Development and Pharmacological Evaluation of New Bone-Targeted ^99mTc-Radiolabeled Bisphosphonates

A novel bisphosphonate, 1-(3-aminopropylamino)­ethane-1,1-diyldiphosphonic acid (<b>3</b>), was coupled to the tridentate chelators di-2-picolylamine, 2-picolylamine-<i>N</i>-acetic acid, iminodiacetic acid, 3-((2-aminoethyl)­thio)-3-(1<i>H</i>-imidazol-4-yl)­propanoic acid, and 2-((2-carboxyethyl)­thio)-3-(1<i>H</i>-imidazol-4-yl)­propanoic acid to form ligands <b>6</b>, <b>9</b>, <b>11</b>, <b>15</b>, and <b>19</b>, respectively. Organometallic complexes of the general formula [Re/^99mTc­(CO)₃(κ³-L)] were synthesized, where L denotes ligand <b>6</b>, <b>9</b>, <b>11</b>, <b>15</b>, or <b>19</b>. The rhenium complexes were prepared at the macroscopic level and characterized by spectroscopic methods. The technetium-99m organometallic complexes were synthesized in high yield and were identified by comparative reversed-phase HPLC with their Re analogues. The ^99mTc tracers were stable <i>in vitro</i> and exhibited binding to hydroxyapatite. In biodistribution studies, all of the ^99mTc complexes exhibited high bone uptake superior to that of <b>25</b>, which is the directly ^99mTc-labeled bisphosphonate <b>3</b>, and comparable to that of ^99mTc-methylene diphosphonate (^99mTc-MDP). The tracers [^99mTc­(CO)₃(<b>6</b>)] (<b>26</b>), [^99mTc­(CO)₃(<b>9</b>)] (<b>27</b>), [^99mTc­(CO)₃(<b>11</b>)] (<b>28</b>), and [^99mTc­(CO)₃(<b>15</b>)] (<b>29</b>) exhibited higher bone/blood ratios than ^99mTc-MDP. <b>26</b> had the highest bone uptake at 1 h p.i. The new bisphosphonates showed no substantial growth inhibitory capacity in PC-3, Saos-2, and MCF-7 established cancer cell lines at low concentrations. Incubation of <b>26</b> with the same cancer cell lines indicated a rapid and saturated uptake. The promising properties of <b>26</b>–<b>29</b> indicate their potential for use as bone-imaging agents

Convenient Route Leading to Neutral <i>fac</i>-M(CO)₃(NNO) Complexes (M = Re, ^99mTc) Coupled to Amine Pharmacophores

The synthesis and characterization of three neutral tricarbonyl fac-M(CO)3(NNO) (M = Re, 99mTc) complexes based on the picolylamine N,N-diacetic acid (PADA) ligand is reported. One of the two carboxylate groups of the PADA ligand is efficiently and conveniently derivatized with an amine nucleophile through the use of the PADA anhydride. In this work, aniline, benzylamine and pyrrolidine were used as model amine nucleophiles. The rhenium complexes were synthesized using the [NEt4]2[Re(CO)3Br3] precursor and fully characterized by elemental analysis, spectroscopic methods, and X-ray crystallography. The analogous technetium-99m complexes were also prepared quantitatively using the [99mTc(CO)3(H2O)3]+ precursor. The reaction scheme presented for the synthesis of the fac-M(CO)3(NNO) (M = Re, 99mTc) complexes can be applied to the development of target-specific radiopharmaceuticals because, in principle, any bioactive pharmacophore bearing an amine group can be used in the place of the model amine nucleophiles

Synthesis and Characterization of Novel “3 + 2” Oxorhenium Complexes, ReO[SNO][NN]

The present paper deals with the synthesis and structural characterization of novel neutral oxorhenium(V) complexes of the general formula ReO[SNO][NN]. The simultaneous action of the tridentate SNO ligand, N-(2-mercaptoacetyl)glycine (1), and the bidentate NN ligand, N-phenylpyridine-2-aldimine (2), on ReOCl3(PPh3)2 leads to the formation of two isomers 4a and 4b of the general formula ReO[SNO][NN], as a result of the different orientations of the NN ligand. In both cases, the SNO donor atoms of the tridentate ligand occupy the three positions in the equatorial plane of the distorted octahedron, whereas the oxo group is always directed toward one of the apical positions. In the first isomer, 4a, the imino nitrogen of the NN ligand occupies the fourth equatorial position and the pyridine type nitrogen is directed trans to the oxo group, while in the second isomer, 4b, the imino nitrogen of the NN ligand occupies the apical position trans to the oxo group and the pyridine type nitrogen completes the equatorial plane of the distorted octahedron. The [SNO][NN] mixed-ligand system was applied in the synthesis of the oxorhenium complex 5 in which the 1-(2-methoxyphenyl)piperazine moiety, a fragment of the true 5-HT1A antagonist WAY 100635, has been incorporated in the NN bidentate ligand (NN is N-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propyl}pyridine-2-aldimine). In this case, high-performance liquid chromatography and NMR showed the existence of one isomer, 5, in which the pyridine nitrogen is trans to the oxo core, as demonstrated by crystal structure analysis

