepage: www.elsevier.com/locate/jorganchem
Review
Rhenium and technetium based radiopharmaceuticals: Development and recent advances Sophie Jürgens, Wolfgang A. Herrmann*, Fritz E. Kühn* Chair of Inorganic Chemistry/Molecular Catalysis, Catalysis Research Centre of the Technische Universität München, Ernst Otto Fischer-Str. 1, 85747 Garching bei München, Germany
a r t i c l e i n f o
a b s t r a c t
Article history: Received 31 May 2013 Received in revised form 12 July 2013 Accepted 15 July 2013
The higher homologues of group 7 transition metals, namely technetium and rhenium, offer radioisotopes suitable for the application as radiopharmaceuticals. Three generations of radiopharmaceuticals have been applied so far, with two of them reaching clinical application. While the first generation does not display a target specific functionality to bind exclusively to one (or few) targets, the second generation allows target specific binding. The synthesis, however, is more sophisticated, but allows in principle a “Lego brick” build up of a radioactive moiety, a linker and a binding moiety. The third generation aims at an “all in one approach”, an organometallic derivative of a “key”, fitting to a specific receptor that also carries the “load” of the radioactive molecule. Although most elegant from design, such molecules are most difficult to develop. With the many available organometallic and inorganic rhenium derivatives, however, at least a much larger variety of specific “second generation” radiopharmaceuticals should be available. Ó 2013 Elsevier B.V. All rights reserved.
Keywords: Rhenium Technetium Radiopharmaceuticals Molecular imaging Targeting Review
Contents 1. 2.
3. 4.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 Overview of rhenium and technetium radiopharmaceuticals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84 2.1. First generation radiopharmaceuticals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84 2.2. Second generation radiopharmaceuticals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85 2.3. Third generation radiopharmaceuticals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86 Modern approaches and recent advances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
1. Introduction Recently group 7 transition metal complexes with N-heterocyclic carbenes ligands were reviewed [1]. Numerous reviews and book articles highlighting the synthesis and application of rhenium and technetium based radiopharmaceuticals have also been published, providing good overviews on the developments preceding their publication [2e8]. However, many organometallic chemists
* Corresponding authors. Tel.: þ49 (0)89 289 13096. E-mail addresses: [email protected] [email protected] (F.E. Kühn).
(W.A.
Herrmann),
0022-328X/$ e see front matter Ó 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jorganchem.2013.07.042
are still unaware of the possibilities their newly synthesized compounds might offer for medicinal applications. The intention of this review is to compile the latest advances concerning the targeted tumor therapy based on organometallic and inorganic building blocks, especially focusing on dextran derivatives utilizing a fac[M(CO)3]þ core. Effective therapy and molecular imaging of tumors continues to be one of the most important challenges of current clinical research. Radiopharmaceuticals present thereby a noninvasive alternative for rapid detection of tumor tissue. Therapy is carried out tumor specifically and therefore at significantly lower radioactive doses as for conventional chemotherapy. A broad variety of rhenium and technetium based radiopharmaceuticals has been
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reported since the first experimental application of 99mTcO 4 for imaging of the thyroid in 1961 [9,10]. This mirrors the fact that rhenium and technetium as group 7 elements can exist in oxidation states from (þVII) to (I) and therefore display rich coordination chemistry. Radiopharmaceuticals are applied in vivo for imaging of tumors and/or radionuclide therapy. The respective utilization of a radioisotope depends on its radioactive nature; whereas g or bþ emitters are used in diagnostic nuclear medicine, b, a- or Auger electron emitters are used for tumor-specific therapy [11]. The targeted radionuclide therapy (TRT) bases thereby on the localization of tumor tissue by the ionizing radiation emitting radionuclides [12]. In contrast to chemotherapy, this radiation is specifically cytotoxic to tumor tissue cells and does not attack surrounding healthy cells. However, neither the amounts of adsorbed radiation doses needed for successful TRT, nor the tolerance doses for healthy tissues cells are exactly defined. A