Monomeric and dimeric complexes of pyrimidine-4,6-dicarboxylic acid with organometallic fac-[M(CO)3]+ (M = Re and 99mTc) core as radiopharmaceutical probes

doi:10.21203/rs.3.rs-4381286/v1

Download PDF

Research Article

Monomeric and dimeric complexes of pyrimidine-4,6-dicarboxylic acid with organometallic fac-[M(CO)₃]⁺ (M = Re and ^99mTc) core as radiopharmaceutical probes

https://doi.org/10.21203/rs.3.rs-4381286/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

The current study describes the synthesis of monomeric and dimeric complexes of pyrimidine-4,6-dicarboxylic acid (H₂pmdc) ligand with the organometallic fac-[M(CO)₃]⁺ (M = Re and ^99mTc) core which are the model for future design of imaging, therapeutic and theranostic radiopharmaceuticals. Monomeric complexes [M(CO)₃(OH₂)(Hpmdc)] (M = Re (1) and ^99mTc (2)) were formed from the reaction of H₂pmdc with [Re(CO)₅Br] and [^99mTc(CO)₃(OH₂)₃]⁺ in aqueous solution respectively. The reaction of [Re(CO)₅Br] with H₂pmdc in ethanol (EtOH) led to the monomeric complex [Re(CO)₃(OH₂)(etpmdc)] (3), where etpmdc⁻ is 6-(ethoxycarbonyl)pyrimidine-4-carboxylate anion which was formed from the mono-esterification of H₂pmdc in parallel with its coordination to the fac-[Re(CO)₃]⁺ unit. Dimeric complex (Et₃NH)₂[(µ-pmdc)₂(Re(CO)₃)₂ (4) was obtained from the reaction of [Re(CO)₅Br] with H₂pmdc in water with addition of triethylamine (Et₃N) as supporting base. The chemical identification of 1, 3 and 4 was achieved by using ¹HNMR, ¹³CNMR, IR, ESI-MS and elemental analysis. Complex 3 was furtherly identified by using single crystal X-ray crystallography. The structural similarities of 1 and 2 was assessed by coinjection in the HPLC with UV/Vis detection coupled with a γ-detector followed by comparison of retention times of the γ-peak of 2 and the UV-peak of 1 which allowed unambiguous identification of 2. Heterodinuclear ^99mTc/Re complex [(µ-pmdc)₂(Re(CO)₃)(^99mTc(CO)₃)₂)]²⁻ (5) was formed by reacting H₂pmdc with [^99mTc(CO)₃(OH₂)₃]⁺ and [Re(CO)₅Br] in aqueous solution. In parallel, the reaction also yielded complexes 1 and 2. The formation of 5 was assessed by injection in the HPLC with UV/Vis detection coupled with a γ-detector which displayed the radiochemical peak with the corresponding UV peak equivalent to that of the homologous non-radioactive complex 4.

Monomeric complex

Dimeric complex

Pyrimidine-4

6-dicarboxylic acid

Rhenium

Technetium

Pyrimidine-4,6-dicarboxylic acid (H₂pmdc) is naturally occurring heterocyclic compound, and it is found in many organisms as building block of biological molecules, and involved in different metabolic pathways [1, 2]. It is involved in the synthesis of purines and pyrimidines bases, which are the building blocks of DNA and RNA, and regulation of the Krebs cycle during glucose metabolism [1, 3]. In addition, H₂pmdc is of interest as it is potentially applied in the synthesis of a variety of compounds, including antibiotics, antivirals, and other drugs [1, 2]. Due to its large number of donor atoms and flexibility as small molecule, H₂pmdc ligand has shown a remarkable capacity in the development of coordination chemistry [4]. The diversity of its coordination mode to metal ions is reflected in the variety of known and stable metal complexes with this ligand, which vary from monomers to ligand-bridged dimers and multimers [4–8]. Furthermore, the H₂pmdc contains two carboxylic acid groups and two imine nitrogens which is advantage in the coordination chemistry since it can be easily functionalized and derivatized [5–8].

Rhenium (Re) and technetium (Tc) are located in Group VII on the Periodic Table of elements and have comparable atomic radii, and consequently display similar coordination chemistry [11]. Therefore, the chemistry of rhenium is used for modelling one of technetium [9, 10]. Due to their location in the middle of the d-block of transition metals, Re and Tc exhibit the properties of both early and later transition metals [9, 11, 12], and display the oxidation state which varies from − 1 to + 7 [12]. The chemistry of Re and Tc is continuing to attract the researchers due to the potential application of these elements in nuclear medicine [13, 11]. Rhenium radioisotopes ^186/188Re are γ and β-emitters and applied in therapeutic nuclear medicine, while technetium radioisotope ^99mTc is γ-emitter and applied in nuclear medicine imaging procedures [11–15]. The similarity in the coordination chemistry of Re and Tc makes possible to share the same biodistribution partners in the body for analogous radiopharmaceuticals based on these elements, and enable the monitoring of their biodistribution using the same γ-ray camera [16].

Organometallic fac-[M(CO)₃]⁺ (M = Re and Tc) core dominates the chemistry of rhenium(I) and technetium(I), and it is well known by its small size, three vacant coordination sites and three flexible and facially arranged CO ligands [11, 17–19]. The fac-[M(CO)₃]⁺ (M = Re and Tc) core displays d⁶ and low-spin electronic configuration, and its complexes are characterized by a distorted octahedral geometry and high kinetic and thermodynamic stability [18–20]. It is routinely coordinate to different chelating ligands leading to the complexes which structurally vary from monomers to ligand-bridged multimers, and even from metal-metal multiply bonded multimers to clusters [11, 17–19]. Organometallic complexes based on the fac-[M(CO)₃]⁺ (M = Re and Tc) core have attracted much attention due particularly to their possible application in the development of radiopharmaceuticals which involve imaging ^99mTc and therapeutic ^186/188Re compounds [15, 21–23]. Due to the small size of octahedral complexes based on the the fac-[M(CO)₃]⁺ (M = Re and Tc) core considerably to the octahedral or square-pyramidal complexes of the corresponding metals in higher oxidation states, they are considered less likely to impact important characteristics of bio-molecules to which they are conjugated to [14, 24].

Pyrimidine derivatives with electron-rich sp²-hybridized nitrogen atoms have been identified as convenient ligands to stabilize the fac-[M(CO)₃]⁺ (M = Re and Tc) core [25, 26]. Despite their variety of possible applications, rhenium and technetium complexes based on the fac-[M(CO)₃]⁺ core (M = Re and Tc) with pyrimidine derivative ligands have not been extensively explored [21, 22], and few examples have been reported. The fac-[M(CO)₃]⁺ core (M = Re and Tc) complexes with pyrimidine nucleoside derivatives have been reported and provided a convenient platform for drugs development [27]. Recently, complexes of the fac-[M(CO)₃]⁺ (M = Re and ⁹⁹Tc/^99mTc) core with pyrimidine based ligands typically orotic acid and its derivatives have been reported [19]. The current study highlights on the fac-[M(CO)₃]⁺ (M = Re and ^99mTc) core complexes with pyrimidine-4,6-dicarboxylic acid (H₂pmdc) (Fig. 1) which are the model for future design of imaging, therapeutic and theranostic radiopharmaceuticals.

