Chemistry and catalysis advances in organometallic chemistry and catalysis
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Scheme 44.2 Reactions of fac-[Re {κ 3
2 B(tim
Me ) 2 }(CO) 3 ] (5) with ethylenediamine and cyclohexyl isonitrile (tim Me = 2-mercapto-1- methylimidazolyl) [38, 39]. (See insert for color representation of the figure.) PPh
3 pzH
pzH 6 9 10 11 Carbon
Rhenium Nitrogen
Oxygen Sulphur
Boron Phosphorous Scheme 44.3 Reactions of fac-[Re {κ 3
3 B(tim
Me ) }(CO) 3 ] (6) with triphenylphosphine and pyrazole (tim Me = 2-mercapto-1- methylimidazolyl) [40, 41]. (See insert for color representation of the figure.) TARGET-SPECIFIC COMPLEXES 595 + N N O O H N N O O N N O O + N N O O O H N N O O O N N O O O C C + O O P P P P O O O O O O O O 99m
Tc 99m
Tc 99m
Tc 99m
Tc C C C C C C N N N N N N OMe
OMe MeO
MeO OMe
OMe + CO CO OC CO OC CO 99m Tc-DMEOP (12) 99m
Tc-TMEOP (13) 99m
Tc-Sestamibi 99m
Tc-Tetrofosmin Figure 44.5 Structures of 99m Tc(I) tricarbonyl complexes with potential as myocardial imaging agents. Our group studied cationic tris(pyrazolyl)methane technetium tricarbonyl complexes bearing a variety of ether functional groups at the pyrazolyl rings and/or at the central carbon atom [49–52]. We expected to improve their biodistribution profile, namely, the heart/liver and heart/lung uptake ratios, as the activity retained in adjacent nontarget organs may hamper the clinical analysis of the heart images. These studies allowed the identification of the lead complexes 12 and 13 (Fig. 44.5), which are anchored by the tris(pyrazolyl)methane ligands HC[3,5-(MeOCH 2 ) 2 pz]
3 (DMEOP) and HC[3,4,5-(MeOCH 2 )
pz] 3 (TMEOP), respectively. Owing to the relatively low water solubility of these ligands, we prepared the respective sodium complexes [Na {HC[3,5-
(MeOCH 2 ) 2 pz]
3 } 2 ]I and [Na {HC[3,4,5-(MeOCH 2 )
pz] 3 } 2 ]I (Fig. 44.6). These salts are completely soluble in aqueous medium and react quantitatively with fac-[ 99m
Tc(CO) 3 (H 2 O) 3 ] + affording the desired compounds (12 and 13) under aqueous conditions [49]. Complexes 12 and 13 exhibited a significant fast and stable heart uptake, as well as a fast blood and liver clearance. Within the tricarbonyl approach, only another 99m
Tc(I) complex stabilized by a tridentate PNP ligand bearing a pendant crown ether has shown a biological behavior comparable to that of 12 and 13 [48]. Our preclinical results were particularly encouraging for fac-[ 99m
Tc(CO) 3 {HC[3,4,5-(CH 3 OCH
2 ) 3 pz] 3 }] + (13) that exhibited an extremely fast liver clearance compared to 99m Tc-
Sestamibi and 99m
Tc-Tetrofosmin (Fig. 44.7) [49, 50]. In vivo data indicated that this 99m
Tc(I) tricarbonyl complex improves the diagnostic accuracy of coronary artery disease, and so deserve to be further evaluated in larger animals and humans as a myocardial perfusion agent. As described earlier for 99m
Tc-sestamibi, the authors have also shown that complex 13 has potential for early detection of cancer and noninvasive monitoring of tumor multidrug resistance (MDR) [52]. 44.6 TARGET-SPECIFIC COMPLEXES Advances in proteomics and genomics have significantly improved the understanding of molecular alterations underlying different diseases, such as changes in expression and functionality of different genes and/or proteins. The noninvasive
596 ORGANOMETALLIC CHEMISTRY OF RHENIUM AND TECHNETIUM FUELED BY BIOMEDICAL APPLICATIONS O18 O6
N1 N5 N7 N9 N11
C1 C29
Na Figure 44.6 Molecular structure of the cation of compound [Na {HC[3,4,5-(MeOCH 2 ) 3 pz]
3 } 2 ]I. (a)
(b) Heart
Liver (c)
Figure 44.7 Representative SPECT image analysis at 40 min after administration of (a) 99m Tc-TMEOP (13), (b) 99m Tc-Sestamibi, and (c) 99m
Tc-Tetrofosmin. Reproduced with permission from John Wiley & Sons. imaging of such alterations with target-specific radiopharmaceuticals can contribute to the monitoring of disease onset and progression, follow-up of innovative therapies in patients, or preclinical models and dosage optimization of novel drugs. In the past few years, the tricarbonyl technology has been abundantly explored on the design of target-specific radiopharmaceuticals, based on protein-like molecules (e.g., peptides, peptide nucleic acids, antibodies, nanobodies, or affibodies) or on small nonpeptidic organic molecules (e.g., amino acids, carbohydrates, folic acid, vitamin B12 derivatives, phosphonates, and enzyme substrates/inhibitors) [11, 12, 53–59]. For bioactive peptides, important achievements have been already obtained, based on, for example, the single amino acids chelate technology (SAAC) that allows a highly flexible functionalization of peptides using solid-phase peptide synthesis (SPPS) [53]. For small nonpeptidic biomolecules, the progresses can be considered more mitigated despite the significant efforts developed worldwide, namely, on steroid derivatives, amino acids, and sugars. Several 99m