main point of overcoming this problem would be a full understanding of the pharmacokinetics of the therapeutical radionuclide agent [13e15]. Imaging of tumor tissue is mainly performed by single photon emission computed tomography (SPECT) and positron emission tomography (PET). These gamma imaging techniques enable a very accurate examination of the interaction between the applied radiopharmaceutical and the targeted tumor tissue. Furthermore, they offer a quantitative approach on monitoring the doses of radionuclides taken into tumor tissue [16e18]. The application of either of these high-resolution molecular imaging techniques depends on the respective isotope. While PET uses light isotopes, e.g. 18 F or 15O, SPECT demands heavy isotopes such as 131I and 67Ga. For PET most isotopes are generated via a cyclotron and subsequently incorporated into biologically active molecules. Most widely applied is fluorodeoxyglucose (18F-FDG), making up for the majority (approximately 90%) of all PET applications [19]. Moreover, PET offers a significant higher imaging sensitivity of up to three orders of magnitude than SPECT due to its higher photon detection efficiency [20]. However, with SPECT longer imaging intervals can be performed, as single photon emitters have a longer half-life time. This enables the observation of in vivo processes for several hours or even days. Plus the longer lifetime of the isotope makes SPECT a less expensive imaging technique than PET. SPECT mainly applies 99mTc for various application fields such as neurochemical or myocardial imaging [21]. In recent years the use of a hybrid technique with computed tomography (CT) has aroused interest as the imaging accuracy of SPECT and PET could be enhanced. More potent SPECT/ CT and PET/CT systems have been introduced, which incorporate multi-slice CT (up to 16 slices), allowing diagnostic CT images [22]. This stresses the fact that not only isotope tracers, but also the development of the imaging modalities are of crucial importance for the future development of radiopharmaceutical chemistry. 99m Tc is considered as the “workhorse” for radiopharmaceutical imaging. Its long-lived isotope 99Tc (half-life time 2.12 105 years) is a be emitter and is formed as a fission product in nuclear reactors. The use of 99mTc displays three major advantages: (i) a g-energy of 140 keV which penetrates tumor tissue while simultaneously presenting a relatively low radiation dose, (ii) a half-life time of 6 h, ensuring reasonable medical imaging intervals and (iii) readily availability at low costs from 99Mo/99mTc generators [23]. First introduced in 1965 for clinical application, the 99Mo/99mTc isotope generator is the main source for 99mTc (see Fig. 1) [24]. The parent isotope 99Mo, processed as molybdate [99MoO4]2, is loaded onto an alumina chromatography column and 99mTc is isolated in great quantity as pertechnetate [99mTcO4] by elution with a 0.15 M saline solution. The be emitting radionuclides 188Re (t1/2 ¼ 16.9 h, Emax ¼ 2.1 MeV) and 186Re (t1/2 ¼ 89.2 h, Emax ¼ 1.1 MeV) can be isolated in an
Fig. 1. Decay of
99
Mo in the
99
Mo/99mTc generator.
analogous fashion from a 188W generator system [25]. Both rhenium radionuclides allow an effective energy transfer to cancer tissue; however 188Re is mostly favored due to its more convenient half-life time. The isotope generators enable a preparation of the respective radiopharmaceuticals directly in hospitals, ensuring a constant availability. Those preparations are therefore carried out in saline, with the permetallate as starting material. Rhenium and technetium pharmaceuticals are organ specific; thus the demands on chemical structure and in vivo behavior can vary strongly. Through choice of ligands, the specific biological moieties and physiochemical properties of the respective radiopharmaceutical can be fine-tuned. 2. Overview of rhenium and technetium radiopharmaceuticals The rhenium and technetium based radiopharmaceuticals can be divided up into three generations, relating to their biological distribution pattern or respective synthetic approach. 