The reported rhenium complexes were characterized by using ¹HNMR, ¹³CNMR, IR and ESI-MS, and complex 3 was additionally characterized by using single crystal X-ray crystallography. Identity of the reported monomeric rhenium and technetium complexes was confirmed by coinjection in the same HPLC with UV/Vis detection coupled with a γ-detector followed by comparison of retention times for UV- and γ-signals. Evidence of the formation of heterodinuclear ^99mTc/Re complex 5 was assessed by the comparison of its HPLC profile with the HPLC profile of its homologous rhenium dimer complex 4 fully characterized by routine chemistry analytical techniques.

2.1. Materials and instrumentation

Caution

^99mTc is weak γ-emitters. All experiments involving ^99mTc were done in the laboratories approved for working with the low-level radioactive materials. All reactions and solution preparations were carried out under an inert N₂ atmosphere. [^99mTcO4]⁻ was eluted from a ⁹⁹Mo / ^99mTc Ultratechnekow FM generator from Mallinckrodt Schweiz AG. The [Re(CO)₅Br] and pyrimidine-4,6-dicarboxylic acid (H₂pmdc) were obtained from the Sigma Aldrich. The ^99mTc precursor complex [^99mTc(CO)₃(OH₂)₃]⁺ was obtained from the reduction of [^99mTcO₄]⁻ according to the reported literature method [28].

The purity of the reported rhenium complexes was confirmed by Ultraperformance Liquid Chromatographic (UPLC) with a Nucleosil C-18 column (100 Å, 5 µm, 250 × 4 mm) which was eluted with a flow rate of 0.5 ml min^− 1, using 0.1% trifluoro-acetic acid (TFA) in H₂O (solvent A) and acetonitrile (solvent B). ¹HNMR and ¹³CNMR spectra were recorded on Bruker Advance 400 and 500 MHz NMR spectrometer. Deuterated methanol (CD₃OD) and water (D₂O) were used as NMR solvents and the peak positions were obtained relatively to tetramethylsilane (SiMe₄). The infrared spectra were recorded on a Perkin-Elmer FT-IR Spectrum Two spectrometer, using ATR technique, and applied as neat samples. HPLC analyses were performed on a Merck Hitachi LaChrom L 7100 pump coupled to a Merck Hitachi LaChrom L7455 photo diode array. UV/Vis detection was performed at 250 nm. The detection of radioactive ^99mTc complexes was performed with Berthold Technologies Flowstar LB513 radiodetectors equipped with YG/BGO cells, respectively. The radiodetectors were coupled to the HPLC systems. Separations were achieved on a Macherey-Nagel C18 reversed-phase column (EC-250 / 3 Nucleosil 100-5 C18) using gradients of CF₃COOH (0.1% in H₂O, solvent A) and MeOH (solvent B). Comparison of the HPLC retention times for the ^99mTc compounds with the corresponding Re compounds confirms the complexes’ identity. Liquid chromatography (ESI-MS) was analysed using BrukerEsquire HCT (ESI) instrument. The elemental analyses for carbon, hydrogen and nitrogen were performed on a Vario EL (ElementarAnalysensystem GmbH) instrument.

Single-crystal X-ray diffraction data was collected at 160(1) K on a Rigaku OD XtaLAB Synergy, Dualflex, Pilatus 200K diffractometer using a single wavelength X-ray source (Mo Kα radiation: λ = 0.71073 Å) [29] from a micro-focus sealed X-ray tube and an Oxford liquid-nitrogen Cryostream cooler. The selected suitable single crystal was mounted using polybutene oil on a flexible loop fixed on a goniometer head and immediately transferred to the diffractometer. Pre-experiment, data collection, data reduction and analytical absorption correction [30] were performed with the program suite CrysAlisPro 20 [31]. Using Olex2, [32] the structure was solved with the SHELXT [33] small molecule structure solution program and refined with the SHELXL 2018/3 program package [34] by full-matrix least-squares minimization on F [30]. PLATON [34, 35] was used to check the result of the X-ray analysis. For more details about the data collection and refinement parameters, see the CIF file.

2.2. Synthesis of [Re(CO)₃(OH₂)(Hpmdc)] (1)

[Re(CO)₅Br] (34.92 mg, 0.086 mmol) and pyrimidine-4,6-dicarboxylic acid (H₂pmdc) (14.45 mg, 0.086 mmol) were added to 10 cm³ of distilled water. The resulting colorless mixture was heated under refluxed for 6 hours, giving an orange-yellow solution, which was filtered after being cooled to room temperature. No precipitate was obtained. The solvent was removed by evaporation and the yellow-orange precipitate of 1 was purified by washing it several times by dichloromethane and diethylether and dried under vacuum. Yield (1) = 65% (25.45 mg). Anal. Calcd. for C₉H₅N₂O₈Re (Mol. Wt. = 455.35 g/mol): C, 23.74; H, 1.11; N, 6.15. Found: C, 23.77; H, 1.10; N, 6.13. IR (νmax/cm^− 1): ѵ(O − H) 3225, 3110; ѵ(C ≡ O)) 2042, 1908, 1932; ѵ(C = O)) 1712; ѵ(C = N) 1636, 1599. ¹HNMR (295K, D₂O, 400MHz) δ ppm: 8.56 (s, 1H, H(3)), 9.66 (s, 1H, H(6)). ¹³CNMR (295K, CD₃OD, 125MHz) δ ppm: 122.76 (C(3)), 159.52 (C(6)), 162.97 (C(4)), 167.41 (C(2)), 171.40 (C(b)), 175.89 (C(a)), 194.96, 198.01 (CO). ESI-MS (m/z): [C₉H₆N₂O₈Re]⁺ or [1 + H]⁺, calculated: 456.97, found: 457.03; [C₉H₄N₂O₇Re]⁺ or [1-H₂O + H]⁺, calculated: 438.96, found: 439.06, [C₁₁H₇N₃O₇Re]⁺ or [1 + MeCN + H-H₂O]⁺, calculated: 479.98, found: 479.99. UPLC (retention time min.): 1.80.

2.3. Synthesis of [^99mTc(CO)₃(OH₂)(Hpmdc)] (2)

300 µl of [^99mTc(CO)₃(OH₂)₃]⁺ in water were mixed with 300µl of 0.01M aqueous solution of pyrimidine-4,6-dicarboxylic acid (H₂pmdc) in vial which was sealed and flushed with N₂ for 15 min. The mixture was heated at 80^oC for 30 min. The solution was brought to r.t. Injection of the solution in the HPLC equipped by gamma and UV detectors displayed the product with a radiochemical yield > 99%. Heating under microwave at the same temperature gave the product in approximately the same yields. The nature of complex 2 was identified by coinjection with [Re(CO)₃(OH₂)(Hpmdc)] (1) in the same HPLC equipped with UV/Vis detection coupled with γ-detector followed by comparison of retention time.