Tc(CO) 3 -labeled small biomolecules with encouraging in vitro properties have been obtained but, TARGET-SPECIFIC COMPLEXES 597 so far, none of them have shown sufficiently good biological profile for further clinical evaluation in humans. The present contribution will not cover all the reported work on the field, to avoid overlap with other comprehensive reviews recently published [11, 12, 53–60]. We have used the tricarbonyl technology for labeling different bioactive peptides, for example, bombesin analogs, RGD (Arg-Gly-Asp)-containing peptides, and melanocortin analogs [61–72]. Concerning melanocortin analogs, it is worth highlighting the achievements obtained on the modulation of their pharmacokinetics, profiting from the versatility of the pyrazolyl-diamine bifunctional chelators (BFCAs). Following initial studies with linear analogs that have shown moderate tumor-targeting capability, a lactam bridge-cyclized α-melanocyte-stimulating hormone (α-MSH) derivative, βAlaNleCycMSH hex
, was synthesized and labeled with the fac-[ 99m
T(CO) 3 ] + core using a pyrazolyl-diamine BFCA with Me substituents at the 3- and 5-positions of the azolyl ring. The resulting radiolabeled cyclic peptide exhibited a very high tumor uptake in B16F1 melanoma tumor-bearing mice (among the highest values reported in the literature), but showed an undesirable accumulation of activity in the liver and intestine [66]. Thereafter, the effect of different azolyl-ring substitution patterns (free carboxylate at the 4-position and/or methyl groups at the 3- and 5-positions) (Fig. 44.8) on the pharmacokinetic profile of the 99m
Tc(CO) 3 -labeled cyclic α-MSH derivative was studied. The different radiopeptides (14–16) displayed subnanomolar binding affinity for the melanocortin type 1 receptor (MC1R) with high and comparable melanoma uptake in B16F1 melanoma-bearing C57BL/6 mice at 1 h p.i. (between 9.90 ± 1.10
%IA/g and 11.82 ± 3.91 %IA/g). The presence of carboxylate substituents at the 4-position of the pyrazolyl ring caused a significant reduction in kidney (circa 90% and 96%) and liver (circa 92% and 88%) uptake, particularly for complex
Fig. 44.9. Furthermore, the radiopeptide 16 presented the highest tumor-to-kidney ratio (7.1 at 4 h p.i.) among all the evaluated α-MSH lactam-based cyclic radiopeptides [72]. Altogether, these results showed that the versatility and favorable coordination capability of pyrazolyl-diamine chelators allowed the tuning of the pharmacokinetic properties of 99m
Tc(CO) 3 - labeled bioactive peptides, without compromising their in vitro and in vivo targeting ability. Owing to their compact and lipophilic character, the fac-[ 99m Tc(CO)
3 ] + core has also been studied for the labeling of central nervous system (CNS) receptor ligands, aiming to find radioactive probes for in vivo monitoring of the density of these receptors. In particular, several research groups have studied 99m
Tc-labeled aryl-piperazine derivatives looking for radioactive probes for specific targeting of 5-hydroxytryptamine (5-HT 1A ) receptors, implicated in major neuropsychiatric disorders such as schizophrenia, anxiety, and depression. Several BFCAs, such as cyclopentadieyls [27], carboranes [73], and dihydrobis(mercaptoimidazolyl)borates [37, 74], have been explored to achieve this goal. Our group focused on dihydrobis(mercaptoimidazolyl)borates, which stabilize neutral and lipophilic 99m
Tc-tricarbonyl complexes easily functionalized with arylpiperazine pharmacophores, through the mercaptoimidazolyl rings. Complexes containing one or two pharmacophores (Fig. 44.10) were synthesized and biologically evaluated. Most of the complexes presented excellent N N N NH 2 O HN NH O H 2 N N H O NH N H NH 2 O HN HN O N H O N HN O NH O N H O HN HN O R 1 R 2 R 3 99m Tc CO CO OC
1 = R
2 = R
3 = H
15: R 1 = R 3 = Me, R
2 = CH
2 COOH
16: R 1 = R 3 = H, R
2 = COOH
+ Figure 44.8 Structures of 99m Tc(CO)
3 -labeled lactam bridge-cyclized α-MSH derivatives obtained using different pyrazolyl-diamine BFCAs.