2.1. First generation radiopharmaceuticals The majority of all commercially established, technetium based imaging agents belongs to the first generation of radiopharmaceuticals. These complexes are perfusion agents and do not display targeting functions. The ligand system is biologically inactive without the metal center, therefore first generation radiopharmaceuticals are also referred to as “technetium/rhenium essentials” or de novo compounds [26]. Preparation of first generation radiopharmaceuticals is carried out via so-called “instant kits”, with the permetallate added directly before in vivo injection. These kits contain the ligand system, a reducing agent (typically a Sn(II) salt), buffer to adjust the pH to labeling conditions, stabilizers and catalysts [27,28]. The ligand system stabilizes thereby the lower oxidation state of the Lewis acidic metal center and determines its biological distribution. The field of application for first generation pharmaceuticals is mainly determined by their physiochemical properties such as hydrophilicity, charge and size of the complex. These properties are believed to determine the biological distribution of the radiopharmaceutical between tissues [29]. A full explanation for the biological distribution and pharmacokinetic path of first generation radiopharmaceuticals has yet to be found. One of the first technetium-based radiopharmaceuticals were 99m Tc-gluconates and 99mTc-glucoheptonates [30]. They were introduced for renal clearing studies, as they display the high hydrophilicity, which is mandatory for renal imaging in order scans the delivery of fluid into the kidneys via the bloodstream concentration [6]. Yet the excretion through the kidneys is too slow do to
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their high plasma protein binding affinity. Therefore 99mTc-gluconates and 99mTc-glucoheptonates are no longer used for renal clearing studies, but for skeleton scintigraphy, which does not demand a fast clearing. These complexes were shown to contain Tc(V) in form of a [TcO]3þ core, which is a classical building block for radiopharmaceuticals [31]. However, their structures are not completely defined, most likely due to multiple stable species at carrier-added level. Another important class of first generation pharmaceuticals is the aminoacetic acid derived complexones [32]. Depending on the complexone, the physicochemical properties of these negatively charged complexes vary strongly. The EHIDA (N-(2,6diethylacetanilido)iminodiacetic acid)technetium complex is a lipophilic complexone and established in liver scintigraphy, which, due to the excretion through the hepatobiliary tract, demands lower hydrophilicity than renal imaging. The highly hydrophilic technetium complex with DTPA (diethylenetriamine pentaacetic acid) has been found as an ideal replacement for 99mTc-gluconate in renal imaging. 188Re labeled DTPA is a radiopharmaceutical for intravascular radiation therapy [33]. The use of DTPA labeled rhenium and technetium compounds is a perfect example for the desired “matched-pair strategy” for technetium and rhenium based radiopharmaceuticals. This strategy aims at same synthetic approaches with different applications for rhenium and technetium based radiopharmaceuticals. So far, none of the prior mentioned complexes could fully be structural characterized. It has been suspected that either a polymeric species is formed, or mixed oxidation states are presented after the intake of the complexone-based radiopharmaceuticals [4]. In contrast to that, the structures of the three todays most widely applied technetium radiopharmaceuticals are well defined (see Fig. 2). One of the most prominent examples is probably the cationic hexa(methoxyisobutylisonitrile)technetium complex [99mTc(CNR)6]þ[(R ¼ CH2Ce(CH3)2OCH3)] (A) [34,35]. It is also known as “sestamibi” (MIBI ¼ methoxyisobutylisonitrile) or under its trade name CardioliteÒ and is applied for myocardial imaging. Due to the d6 configuration of the technetium center, the cationic complex is highly stable towards ligand loss or oxidation. The low oxidation state of the Tc(I) center is stabilized by the high reducing potential of the isonitrile ligands. Bearing a HMPAO (hexamethylpropyleneamineoxime) ligand, the neutral complex CeretecÒ (B) contains a [Tc]O]3þ core [36]. CeretecÒ is lipophilic and is used for imaging of the cerebral blood flow, as it is able to pass the blood brain Barrier (BBB). The stereochemistry is extremely important for CeretecÒ; while the D,Lisomers pass the braineblood-barrier, the meso form is not cerebrally extracted. Tc-MAG3 (mag ¼ mercaptoacetyltriglycine) (C), also called TechnescanÒ, is the agent of choice for renal clearing studies
Fig. 2. Prominent
99m
85