2.4. Synthesis of [Re(CO)₃(OH₂)(etpmdc)] (3)

[Re(CO)₅Br] (34.92 mg, 0.086 mmol) and pyrimidine-4,6-dicarboxylic acid (H₂pmdc) (14.45 mg, 0.086 mmol) were added to 10 cm³ of ethanol. The resulting colorless mixture was heated under refluxed for 6 hours, giving orange solution, which was filtered after being cooled to room temperature, giving an orange precipitate of [Re(CO)₃(OH₂)(etpmdc)] (3). Compound 3 was purified by washing it several times by ethanol and diethylether, and dried under vacuum. Orange-yellow crystals suitable for X-ray diffraction analysis were obtained by the slow evaporation of the filtrate over 4 weeks at room temperature. The crystals of 3 have been also grown from recrystallization of precipitate of 3 in ethanol with 20% of dichloromethane in 3 weeks by the slow evaporation of solvents at room temperature. Yield (1) = 87% (31.18 mg). Anal. Calcd. for C₁₁H₉N₂O₈Re (Mol. Wt. = 483.41 g/mol): C, 27.33; H, 1.88; N, 5.80. Found: C, 27.29; H, 1.85; N, 5.77. IR (νmax/cm^− 1): ѵ(O − H) 3364; ѵ(C ≡ O)) 1873, 1883, 2015; ѵ(C = O)) 1689; ѵ(C = N) 1585, 1581; ѵ(C − H) 3089, 3091. ¹HNMR (295K, CD₃OD, 400MHz) δ ppm: 1.45 (t, 3H, CH₃), 4.52 (q, 2H, CH₂), 4.07 (s, 2H, H₂O), 8.61 (s, 1H, H(3)), 9.64 (s, 1H, H(6)). ¹³CNMR (295K, CD₃OD, 125MHz) δ ppm: 14.85 (CH₃), 64.88 (CH₂), 123.13 (C(3)), 160.72 (C(6)), 160.76 (C(4)), 162.34 (C(2)), 164.30 (C(b)), 173.79 (C(a)), 197.37, 197.05, 193.94 (CO). ESI-MS (m/z): [C₁₁H₈N₂O₇Re]⁺ or [3-H₂O + H]⁺, calculated: 466.99, found: 467.21, [C₁₃H₁₁N₃O₇Re]⁺ or [3 + MeCN + H-H₂O]⁺, calculated: 508.02, found: 508.15.

2.5. Synthesis of (Et₃NH)₂[(µ-pmdc)₂(Re(CO)₃)₂] (4)

Pyrimidine-4,6-dicarboxylic acid (H₂pmdc) (20.67 mg, 0.123 mmol) was added to [Re(CO)₅Br] (49.95 mg, 0.123 mmol) in 10 cm³ of distilled water and 3 drops of triethylamine (Et₃N). The resulting colourless mixture was refluxed for 24 hours, giving an orange solution, which was filtered after being cooled to room temperature. No precipitate was formed; the filtrate was removed giving an orange precipitate of 4 which was purified by washing it several times by dichloromethane and diethylether. Yield = 85% (56.30 mg). Anal. Calcd. for C₃₀H₃₆N₆O₁₄Re₂ (Mol. Wt. = 1077.06 g/mol): C, 33.45; H, 3.37; N, 7.80. Found: C, 33.41; H, 3.32; N, 7.78. IR (νmax/cm^− 1): ѵ(C ≡ O)), 2016, 1875; ѵ(C = O) 1646, ѵ(C = N) 1599, 1538, ѵ(C-H) 2988. ¹H-NMR (295K, D₂O, ppm, 400MHz) δ ppm: 1.28 (t, 18H, 9CH₃), 3.20 (q, 12H, 6CH₂), 8.44 (s, 2H, H(3)), 9.59 (s, 2H, H(6)). ¹³CNMR (295K, D₂O, 125MHz) δ ppm: 8.04 (CH₃), 46.64 (CH₂), 120.33 (C(3)), 156.80 (C(6)), 160.48 (C(4)), 164.89 (C(2)), 168.80 (C(b)), 173.41 (C(a)), 193.00, 195.59 (CO). ESI-MS (m/z): [C₁₈H₅N₄O₁₄Re₂]⁻ or [4 + H]⁻, calculated: 872.89, found: 872.91; [C₂₀H₁₀N₅O₁₄Re₂]⁺ or [4 + 3H + MeCN]⁺, calculated: 915.93, found: 916.10. UPLC (retention time min.): 2.06.

2.6. Synthesis of [(µ-pmdc)₂(Re(CO)₃)(^99mTc(CO)₃)]²⁻ (5)

600 µl of [^99mTc(CO)₃(OH₂)₃]⁺ in water, 300µl of 0.1M aqueous solution of pyrimidine-4,6-dicarboxylic acid (H₂pmdc) and [Re(CO)₅Br] (0.84 mg, 2µmol) were mixed in vial which was sealed and flushed with N₂ for 15 min. The mixture was heated at 80^oC for 45-min. The solution was brought to r.t. and injection of the product in the HPLC equipped by gamma and UV detectors displayed complex 5 with a radiochemical yield of 35% and it is parallelly formed with complex 1 and 2. By repeating this reaction with exclusion of [^99mTc(CO)₃(OH₂)₃]⁺, dimeric complex 4 was also formed.

3.1. Synthesis of [Re(CO)₃(OH₂)(Hpmdc)] (1), [^99mTc(CO)₃(OH₂)(Hpmdc)] (2) and [Re(CO)₃(OH₂)(etpmdc)] (3)

Monomeric complex [Re(CO)₃(OH₂)(Hpmdc)] (1) was formed by reacting the chelating ligand pyrimidine-4,6-dicarboxylic acid (H₂pmdc) with [Re(CO)₅Br] in distilled water (Scheme 1). The formation of 1 was enhanced by the denticity of H₂pmdc ligand and its good solubility in polar solvents like water. Complexes 1 is orange-yellow colored and it is soluble in polar solvents like water, ethanol and methanol and display low solubility in non-polar solvents. Technetium (99m) complex homologous of 1 typically [^99mTc(CO)₃(OH₂)(Hpmdc)] (2) was directly formed from the reaction of fac-[^99mTc(CO)₃(OH₂)₃]⁺ with H₂pmdc in water at 80^oC for 30 min (Scheme 1). Complex 2 was also formed by heating aqueous fac-[^99mTc(CO)₃(OH₂)₃]⁺ solution with H₂pmdc in microwave under the same reaction conditions. The Hpmdc⁻ anion in the complexes 1 and 2, coordinated to the fac-[M(CO)₃]⁺ core as bidentate N,O-donor chelate, coordinating to the metal center via one of the pyrimidinic nitrogens and carboxylate-oxygen atoms, giving five-membered metallacycle ring (Scheme 1).