598 ORGANOMETALLIC CHEMISTRY OF RHENIUM AND TECHNETIUM FUELED BY BIOMEDICAL APPLICATIONS 15 16
Liver Figure 44.9 Scintigraphic images of a melanoma-bearing mouse injected with 99m T(CO)
3 -labeled melanocortin analogs 15 and 16. [72]. 17 Carbon
Rhenium Nitrogen
Oxygen Sulphur
Boron Figure 44.10 Molecular structure of a dihydrobis(mercaptoimidazolyl)borate Re(I) tricarbonyl complex containing two arylpiperazine pharmacophores [74] (See insert for color representation of the figure.) nanomolar or subnanomolar affinity (IC 50 values) toward the 5-HT 1A receptors, when linkers of appropriate length were used to attach the pharmacophore to the metal moiety. However, all the complexes have shown a relatively poor brain uptake in mice. The targeting of enzymes with radioactive probes is considered of great importance in the diagnosis and follow-up of different oncological pathologies and cardiovascular diseases. Several groups investigated the labeling of enzyme inhibitors or substrates using the tricarbonyl approach (e.g., carbonic anhydrase [75], histone deacetylase [76], epidermal growth factor receptor tyrosine kinase (EGFR-TK) [16], and human thymidine kinase (hTK)[77–81]). In our group, we studied pyrazolyl-diamine Re(I) and 99m
Tc(I) complexes bearing l-arginine derivatives for in vivo nitric oxide synthase (NOS) targeting (Fig. 44.11) [82–84]. NOS is the eukaryotic enzyme responsible for the endogenous catalytic oxidation of l-arginine to l-citrulline that generates nitric oxide (NO), a key mammalian signaling mediator in several physiological processes. Overproduction of NO by iNOS has been linked to many diseases, particularly cancer. In vitro studies with Re N N
NH 2 O N H COOH HN NH H N NO 2 M CO CO
OC M = Re (18), M = 99m Tc (18a), n = 4 M = Re (19), M = 99m
Tc (19a), n = 1 n +
Examples of l-arginine-containing M(I) tricarbonyl complexes.
TARGET-SPECIFIC COMPLEXES 599 complexes have shown that the affinity of inhibitor-containing conjugates to iNOS is less affected on metallation than the substrate-containing conjugates. The Re complexes bearing guanidino-substituted analogs of l-arginine retained considerable inhibitory action, and are the first examples of organometallic complexes inhibiting the iNOS [82, 83]. Remarkably, a nitro- arginine-containing Re complex (18) (Fig. 44.11) showed a K
value of 6 μM, comparable to that of the organic inhibitor
ω -nitro-l-arginine. Complex 18 also suppressed NO biosynthesis in lipopolysaccharide (LPS)-treated macrophages, but the 99m Tc congener (18a) did not show any significant uptake in most tissues of LPS-treated mice compared to a control group. However, the related complex 19a (Fig. 44.11) showed an enhanced uptake in the LPS-treated animal model, due most probably to iNOS upregulation [83]. These results indicate that this family of complexes may hold promise for the design of SPECT probes for in vivo targeting of iNOS. Bisphosphonates (BPs) are a class of small molecules highly important in the treatment of osteoporosis as they inhibit osteoclatic bone resorption. Owing to their osteotropic properties, the labeling of BPs with 99m
Tc and 186/188
Re can provide radioactive tools useful for bone scintigraphy and therapy, respectively. Taking this into consideration, the authors’ group has studied the labeling of pamidronate (PAM) and alendronate (ALN) with the fac-[ 99m
Tc(CO) 3 ] + core using pyrazolyl diamine chelators (Fig. 44.12) [85, 86]. The resulting 99m Tc complexes were chemically identified by high performance liquid chromatography (HPLC) comparison with their corresponding Re surrogates, which were fully characterized. The biological evaluation of the PAM derivatives (complexes 20a and 21a) in mice has shown a bone uptake comparable to that of a radiopharmaceutical in clinical use ( 99m
Tc-MDP) with a favorable and fast clearance from most soft tissues (Fig. 44.13). Other authors have also labeled the same BPs with fac-[ 188 Re(CO)