Convenient Route Leading to Neutral <i>fac</i>-M(CO)₃(NNO) Complexes (M = Re, ^99mTc) Coupled to Amine Pharmacophores

The synthesis and characterization of three neutral tricarbonyl fac-M(CO)3(NNO) (M = Re, 99mTc) complexes based on the picolylamine N,N-diacetic acid (PADA) ligand is reported. One of the two carboxylate groups of the PADA ligand is efficiently and conveniently derivatized with an amine nucleophile through the use of the PADA anhydride. In this work, aniline, benzylamine and pyrrolidine were used as model amine nucleophiles. The rhenium complexes were synthesized using the [NEt4]2[Re(CO)3Br3] precursor and fully characterized by elemental analysis, spectroscopic methods, and X-ray crystallography. The analogous technetium-99m complexes were also prepared quantitatively using the [99mTc(CO)3(H2O)3]+ precursor. The reaction scheme presented for the synthesis of the fac-M(CO)3(NNO) (M = Re, 99mTc) complexes can be applied to the development of target-specific radiopharmaceuticals because, in principle, any bioactive pharmacophore bearing an amine group can be used in the place of the model amine nucleophiles

Curcumin as the OO Bidentate Ligand in “2 + 1” Complexes with the [M(CO)₃]⁺ (M = Re, ^99mTc) Tricarbonyl Core for Radiodiagnostic Applications

The synthesis and characterization of “2 + 1” complexes of the [M(CO)3]+ (M = Re, 99mTc) core with the β-diketones acetylacetone (complexes 2, 8) and curcumin (complexes 5, 10 and 6, 11) as bidentate OO ligands, and imidazole or isocyanocyclohexane as monodentate ligands is reported. The complexes were synthesized by reacting the [NEt4]2[Re(CO)3Br3] precursor with the β-diketone to generate the intermediate aqua complex fac-Re(CO)3(OO)(H2O) that was isolated and characterized, followed by replacement of the labile water by the monodentate ligand. All complexes were characterized by mass spectrometry, NMR and IR spectroscopies, and elemental analysis. In the case of complex 2, bearing imidazole as the monodentate ligand, X-ray analysis was possible. The chemistry was successfully transferred at 99mTc tracer level. The curcumin complexes 5 and 6, as well as their intermediate aqua complex 4, that bear potential for radiopharmaceutical applications due to the wide spectrum of pharmacological activity of curcumin, were successfully tested for selective staining of β-amyloid plaques of Alzheimer’s disease. The fact that the complexes maintain the affinity of the mother compound curcumin for β-amyloid plaques prompts for further exploration of their chemistry and biological properties as radioimaging probes

Remarkable Brain Penetration of Cyclopentadienyl M(CO)₃⁺ (M = ^99mTc, Re) Derivatives of Benzothiazole and Benzimidazole Paves the Way for Their Application as Diagnostic, with Single-Photon-Emission Computed Tomography (SPECT), and Therapeutic Agents for Alzheimer’s Disease

The synthesis and evaluation of three novel 99mTc complexes (99mTc-1–3) and their corresponding Re complexes (Re-1–3), in which the phenyl ring of 2-phenylbenzothiazole or 2-phenylbenzimidazole is replaced by the cyclopentadienyl tricarbonyl [Cp99mTc­(CO)3] core, are reported. Both 99mTc and Re complexes were prepared from the corresponding ferrocenyl derivatives, and the Re complexes were fully characterized by elemental analysis, spectroscopic methods, and X-ray crystallography. The complexes exhibit effective in vitro binding to β-amyloid (Aβ) plaques and fibrils, inhibit Aβ fibril formation, and significantly reduce Aβ-induced cytotoxicity and reactive oxygen species production in neuronal cell cultures. The brain uptake of the 99mTc complexes ranges between 7.94 and 3.99% ID/g at 2 min p.i., being the highest recorded for potential 99mTc Aβ plaque imaging probes in mice. Powered by their high brain uptake, the complexes represent strong theranostic candidates against Alzheimer’s disease combining single-photon-emission computed tomography diagnostic (99mTc complexes) and antiamyloid therapeutic (Re complexes) potential

Effective Labeling of Amine Pharmacophores through the Employment of 2,3-Pyrazinedicarboxylic Anhydride and the Generation of <i>fac-</i>[M(CO)₃(PyA)P] and <i>cis–trans</i>-[M(CO)₂(PyA)P₂] Complexes (PyA = Pyrazine-2-carboxylate, P = Phosphine, M = Re, ^99mTc)