The complex [Re(CO)₃(OH₂)(etpmdc)] (3) was obtained from the reaction of H₂pmdc with [Re(CO)₅Br] in ethanol. The formation of 6-(ethoxycarbonyl)pyrimidine-4-carboxylate (etpmdc⁻) anion was surprisingly enhanced by [Re(CO)₅Br]-catalysed mono-esterification of H₂pmdc and simultaneously coordinated to the fac-[M(CO)₃]⁺ core as Hpmdc⁻ in 1 and 2. The ability of rhenium(I) complexes [Re(CO)₅X] (X = Cl, Br) to catalyse esterification reaction of carboxylic acid by alcohol was previously reported in the literature [11], and it is supported by the Lewis acidity character of these complexes [11]. The reaction of 5-(5-aminopyrimidine-2,4(1H,3H)-dioxamido)-1,2,3,6-tetrahedro-2,6-dioxopyrimidine-4-carboxylic acid (H₂amp) with [Re(CO)₅Cl] in ethanol which led to the rhenium(I) complex [Re(CO)₃(H₂O)(amef)] where amef is 5-(5-ammoniumpyrimidine-2,4(1H,3H)-dioxamido)-1,2,3,6-tetrahedro-2,6-dioxopyrimidine-4-ethylformate, and was formed by [Re(CO)₅Cl]-catalysed esterification of H₂amp by ethanol, and coordinated to the fac-[Re(CO)₃]⁺ core as a bidentate N,N-donor chelate [11]. Complexes 3 is orange and it is soluble in polar solvents like water, ethanol and methanol but not soluble in non-polar solvents. Attempt to synthesize ^99mTc complex homologous of 3 in the same synthetic route as one used for the synthesis of [^99mTc(CO)₃(OH₂)(Hpmdc)] (2) with addition of ethanol was not successful but the reaction also led to complex 2.

A variety of metal complexes of pyrimidine-4,6-dicarboxylic acid (H₂pmdc) such as lanthanide(III) [6], scandium (III) [7] and manganese(II) [8] have been reported, and H₂pmdc ligand coordinated to the above-mentioned metal ions as in complexes 1 and 2. To the best of our knowledge, the complexes [Re(CO)₃(OH₂)(Hpmdc)] (1) and [^99mTc(CO)₃(OH₂)(Hpmdc)] (2) are the first reported rhenium and technetium complexes with pyrimidine-4,6-dicarboxylic acid (H₂pmdc) ligand. Due to the lability of aqua-ligand, complexes 1, 2 and 3 are biologically important as aqua-ligand have been identified to exchange with a variety of biological molecules in biological system [19]. Such exchange shall not affect the rest part of complexes 1, 2 and 3 as result of high kinetic and thermodynamic stability of complexes based on the organometallic fac-[M(CO)₃]⁺ (M = Re and Tc) unit, granting the potential application of these complexes as radiopharmaceutical probes.

By eluting complex 1 in the ultraperformance liquid chromatography (UPLC) system, it was detected at the retention time of 1.80 min (Fig. S1). The vibrational peaks at 2042, 1908 and 1932 cm^− 1 in the infrared spectrum of 1 (Fig. S2) are ascribed to the fac-[Re(CO)₃]⁺, and they are at 1873, 1883, 2015 cm^− 1 in 3 (Fig. S6). The peaks at 3225 and 3110 cm^− 1 in 1 are ascribed to the ѵ(O − H) for the free OH in the coordinated ligand and water respectively whereas the ѵ(O − H) for the OH of the coordinated water in 3 occur at 3364 cm^− 1 (Figure S6). The ¹HNMR spectrum of 1 in D₂O (Fig. S3) displayed two protons H(3) and H(6) at 8.56 and 9.66 ppm respectively. Homologous protons in 3 occur at 8.61 and 9.64 ppm respectively in the ¹HNMR of 3 measured in CD₃OD (Fig. S7). The triplet and quartet signals at 1.45 ppm and at 4.52 ppm in the ¹HNMR of 3 are assigned to the -CH₃ and -CH₂ respectively, while the protons of the coordinated water are displayed as singlet signal at 4.07 ppm. The ¹³CNMR in CD₃OD gave the promised signals at 122.76, 159.52, 162.97, 167.41, 171.40, 175.89 ppm for 1 (Fig. S4); and 123.13, 160.72, 160.76, 162.34, 164.30, 173.79 for 3 (Fig. S8). The signals at 194.96 and 198.01 ppm are due to CO ligands in 1 and they are at 197.37, 197.05, 193.94 ppm in 3. The signals at 14.85 and 64.88 ppm in the ¹³C NMR of 3 are ascribed to -CH₃ and -CH₂ respectively. Liquid chromatography-mass spectrometry (ESI-MS) analysis of complex 1 (Fig. S5) displayed m/z peaks at 457.03 ascribed to [C₉H₆N₂O₈Re]⁺ or [1 + H]⁺ and 438.06 in accordance with [C₉H₄N₂O₇Re]⁺ or [1-H₂O + H]⁺ as well as 479.99 reflecting [C₁₁H₇N₃O₇Re]⁺ or [1 + MeCN + H-H₂O]⁺. Similarly, ESI-MS spectrum of 3 (Fig. S9) showed m/z peaks typically 467.21 for [C₁₁H₈N₂O₇Re]⁺ or [3-H₂O + H]⁺, and 508.15 for [C₁₃H₁₁N₃O₇Re]⁺ or [3 + MeCN + H-H₂O]⁺.

The Fig. 2 shows ORTEP drawing of complex 3 and its crystal details and structure refinement data are described in Table 1. The CCDC 2260652 contains the supplementary crystallographic data for 3, and can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. As generally observed to rhenium(I) complexes based on the fac-[Re(CO)₃]⁺ unit, the geometry around the rhenium metal center is a distorted octahedral [11, 18, 19], with oxygen atom of the coordinated water O(4) and two donor atoms N(1) and O(5) of etpmdc⁻ anion in a facial arrangement as imposed by the fac-[Re(CO)₃]⁺ core.

Table 1

Structure refinement parameters data and selected bond lengths (Å) and angles (˚) for [Re(CO)₃(OH₂)(etpmdc)] (3)
Structure refinement Parameters	Structure refinement Parameters data	Selected bond lengths (Å) and angles (˚)
Chemical formula Formula weight Temperature (K) Crystal system Space group Unit cell dimensions (Å˚) Crystal size/mm³ Volume (Å ³) Z Density (calc.) (g/cm³) Absorption coefficient (mm^− 1) F (000) Radiation θ range for data collection (deg) Index ranges h,k,l max Reflections collected Independent reflections Data/restraints/parameters Goodness-of-fit on F² Final R indexes [I > = 2σ (I)] Final R indexes [all data] Largest diff. peak and hole(e/Å³)	C₁₁H₉N₂O₈Re 483.40 160 K Monoclinic P 2₁/c a = 7.05850(12) α = 90 b = 7.82584(13) β = 93.1000(16) c = 24.5852(5) γ = 90 0.14 × 0.08 × 0.01 1356.07(4) 4 2.368 9.006 912.0 MoKα (λ = 0.71073) 5.464 to 61.016 -10 ≤ h ≤ 10,-10 ≤ k ≤ 11,-35 ≤ l ≤ 35 41731 4123 [R_int =0.0320, R_sigma = 0.0157] 4123/0/208 1.148 R₁ = 0.0200, wR₂ = 0.0395 R₁ = 0.0227, wR₂ = 0.0402 1.53/-1.41	Re(1)-C(1) 1.922(3) Re(1)-C(2) 1.900(3) Re(1)-C(3) 1.900(3) Re(1)-O(4) 2.211(2) Re(1)-O(5) 2.1489(19) Re(1)-N(1) 2.179(2) C(4)-O(5) 1.272(3) C(4)-O(6) 1.235(3) C(9)-O(7) 1.213(3) C(9)-O(8) 1.309(3) C(10)-O(8) 1.474(3) C(5)-N(1) 1.349(3) C(8)-N(1) 1.348(3) C(8)-N(2) 1.327(3) C(7)-N(2) 1.339(3) C(2)-Re(1)-O(5) 175.09(11) C(3)-Re(1)-O(4) 176.93(11) C(1)-Re(1)-N(1) 170.68(11) O(5)-Re(1)-N(1) 75.19(7) Re(1)-C(1)-O(1) 176.9(3) C(2)-Re(1)-C(1) 88.41(13) O(5)-Re(1)-O(4) 83.39(7) N(1)-Re(1)-O(4) 81.99(8) C(3)-Re(1)-C(1) 86.41(14)