[37,38]. TechnescanÒ contains likewise to CeretecÒ a [Tc]O]3þ core. The tetradentate mercaptoacetyltriglycine ligand acts as a N3S donor. The carboxyl groups of TechnescanÒ are four times deprotonated upon coordination at physiological pH, therefore a high hydrophilicity of the resulting monoanionic complex is presented. The interaction of TechnescanÒ with renal receptors is believed to rely on the polarity of the complex, given by the deprotonated carboxyl group and the [Tcv]O]3þ core [2,39]. CeretecÒ and TechnescanÒ both comprise high complex stability as pseudo ring closing of the oxime ligands occurs due to hydrogen bridges. First generation radiopharmaceuticals base on an easy, one-step preparation which can be executed directly at hospitals. Due to the convenient synthesis and relatively low costs, first generation radiopharmaceuticals account for the majority of todays radiopharmaceuticals in clinical use [4,35,40]. However, the first generation of pharmaceuticals has been found mainly through “trial and error” approaches. The second generation pharmaceuticals emanate from a more sophisticated synthetic approach, aiming at specifically designed radiopharmaceuticals. 2.2. Second generation radiopharmaceuticals Second generation radiopharmaceuticals are target-specific, meaning that they are designed to bind to a particular receptor. Preparation of second generation radiopharmaceuticals is carried out via bifunctional chelators (BFC) [41]. These ligands exhibit two functions: covalent binding to the radioactive precursor and conjugation to a biovector. Possible target biovectors are amongst others peptides, proteins or pharmacophores. This preparation displays the challenge of tightly binding the radioactive precursor while not influencing the in vivo behavior of the biovector. The biodistribution of the radiopharmaceutical can be influenced by the use of linker between the chelated metal center and the biovector. This was for instance demonstrated by Novak-Hofer et al. for liver metabolism and improved tumor targeting of 67Cu labeled antibody fragments [42]. First generation radiopharmaceuticals can also be utilized as building blocks for the synthesis of second generation radiopharmaceuticals. The carboxylic ligands of TechnescanÒ for example are an ideal position for further linking to biomolecules [43]. Most commonly, the carboxylate and/or amine functions of polyaminopolycarboxylic acids are used as for chelating. Throughout the last decades, a vast number of cyclic and acyclic polyaminopolycarboxylic chelating ligands for second (and respectively first) generation radiopharmaceuticals has been reported. Fig. 3 gives an exemplary overview of the most common ones. Diethylenetriaminepentacetic acid (DTPA), 1,4,7,10-tetraazac yclododecane-1,4,7,10-tetraacetic acid (DOTA) and the cross-bridged tetraazamocycle derivative 3,6,10,13,15,18-hexaazabicyclo[6.6.4]
Tc radiopharmaceuticals in clinical use: (A) CardioliteÒ; (B) CeretecÒ; (C) TechnescanÒ.
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Fig. 3. Chelate ligands.
octadecane (SAR) are three of the most broadly evaluated BFCs. The activation of the respective connecting functional group is achieved by common organic synthesis methods [32]. Neuroreceptor targeting is one important subject of current research and development of second generation radiopharmaceuticals. Applicable radiopharmaceuticals need to possess: (i) low molecular weight (Mw 600 Da), (ii) moderate lipophilicity, (iii) neutral charge and (iv) high specificity and selectivity for one receptor [44,45]. These factors are important for the molecules in order to pass the braineblood-barrier and can be met efficiently by means of precise drug design. However, many challenges, mainly concerning synthesis and related high costs, still need to be overcome. 99m Tc labeled tropane systems have shown to target brain receptors with high affinity and have been evaluated for neurodegenerative and psychiatric diseases such as Alzheimer, Parkinson disease or schizophrenia [46e48]. The DADS chelated [Tc]O]3þ core for instance is an excellent imaging agent for the dopamine transporter (DAT) in the brain. The DADS system comprises of an ethylenedicysteine (ECD) framework with two ester functionalities in the backbone. One promising DADS candidate is 99mTc-TRODAT-1 (Fig. 4) which exhibits excellent binding affinity to the dopamine receptor and has successfully passed all preclinical test phases and was clinically accepted in 2007 [49]. In general, high yields and good selectivities are extremely important for the preparation of second generation radiopharmaceuticals. As the labeled and unlabeled biovectors are both active, competitive binding to the targeted receptor occurs otherwise in a significant degree. Therefore ratios for clinical application are generally desired to be at 95 or above [2]. 2.3. Third generation radiopharmaceuticals Third generation radiopharmaceuticals apply the so-called integrated labeling concept. Essential structure parts of biomolecules, mostly hormones, are mimicked and the metalorganic complex is incorporated into the carbon skeleton. In contrast to second generation radiopharmaceuticals, binding to an intrinsic receptor occur, rather than coupling to a receptor-binding biovector. These
Rhe
Fig. 4. Tc-TRODAT-1.