The fac-[M­(CO)3(PyA)­(P)] and cis–trans-[M­(CO)2(PyA)­(P)2] neutral complexes (M is Re or 99mTc), based on the mixed ligand strategy with pyrazine-2-carboxylic acid (PyAH) as the bidentate N,O and triphenylphosphine as the monodentate P ligand, are presented. Through the employment of the anhydride of pyrazine-2,3-dicarboxylic acid (PyDA), the PyAH scaffold was conveniently derivatized with the model bioactive amine 1-(2-methoxyphenyl)­piperazine, the active part of the 5-HT1A antagonist WAY100635. Reaction of either PyAH or the pharmacophore-bearing PyAH ligand (L1H) with fac-[M­(CO)3]+ core in water yielded the intermediate fac-[M­(CO)3(PyA)­(H2O)] complexes. The labile aqua ligand was easily replaced by PPh3 to yield the fac-[Re­(CO)3(PyA)­(PPh3)] complexes, while in toluene under reflux, the cis–trans-[Re­(CO)2(PyA)­(PPh3)2] complexes were obtained. The latter complexes were alternatively obtained from mer-[Re­(CO)3(PPh3)2Cl] by refluxing with the PyA ligand in toluene. The analogous 99mTc complexes were synthesized quantitatively, showing excellent stability in competition studies. The methodology described herein represents a practical procedure for the effective integration of the fac-[M­(CO)3]+ core with amine-bearing biologically active compounds for diagnosis/therapy

Curcumin as the OO Bidentate Ligand in “2 + 1” Complexes with the [M(CO)₃]⁺ (M = Re, ^99mTc) Tricarbonyl Core for Radiodiagnostic Applications

The synthesis and characterization of “2 + 1” complexes of the [M(CO)3]+ (M = Re, 99mTc) core with the β-diketones acetylacetone (complexes 2, 8) and curcumin (complexes 5, 10 and 6, 11) as bidentate OO ligands, and imidazole or isocyanocyclohexane as monodentate ligands is reported. The complexes were synthesized by reacting the [NEt4]2[Re(CO)3Br3] precursor with the β-diketone to generate the intermediate aqua complex fac-Re(CO)3(OO)(H2O) that was isolated and characterized, followed by replacement of the labile water by the monodentate ligand. All complexes were characterized by mass spectrometry, NMR and IR spectroscopies, and elemental analysis. In the case of complex 2, bearing imidazole as the monodentate ligand, X-ray analysis was possible. The chemistry was successfully transferred at 99mTc tracer level. The curcumin complexes 5 and 6, as well as their intermediate aqua complex 4, that bear potential for radiopharmaceutical applications due to the wide spectrum of pharmacological activity of curcumin, were successfully tested for selective staining of β-amyloid plaques of Alzheimer’s disease. The fact that the complexes maintain the affinity of the mother compound curcumin for β-amyloid plaques prompts for further exploration of their chemistry and biological properties as radioimaging probes

Synthesis and Characterization of <i>fac</i>-[M(CO)₃(P)(OO)] and <i>cis-trans</i>-[M(CO)₂(P)₂(OO)] Complexes (M = Re, ^99mTc) with Acetylacetone and Curcumin as OO Donor Bidentate Ligands

The synthesis and characterization of neutral mixed ligand complexes <i>fac-</i>[M­(CO)₃(P)­(OO)] and <i>cis-trans</i>-[M­(CO)₂(P)₂(OO)] (M = Re, ^99mTc), with deprotonated acetylacetone or curcumin as the OO donor bidentate ligands and a phosphine (triphenylphosphine or methyldiphenylphosphine) as the monodentate P ligand, is described. The complexes were synthesized through the corresponding <i>fac-</i>[M­(CO)₃(H₂O)­(OO)] (M = Re, ^99mTc) intermediate aqua complex. In the presence of phosphine, replacement of the H₂O molecule of the intermediate complex at room temperature generates the neutral tricarbonyl monophosphine <i>fac</i>-[Re­(CO)₃(P)­(OO)] complex, while under reflux conditions further replacement of the trans to the phosphine carbonyl generates the new stable dicarbonyl bisphosphine complex <i>cis-trans</i>-[Re­(CO)₂(P)₂(OO)]. The Re complexes were fully characterized by elemental analysis, spectroscopic methods, and X-ray crystallography showing a distorted octahedral geometry around Re. Both the monophosphine and the bisphosphine complexes of curcumin show selective binding to β-amyloid plaques of Alzheimer’s disease. At the ^99mTc tracer level, the same type of complexes, <i>fac</i>-[^99mTc­(CO)₃(P)­(OO)] and <i>cis-trans</i>-[^99mTc­(CO)₂(P)₂(OO)], are formed introducing new donor combinations for ^99mTc­(I). Overall, β-diketonate and phosphine constitute a versatile ligand combination for Re­(I) and ^99mTc­(I), and the successful employment of the multipotent curcumin as β-diketone provides a solid example of the pharmacological potential of this system