The rhenium-centered bond angles C(2)-Re(1)-O(5) = 175.09(11)^o, C(3)-Re(1)-O(4) = 176.93(6)^o and C(1)-Re(1)-N(1) = 170.68(11)^o deviated from the linearity supporting the distortion in 3. Such distortion is furtherly supported by rhenium-centered bond angles C(2)-Re(1)-C(1) = 88.41(13)^o, (5)-Re(1)-O(4) = 83.39(7) ^o, N(1)-Re(1)-O(4) = 81.99(8)^o and C(3)-Re(1)-C(1) = 86.41(14) ^o which deviated from the orthogonality.

The etpmdc⁻ chelate coordinated to rhenium(I) center via one of the pyrimidinic nitrogen N(1) and carboxylate oxygen O(5) forming a bite angle of O(5)-Re(1)-N(1) = 75.19(7)^o. For the reported similar pyrimidine derivatives complexes of rhenium(I), this angle was found 75.54(6)^o and 75.14(5)^◦ [19, 36]. The bond distance Re(1)-O(5) = 2.1489(19) Å in 3 agrees well with the reported R^I-O distances in pyrimidine derivatives complexes of rhenium(I) based on the fac-[Re(CO)₃]⁺ unit [19, 36]. The Re − N(1) bond distance of 2.179(2) Å is compatible with the range 2.15 − 2.22 Å previously reported for rhenium(I) − N(imines) distances [11, 37]. The average Re-C bond distances is 1.907(3) Å, and falls in the range 1.900(2)-1.928(2) Å reported for Re^I-C distances [11, 18, 19]. The crystal packing diagram of 3 (Fig. S16) displays two asymmetric units in the unit cell and four intramolecular hydrogen bonds (blue dashed) which are typically C(8)-H(8)..O(6), C(10)-H(10A)..O(3), O(4)-H(4A)..O(3) and O(4)-H(4B)..O(6).

Due to very low concentration of ^99mTc in solution which exists in nano-scale and similarity in the coordination chemistry of Re and Tc, the structural identity of ^99mTc-complexes is routinely confirmed by comparing their HPLC profiles with HPLC profiles of the homologous rhenium complexes, fully characterized by routine chemistry analytical techniques [19]. This consists of coinjecting ^99mTc complex with its homologous rhenium complex in the HPLC with UV/vis detection coupled with a γ-detector followed by comparison of retention times of the displayed γ-peaks of ^99mTc complex and UV peak of Re complex [19]. Therefore, the chemical similarity of 1 and 2 was assessed by coinjection of 10 µl of these complexes in the HPLC with UV/vis detection coupled with a γ-detector, and complex 1 was detected at R_t = 11.7 min in UV (Fig. 3b) which coincides with the radiochemical peak of 2 detected at R_t = 12.8 min in γ (Fig. 3a) confirming their structural similarity. The difference of 1.1 min for 1 and 2 is due to the UV/vis and γ-detectors separation and HPLC settings [19].

3.2. Synthesis of (Et₃NH)₂[(µ-pmdc)₂(Re(CO)₃)₂ (4) and [(µ-pmdc)₂(Re(CO)₃)(^99mTc(CO)₃)]²⁻ (5)

Dimeric complex (Et₃NH)₂[(µ-pmdc)₂(Re(CO)₃)₂] (4) was obtained from the reaction of H₂pmdc with [Re(CO)₅Br] in distilled water with addition of triethylamine (Et₃N) as supporting base (Scheme 2). Complexes 4 is orange and it is soluble in polar solvents like water, ethanol and methanol, and exhibit a very low solubility in non-polar organic solvents. In the dimer 4, pmdc^− 2 coordinated to the fac-[M(CO)₃]⁺ core as bidentate N,O-donor chelate, coordinating to the metal center via on of the pyrimidinic nitrogen and carboxylate-oxygen atoms, and the other carboxylate oxygen atom is coordinated to the other fac-[Re(CO)₃]⁺ core. The reaction of [^99mTc(CO)₃(OH₂)₃]⁺ and [Re(CO)₅Br] with H₂pmdc led to the heterodinuclear ^99mTc/Re complex [(µ-pmdc)₂(Re(CO)₃)(^99mTc(CO)₃)]²⁻ (5) (Scheme 2), and it is parallelly formed with complexes 1 and 2.

Similar dimers of scandium(III) [15] and manganese(II) [32] with H₂pmdc have been reported and pmdc²⁻ coordinated to the metal center as in complexes 4 and 5. Complex 4 and 5 have shown good stability in aqueous solution. The previous studies revealed that the pKa value of organic acid ligands reflects its relative coordination ability to the metal ions, and determine the strength of the resulting metal-ligand bonds, and therefore the stability of metal-organic framework [38]. High value of pKa for organic acid ligands indicates its deprotonation weakness, and such ligand will mostly necessitate the supporting base to promote its deprotonation for coordinating to the metal ions [39–41]. The deprotonated organic acid ligand with high value of pKa strongly coordinates to the metal ions resulting in metal-organic framework with high stability [38]. The H₂pmdc ligand is a weak acid with pKa value of 2.035, and therefore, its full deprotonation for forming dinuclear rhenium complex 4 necessitated triethyl amine (Et₃N) as supporting base, and this complex has shown a significant stability. Similarly for forming heterodinuclear ^99mTc/Re complex 5, the full deprotonation of H₂pmdc has been supported by unidentified anionic base which is in place as a counterion of the cationic precursor complex [^99mTc(CO)₃(OH₂)₃]⁺.

In the infrared spectrum of 4 (Fig. S11), sharp bands at 2016 and 1875 cm^− 1 are associated with fac-[Re(CO)₃]⁺ units. In the ¹HNMR spectrum of 4 in D₂O (Fig. S12), the CH₃ and CH₂ protons of Et₃NH⁺ counterions occur as triplet at 1.28 ppm and quartet at 3.20 ppm respectively. The singlet signals at 8.44 and 9.59 ppm are ascribed to H(3) and H(6) respectively. The ¹³CNMR of 4 in D₂O (Fig. S13) displayed signals at 8.04 and 46.64 ppm for CH₃ and CH₂ respectively for Et₃NH⁺ counterions. The carbon atoms of the coordinated pmdc²⁻ ligands occur at 120.33, 156.80, 160.48, 164.89, 168.80 and 173.41 ppm; while the carbona toms of the CO ligands are displayed at 193.00 and 195.59 ppm. Complex 4 was eluted in the UPLC and it was detected at 2.06 min (Fig. S10). The m/z peaks principally 872.91 [C₁₈H₅N₄O₁₄Re₂]⁻ or [4 + H]⁻, 916.10 [C₂₀H₁₀N₅O₁₄Re₂]⁺ or [4 + 3H + MeCN]⁺ were detected in liquid chromatography-mass spectrometry (ESI-MS) analysis of 4 (Fig. S14 and Fig. S15) and furtherly confirmed its structure.