analogs are biologically inactive without the radioactive metal complex [50,51]. Mostly steroid analogs, such as progesterone and testosterone, have been synthesized and tested for application [48,52]. The radioactive metal is incorporated into the carbon skeleton structure by binding over bidentate or tetradentate chelate ligands (for example carboxylate or aminethiol groups). The metal center and its ligands are generally insulated by metal oxygen double bonds in order to mimic the electronical structure of the respective hormone. Numerous complexes with bis-bidentate ligands were prepared and tested for their in vivo stability, amongst other S2 (ethane-l,2dithiol [53]) or OS (2-mercaptoethanol [54]) ligands. However, the use of bidentate chelators displays several disadvantages in comparison to tetradentate ligands: (i) introduction of substituents onto the carbon atom backbone of the bidentate ligand creates a significantly higher number of possible stereoisomers, (ii) onesided complex modifications are extremely difficult as the bisbidentate complex is symmetrical and (iii) insufficient in vivo stability occurs due to higher ligand exchange lability than for tetradentate ligands [55]. Therefore preparation is mainly based on tetradentate ligands. The synthetic routes were first introduced by Katzenellenbogen and coworkers, giving straight forward access to rhenium and technetium labeled steroid analogs [56]. They described the synthesis of a tetradentate oxorhenium(V) complex with an amino amido thioether thiol (AATT) ligand, in which the metal complex replaced the CD ring portion of the estradiol (see Fig. 5). The rhenium estradiol template B is a close steric congener, displaying the same molecular volume and reasonable in vivo complex stability. However, only minor binding affinity to the receptor in comparison to estradiol was exhibited. This highlights the fact that metal complexes must be in accordance with the mimicked biomolecule concerning electronic complementarity, as well as structural properties. Although synthetic routes and structural information have been known for over 20 years [55,57], no clinical application for therapy or imaging has been established so far. This stresses that it is extremely difficult to mimic the original physiochemical and stereochemical properties of the hormone with a metalorganic complex incorporated into the analog. Research and development is further carried out for tetradentate ligands.
Fig. 5. Estradiol (A) and rhenium estradiol template (B).
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Fig. 6. Preparation of the [M(H2O)3(CO)3] complex.
Fig. 7. LymphoseekÒ.
A research field of high interest throughout the last years has been the prostate specific membrane antigen (PSMA) targeting compounds developed by Zubieta et al. [58]. These complexes base on the application of single amino acid chelate (SAAC) systems for the complexation of metal precursors. The chelators derive from amino acids or amino acid analogs and possess a tridentate chelating moiety which is ideal for the complexation of the fac-[M(CO)3]þ core. It could be demonstrated that an exclusive binding to PSMA molecules, exposing the surface of living prostate cancer cells, occurs [59]. Currently Phase II clinical trials are being run; these complexes may therefore become the first third generation pharmaceuticals approved for medical application to humans. 3. Modern approaches and recent advances Recent research focus has mainly been set on designing new second generation radiopharmaceuticals for improved receptor targeting. Numerous complexes labeled with technetium or rhenium cores have been published within the last decades. The applied cores range from more “classical” cores, such as the former mentioned [Tc]O]3þ, to more recent cores like [Tc]3þ and [Tc] N]2þ [32,44,60,61]. Special interest has been drawn to the usage of fac-[M(CO)3]þ labeled complexes, due to convenient properties concerning preparation and feasible ligands. First introduced by Alberto et al. in 1998 [62,63], [M(CO)3(H2O)3]þ has proven to be a convenient