3 ] + using dipyridyl amine (dpa) BFCAs. Most relevantly, preclinical studies of one of these complexes, fac-[ 188 Re(CO)
3 (dpa-ALN)], indicated that it is superior to 188 Re-HEDP, presenting greater accumulation in regions of high metabolic activity and displaying an enhanced resistance toward in vivo oxidation to perrhenate [87]. N N N NH 2 HN O M CO CO OC P P OH O − O HO OH O − O M = Re (20), M = 99m Tc (20a), n = 1 M = Re (21), M = 99m
Tc (21a), n = 2 n = 1, 2 n +
BP-containing pyrazolyldiamine M(I) tricarbonyl complexes for bone targeting. 21a
99m Tc-MDP
Figure 44.13 Planar whole-body gamma camera images of rats injected with complex 21a and 99m Tc-MDP at 2 h p.i. Reproduced with permission from The Royal Society of Chemistry. (See insert for color representation of the figure.) 600 ORGANOMETALLIC CHEMISTRY OF RHENIUM AND TECHNETIUM FUELED BY BIOMEDICAL APPLICATIONS Altogether, these results clearly indicate that these Tc(I)/Re(I) tricarbonyl complexes are a class of complexes with great potential as bone targeting radiopharmaceuticals for diagnostic or therapeutic applications in nuclear medicine. Multifunctional 99m
Tc compounds displaying cell-specific uptake and ability to target the nucleus might have potential for targeted therapy as 99m Tc is also an Auger electron-emitting radiometal. The design of this type of complexes has been pioneered by Alberto et al., who have shown that a trifunctional 99m
Tc(I) tricarbonyl complex, containing a pyrene intercalator and an nuclear localisation signal (NLS) peptide, reaches the nucleus of B16-F1 mouse melanoma cells and induces much stronger radiotoxic effects than 99m
TcO 4 – [88]. Alberto et al. also demonstrated that a [2 +1] Re(I) tricarbonyl complex bearing acridine orange (AO) as a DNA-binding group can target the nucleus of murine B16F1 cells without needing a carrier NLS sequence [89]. For this type of application, we have also evaluated pyrazolyl-diamine Re(I)/ 99m Tc(I)
tricarbonyl complexes bearing anthracene (22/22a) and AO groups (23/23a) (Fig. 44.14) [90–92]. We have shown that this type of complexes rapidly entered the cells and accumulated inside the nucleus. Complex 22a, having the anthracenyl substituent at the 4-position of the pyrazolyl ring, exhibited pronounced radiotoxicity and induced an apoptotic cellular outcome [91]. These encouraging results prompted the synthesis of pyrazolyldiamine 99m
Tc(I)/Re(I) tricarbonyl complexes bearing Bombesin (BBN) analogs and AO intercalators. We have shown that complex 24a, containing the GGG-BBN Bombesin [7–14] peptide (Fig. 44.14), presented a high cellular internalization in PC3 cells and a remarkably high nuclear uptake in the same cell line. Live cell confocal imaging microscopy studies (Fig. 44.15) with the Re congener (24) have shown a considerable accumulation of fluorescence into the nucleus with uptake kinetics similar to that exhibited by 24a. These compounds are the first examples of 99m Tc bioconjugates that combine specific cell targeting with nuclear internalization, a crucial issue for the exploitation of 99m
Tc in Auger therapy [93]. The design of nanoplatforms for in vivo molecular imaging applications and/or drug delivery is a growing field. We and other groups have explored the tricarbonyl technology to label mannosylated dextran derivatives, aiming the design of specific nanostructures for sentinel lymph node detection (SLND). To achieve this goal, dextran was functionalized with pyrazolyldiamine or cysteine chelators to stabilize the fac-[M(CO) 3 ] + (M = 99m Tc, Re) core and with mannose to provide NH NH
N M OC OC CO N NMe 2 NMe 2 NH O N N N NH 2 R M CO CO OC M = Re (22), M = 99m Tc (22a) R = H, M = Re (23), M = 99m
Tc (23a) R = (CH
2 ) 3 CONH-GGG-BBN[7-14], M = Re (24), M = 99m
Tc (24a) Figure 44.14 M(I) tricarbonyl complexes functionalized with polyaromatic DNA intercalators and BBN analogs. Download 11.05 Mb. Do'stlaringiz bilan baham: 
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