The starting reagent used to synthesize compounds 1, 3 and 4 is [Re(CO)₅Br]. As the ligand H₂pmdc was deprotonated and release H⁺ ions in solution, the bromide ions (Br⁻) reacted with H⁺ ions from the deprotonated H₂pmdc to form hydrobromic acid (HBr) as reaction byproduct. The HBr is inorganic acid and due to its high solubility in organic solvents, it was eliminated by several time washing of compounds 1, 3 and 4 using organic solvents. In addition, the HBr has some degree of volatility and a particular quantity of it was eliminated by being volatilized in the air. Therefore, there is no Br maintained in the isolated materials of 1, 3 and 4 [11, 19]. The formation of rhenium(I) complexes from [Re(CO)₅X] (X = Cl, Br) without the ligand deprotonation only leads to rhenium(I) complexes with Br⁻ or Cl⁻ ligand maintained in the isolated products [11, 18].

Injection of 10 µl of the product from the reaction of [^99mTc(CO)₃(OH₂)₃]⁺ with H₂pmdc and [Re(CO)₅Br] in the HPLC with UV/vis detection coupled with a γ-detector displayed signals at retention times of 12.1 and 18.7 min in gamma with signal corresponding to the unreacted [^99mTc(CO)₃(OH₂)₃]⁺ and low intensity signal due to [^99mTcO₄]⁻ from the oxidation of ^99mTc^I to ^99mTc^VII (Fig. 4a). It has also shown two signals in UV at 11.2 and 18.4 min (Fig. 3b). The signal at R_t = 11.2 min in UV (Fig. 4b) is due to the formation of [Re(CO)₃(OH₂)(Hpmdc)] (1) which coincides with the radiochemical signal at R_t = 12.1 min in γ (Fig. 3a) suggesting the formation of [^99mTc(CO)₃(OH₂)(Hpmdc)] (2) as observed in Fig. 2. The difference of 0.9 min for 1 and 2 is due to the detector separation and HPLC settings. The signal at R_t = 18.4 min in UV (Fig. 4b) is due to the formation of heterodinuclear ^99mTc/Re complex [(µ-pmdc)₂(Re(CO)₃)(^99mTc(CO)₃)]²⁻ (5) which coincides with its radiochemical signal at R_t = 18.7 min in γ (Fig. 4a), and the difference of 0.3 min is also due to the UV and γ-detectors separation and HPLC settings, and it was formed at yield of approximatively 35%. The obtained low yield of complex 5 (35%) is due to the fact that it was parallelly formed with complex 1 and 2. In addition, unreacted quantity of [^99mTc(CO)₃(OH₂)₃]⁺ and its small quantity which has been oxidized to [^99mTcO₄]⁻ also partially contributed to such low yield of complex 5.

The product at R_t = 18.7 min in γ is [(µ-pmdc)₂(Re(CO)₃)(^99mTc(CO)₃)]²⁻ (5) rather than the dimer [(µ-pmdc)₂(^99mTc(CO)₃)₂]²⁻ due to the fact that the low concentrations of ^99mTc makes the formation of dimeric ^99mTc species kinetically unlikely [19], and even if it is formed, it should not be detected in the UV as observed for [(µ-pmdc)₂(Re(CO)₃)(^99mTc(CO)₃)]²⁻ (5) (Fig. 5b) due to its extremely low concentration. The formation of [(µ-pmdc)₂(Re(CO)₃)(^99mTc(CO)₃)]²⁻ (5) was furtherly confirmed by injecting its homologous non-radioactive dimer complex [(µ-pmdc)₂(Re(CO)₃)₂]²⁻ (4) in the same HPLC which also displayed the UV signal at 18.4 min equivalent to that of [(µ-pmdc)₂(Re(CO)₃)(^99mTc(CO)₃)]²⁻ (5) (Fig. 4b). The observed similar retention times in UV for 4 and 5 confirms their structural identity. This is furtherly supported by the fact that the metals technetium and rhenium are located in the same position in the Periodic Table of elements, and have comparable atomic radii, and their homologous complexes should consequently display the same electronic properties and coordination parameters [11, 42]. Further characterizations of heterometallic radiocomplex 5 are not applicable due to the above-mentioned reason of its low concentration in solution.

A few numbers of heterodinuclear complexes containing Re and ^99mTc were previously reported in the literature. Recently, the highly stable complex [^99mTcRe₃ (µ₃-OH)₄(CO)₁₂] has been reported, and it was obtained at 94% yield from the reaction of aqueous [^99mTc(CO)₃(OH₂)₃]⁺ with [Re₃ (µ₂-OH)₃(µ₃-OH)(CO)₉]⁻ [17]. The formation of ^99mTcRe₃ (µ₃-OH)₄(CO)₁₂] was also achieved at 90% yield from the reaction of aqueous [^99mTc(CO)₃(OH₂)₃]⁺ with (NEt₄)₂[ReBr₃(CO)₃] [17]. The reaction of (E)-2-((m-tolylimino)methyl)phenol ligand with [^99mTc(CO)₃(OH₂)₃]⁺and (NEt₄)₂[ReBr₃(CO)₃] in acetonitrile has been also studied, and led to the heterodinuclear ^99mTc/Re complex with exception stability [17]. Heterodinuclear ^99mTc/Re complex namely [Re(CO)₃(bipy){(4-PyrIDA)^99mTc(CO)₃}] where 4-PyrIDA is N-carboxylato-N-(pyridin-4-ylmethyl)glycinate has been reported as the first example of ^99mTc/Re-based heterometallic assembly which could act as a potential bimodal optical/SPECT probe [43]. Such complex displayed similar retention time in the HPLC with its homologous dinuclear Re complex [Re(CO)₃(bipy){(4-PyrIDA)Re(CO)₃}] fully characterized by routine analytical techniques [43] confirming their structural identity as observed for complexes 4 and 5 reported in this study. Dinuclear Re and its homologous heterodinuclear ^99mTc/Re complexes based on the fac-[M(CO)₃]⁺ core typically [Re(CO)₃(pyta-COOMe){(4-pyrIDA)Re(CO)₃}] and [Re(CO)₃(pyta-COOMe){(4-pyrIDA)^99mTc(CO)₃}] where pyta-COOMe and PyrIDA are methyl 2-(4-(2-pyridyl)-[1, 2, 3]triazol-1-yl)acetate and 2,2'-((pyridin-4-ylmethyl)azanediyl)diacetate) respectively have been also reported [44]. Heterodinuclear ^99mTc/Re complex [Re(CO)₃(pyta-COOMe){(4-pyrIDA)^99mTc(CO)₃}] was the first reported example of a functionalized dual fluorescent/radiolabeled imaging agent, and it was characterized by comparing its HPLC profile with the HPLC profile of its homologous and fully characterized dinuclear Re complex Re(CO)₃(pyta-COOMe){(4-pyrIDA)Re(CO)₃}] [44]. Both complexes displayed similar retention times in the HPLC as observed for complexes 4 and 5 reported in this study confirming their structural identity [44].