precursor for the preparation of fac-[M(CO)3]þ complexes [64] Fig. 6. A major advantage of the [M(CO)3]þ core is the variety of possible, well coordinating ligands, which can bind in a mono-, bior tridentate fashion. Most fac-[M(CO)3]þ complexes show high stability in serum or in vivo due to the kinetically inert d6 low spin system. The CO ligands are tightly bound due to back bonding, whereas the H2O ligands are labile and easily replaced in ligand exchange reactions. A broad number of complexes obtained by ligand exchange reactions have therefore been reported since 1998 [65e67]. Fac-[M(CO)3]þ based complexes have been synthesized and tested for several application fields and various metal cores [68,69]. An important and relatively new research field is thereby sentinel lymph node detection (SLND), as it enables the early detection of metastases for different cancer types such as breast or prostate cancer. The sentinel lymph nodes have the highest probability to contain tumor metastases prior to subsequent nodes. Lymphatic mapping of the sentinel lymph nodes has been confirmed to have a false negative rate of less than 5% for the prediction of axillary nodal status in breast cancer [59,70,71]. SLND is commonly carried out via a colloidal technique with injection of a technetium radiolabeled colloid and a blue dye. The blue dye is herein applied for improved visualization of the lymphatic drainage. The most commonly used technetium colloids are 99mTc-human serum albumin colloids (HSA) and filtered 99mTc-sulfur colloids (fTcSC). However, these colloids exhibit disadvantages concerning persistent retention and their clearance rate from the injection site [72e74]. Therefore
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Fig. 8. Mannosylated dextran derivatives for sentinel lymph node targeting.
alternatives to the more conventional colloids would be preferred for clinical application. An ideal lymph node targeting compound would have to meet the following criteria: (i) rapid clearance from the injection site, (ii) rapid uptake in the sentinel lymph nodes, (iii) high in vivo stability and (iv) high and prior retention in the sentinel lymph nodes [75,76]. This approach is conducted for the recently (by the US Food and Drug Administration (FDA)) approved 99mTc tilmanocept, also called LymphoseekÒ due to its specificity for lymph node targeting. LymphoseekÒ is the first new drug for lymph node mapping to be approved for clinical application since isosulfan blue in 1981 [77] Fig. 7. The compound consists of a dextran backbone, which is modified with a mannose unit. By introducing mannose into the dextran backbone, a specific targeting of the lymph node mannose receptors is intended [78]. The receptor displayed by sentinel lymph nodes is mannose specific and binds carbohydrates that terminate with a mannose glycoside [79]. Coordination of 99mTc is achieved via the classical bifunctional chelator DTPA. Its relatively small size (molecular weight z19 kDa, mean molecular diameter 7.1 nm) enables LymphoseekÒ to exit the injection site rapidly and to quickly accumulate in first-echelon nodes [80,81]. Santos and coworkers introduced the first fully characterized fac-[99mTc(CO)3]þ mannosylated dextran derivative for sentinel lymph node targeting in 2011 [78]. Fig. 8 shows the synthesized complex. The dextran backbone (molecular weight z10 kDa) was functionalized with pyrazolyl-diamine or cysteine for stabilization of the fac-[M(CO)3]þ core. S-Derivatized cysteines are efficient SNO chelators for the fac-[99mTc(CO)3]þ core and are suitable for the attachment of mannose units at the same time. These complexes display higher in vivo stability than those that apply classical BFCs for coordination of the 99mTc [82,83]. SPECT/CT studies confirmed a high uptake and retention in the sentinel lymph nodes, as well as fast injection site clearance [84]. As a simple “one pot” synthesis at high yields is possible, the fac-[99mTc(CO)3]þ mannosylated dextran derivatives stand exemplarily for new second generation radiopharmaceuticals for improved receptor targeting. 4. Conclusions A variety of inorganic and organometallic derivatives of Tc and Re are applied in radiopharmaceuticals. The clinically applied
compounds, however, are quite far behind the possibilities modern synthetic chemistry would allow. Particularly a “Lego brick” approach for synthesizing second generation radiopharmaceuticals appears quite promising. Limiting factors are the time of synthesis (in comparison to the half-life of the radioactive nuclei), the sophistication of synthesis (to allow a post-generator synthesis in hospitals) and the toxicity of the organometallic/inorganic moieties and their degradation/decomposition products in the body. Much more research and chemistry/biology/medicine cooperation will be needed in this area to transform both biologic constraints and requirements and synthetic inorganic and organometallic knowledge into useful medicinal applications.
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