Multinuclear complexes are advantageous in medicinal inorganic chemistry as they may target more than one unit in the body, and can be delivered by more than one bioactive moiety [17]. In addition, the possibility of combining radiometal agents with cytotoxicity and imaging properties gave rise to a new concept of molecule-based theranostic radiopharmaceuticals with a specific amount of therapeutic and imaging agents [17]. In this way, the existence of similar coordination chemistry between Re and Tc makes possible to afford stable heterodinuclear ^99mTc/^186/188Re complexes with ^99mTc and ^186/188Re showing similar electronic properties, and such complexes act as theranostic radiopharmaceuticals displaying imaging and therapeutic properties [45]. Therefore, heterodinuclear ^99mTc/Re complex [(µ-pmdc)₂(Re(CO)₃)(^99mTc(CO)₃)]²⁻ (5) reported in this study will be a model for future design of theranostic radiopharmaceuticals combining imaging and therapy.

In this work, monomeric and dimeric complexes of the fac-[M(CO)₃]⁺ (M = Re and ^99mTc) core with pyrimidine-4,6-dicarboxylic acid (H₂pmdc) ligand have been synthesized and characterized. These complexes are the model for future design of radiopharmaceuticals. The structural identification of ^99mTc-complexes is challenge due to its very low concertation in solution. As previously reported in the literature, the structural identity of ^99mTc-complexes reported in this study was achieved by comparing their HPLC profiles with HPLC profiles of their homologous rhenium complexes, fully characterized by routine chemistry analytical techniques. The existence of very low concentrations of ^99mTc in solution also make the color of its complexes not detectable, and they are always colorless, and it is the reason why the solution of complexes 2 and 5 did not show any color. Although the coordination mode of H₂pmdc in 1–4 was previously reported for other transition metal ions, compounds 1–4 are the first reported complexes of H₂pmdc with rhenium and technetium metals. In future, the reported heterodinuclear ^99mTc/Re complex 5 will extend the theranostic modalities beyond mononuclear complexes. For further studies, our research efforts will be extended by reacting H₂pmdc with [⁹⁹TcCl₃(CO)₃)]²⁻ for ensuring that ⁹⁹Tc complexes homologous to 1–4 will be formed. Furthermore, a mixture of [⁹⁹TcCl₃(CO)₃)]²⁻ with [^99mTc(CO)₃(OH₂)₃]⁺ and [ReBr(CO)₅] with [⁹⁹TcCl₃(CO)₃)]²⁻ will be reacted with H₂pmdac ligand for ensuring that the heterodinuclear ^99mTc/⁹⁹Tc and ⁹⁹Tc/Re complexes respectively similar to 5 will be obtained. In addition, aqueous [^99mTc(CO)₃(OH₂)₃]⁺ and [ReBr(CO)₅] will be reacted with the ligands analogous to H₂pmdc typically pyrimidine-4,6-diyldimethanol, hexahydropyrimidine-4,6-dicarboxylic acid and 1,2,3,4-tetrahydropyrimidine-4,6-dicarboxylic acid for ensuring that they will behave as H₂pmdc.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Author Contribution

JM: design the manuscript and synthesis and analysis of complexesGH: Writing Introduction and contribute crystal data interpretation and records.JS: Contributes in the interpretation of 1HNMR and HPLC data.TM: Contributes in Interpretation of IR and ESI-MS data and review of entire manuscript.JN: Contributes Literature reported in this manuscript as well as 13CNMR data interpretationTU: Contributes in writing the manuscript.TM: Edit the entire manuscript and provide input in interpretation of NMR and ESI-MS data.OB: He is the one who measured and provide data of the crystal structure reported in this manuscript.GB: Provide ideas in purification of the reported complexes and reviewed the entire manuscript.

Acknowledgement

Prof. Alberto Roger, Henrik Braband, University of Zurich and Research Group under Prof. Alberto Roger are strongly acknowledged.

C.R. Nathan Rose, S. Stanley Ng, J. Mecinovic, B.M.R. Lienard, S.H. Bello, Z. Sun, M. A. McDonough, U. Oppermann, C.J. Schofield, Inhibitor scaffolds for 2-oxoglutarate-dependent histone lysine demethylases, J. Med. Chem. 51, 7053–7056 (2008) https://doi.org/10.1021/jm800936s.
D.V. Sharma,N. Chitranshi, A. Kumar Agarwal, Significance and biological importance of pyrimidine in the microbial world, Int. J. Med. Chem.2014, 202784 (2014), https://doi.org/10.1155/2014/202784.
E.K. Paige Arnold, L.W.S. Finley, Regulation and function of the mammalian tricarboxylic acid cycle, J. Biol. Chem. 299, 102838 (2023), https://doi.org/10.1016/j.jbc.2022.102838.
J. Cepeda, S. Pérez-Yáñez, G. Beobide, O. Castillo, J.Á. García, M. Lanchasa, A. Luquea, Enhancing luminescence properties of lanthanide(iii)/pyrimidine-4,6-dicarboxylato system by solvent-free approach, Dalton Trans. 44, 6972–6986 (2015), https://doi.org/10.1039/C4DT03797A.
B. Oier Pajuelo-Corral, J.A. García, O. Castillo, A. Luque, A. Rodríguez-Diéguez, J. Cepeda, Single-Ion Magnet and Photoluminescence Properties of Lanthanide(III) Coordination Polymers Based on Pyrimidine-4,6-Dicarboxylate, Magnetochemistry 7, 8 (2021) https://doi.org/10.3390/magnetochemistry7010008.
J. Cepeda, R. Balda, G. Beobide, O. Castillo, J. Fernández, A. Luque, S. Pérez Yáñez, P. Román, D. Vallejo-Sánchez,Lanthanide(III)/Pyrimidine-4,6-dicarboxylate/Oxalate Extended Frameworks: A Detailed Study Based on the Lanthanide Contraction and Temperature Effects, Inorg. Chem. 50, 8437–8451, (2011), https://doi.org/10.1021/ic201013v.
J. Cepeda, S. Pérez Yáñez, S. Beobide, G. Castillo, O. Luque, A. Wright, P.A. Sneddon, S. Ashbrook, E. Sharon,Exploiting synthetic conditions to promote structural diversity within the scandium(III)/pyrimidine-4,6-dicarboxylate system, Cryst. Growth Des. 15, 2352-2363 (2015) https://doi.org/10.1021/acs.cgd.5b00154.
G. Beobide, W. Wen-guo, O. Castillo, A. Luque, P. Román, G. Tagliabue, S. Galli, J.A.R. Navarro, Manganese(II) Pyrimidine-4,6-dicarboxylates: Synthetic, Structural, Magnetic, and Adsorption Insights, Inorg. Chem. 47, 5267–5277 (2008), https://doi.org/10.1021/ic8002788.
J. Mukiza, T.I.A. Gerber, E. Hosten, F. Taherkhani, M. Nahali, A (μ-O)(μ-Br)Re^IV₂ metal–metal triple bond complex with a bridging tridentate ligand: Synthesis, structure and DFT study Inorg. Chem. Commun. 49, 5–7 (2014), https://doi.org/10.1016/j.inoche.2014.09.005.
F.A. Cotton, G. Wilkinson, C.A. Murillo, M. Bochmann, Advanced Inorganic Chemistry, John Wiley & Sons, 6th Ed. New York, (1999), John Wiley & Sons (1999).pdf (uc.edu).
J. Mukiza, Rhenium Complexes with Pontentially Multidentate Ligands Containing the Amino, Imino, Hydroxy and Thiol Groups, PhD Thesis, Nelson Mandela Metropolitan University, (2016), http://hdl.handle.net/10948/12308.
J. Mukiza, O. Blacque, G. Habarurema, E. Kampire, The reaction of oxidorhenium(V) with dipodal and tripodal aroylhydrazines: formation of dinuclear and trinuclear aroylhydrazone-bridged rhenium(V) complexes New J. Chem., 44, 7080-7090 (2020),https://doi.org/10.1039/D0NJ00182A.
E. Zangoni, PhD thesis, Synthesis, quality control and pharmacological studies of ^99mTc- and ¹⁸⁸Re-radiopharmaceuticals for imaging and therapy, PhD Thesis, Universita Degli Studi di Padova, 2009, https://www.research.unipd.it/handle/11577/3426623.
A.C. Kluba, T.L. Mindt, Click-to-Chelate: Development of Technetium and Rhenium-Tricarbonyl Labeled Radiopharmaceuticals, Molecules 18, 3206-3226 (2013), https://doi.org/10.3390/molecules18033206.
A.J. North, J.A. Karas, M.T. Ma, P.J. Blower, U. Ackermann^,J.M. White,P.S. Donnelly, Rhenium and Technetium-oxo Complexes with Thioamide Derivatives of Pyridylhydrazine Bifunctional Chelators Conjugated to the Tumour Targeting Peptides Octreotate and Cyclic-RGDfK, Inorg. Chem. 56, 9725-9741 (2017), https://doi.org/10.1021/acs.inorgchem.7b01247.
J. Mukiza, E. Byamukama, J. Sezirahiga, K.N. Ngbolua, V. Ndebwanimana, Rwanda Med. J. 75, 14-22, (2018), http://www.bioline.org.br/pdf?rw18003.
A. Frei, P.P. Mokolokolo, R. Bolliger, H. Braband, M.S. Tsosane, A. Brink, A. Roodt, R. Alberto, Self-Assembled Multinuclear Complexes Incorporating ^99mTc, Chem. Eur. J. 24, 10397-10402 (2018), https://doi.org/10.1002/chem.201800600.
J. Mukiza, H. Braband, R. Bolliger, O. Blacque, R. Alberto, J.B. Nkurunziza, A novel benzoylthiourea derivative with a triazinethione moiety: Synthesis and coordination with the organometallic fac-[Re(CO)₃]⁺ core, Inorg. Chim. Acta 516, 120116 (2021), https://doi.org/10.1016/j.ica.2020.120116.
J. Mukiza, H. Braband, R. Bolliger, Q. Nadeem, G. Habarurema, J. Sezirahiga, T. Uwambajineza, T. Fox, O. Blacque, R. Alberto, Complexes of orotic acid and derivatives with the fac-[M(CO)₃]⁺ (M = Re and ⁹⁹Tc/^99mTc) core as radiopharmaceutical probes, Inorg. Chim. Acta 539, 121037 (2022), https://doi.org/10.1016/j.ica.2022.121037. Q. Nadeem, D. Can, Y. Shen, M. Felber, Z. Mahmooda, R. Alberto, Synthesis of tripeptide derivatized cyclopentadienyl complexes of technetium and rhenium as radiopharmaceutical probes, Org. Biomol. Chem. 12, 1966–1974 (2014),https://doi.org/10.1039/C3OB41866A.
H. Braband, U. Abram, Tricarbonyl complexes of rhenium(I) and technetium(I) with thiourea derivatives, J. Organomet. Chem. 689, 2066-2072 (2004), https://doi.org/10.1016/j.jorganchem.2004.03.017.
R. Alberto, R. Schibli, R. Waibel, U. Abram, A.P. Schubiger, Basic aqueous chemistry of [M(OH₂)₃(CO)₃]⁺ (M=Re, Tc) directed towards radiopharmaceutical application, Coor. Chem. Rev. 190-192, 901–919 (1999), https://doi.org/10.1016/S0010-8545(99)00128-9.
S.J. Carrington, I. Chakraborty, J.M.L. Bernard, P.K. Mascharak, A Theranostic Two-Tone Luminescent PhotoCORM Derived from Re(I) and (2-Pyridyl)-benzothiazole: Trackable CO Delivery to Malignant Cells, Inorg. Chem. 55, 7852-7858, (2016), https://doi.org/10.1021/acs.inorgchem.6b00511.
D. Can, P. Schmutz, S. Sulieman, B. Spingler, R. Alberto, [(Cp-R)M(CO)₃] (M = Re or ^99mTc) conjugates for theranostic receptor targeting CHIMIA Int. J. Chem. 67, 267-270 (2013), https://doi.org/10.2533/chimia.2013.267.
T. Mindt, H. Struthers, E. García-Garayoa, D. Desbouis, R. Schibli, Strategies for the Development of Novel Tumor Targeting Technetium and Rhenium Radiopharmaceuticals, Chimia 61, 725-731 (2007), https://doi.org/10.2533/chimia.2007.725.
A. Al-Ibraheem, A. Buck, B.J. Krause, K. Scheidhauer, M. Schwaiger, Clinical Applications of FDG PET and PET/CT in Head and Neck Cancer, J. Oncol. 2009,208725 (2009), https://doi.org/10.1155/2009/208725.
R. Schibli, M. Natter, L. Scapozza, M. Birringer, P. Schelling, C. Dumas, J. Schoch, P.A. Schubiger, First organometallic inhibitors for human thymidine kinase: synthesis and in vitro evaluation of rhenium(I)- and technetium(I)-tricarbonyl complexes of thymidine, J. Organomet. Chem. 668, 67-74 (2003), https://doi.org/10.1016/S0022-328X(02)02100-9.
L. Wei, J. Babich, W.C. Eckelman, J. Zubieta, Rhenium Tricarbonyl Core Complexes of Thymidine and Uridine Derivatives, Inorg. Chem. 44, 2198−2209 (2005), https://doi.org/10.1021/ic048301n.
R. Alberto, K. Ortner, N. Wheatley, R. Schibli, A.P. Schubiger, Synthesis and properties of boranocarbonate: a convenient in situ CO source for the aqueous preparation of [^99mTc(OH₂)₃(CO)₃]⁺, J. Am. Chem. Soc. 123, 3135-3136 (2001), https://doi.org/10.1021/ja003932b.
Rigaku Oxford Diffraction, (2018), https://www.rigaku.com/de/node/808.
R.C. Clark, J.S. Reid, The analytical calculation of absorption in multifaceted crystals, Acta Cryst. A51, 887-897 (1995), https://doi.org/10.1107/S0108767395007367.
Rigaku Oxford Diffraction, CrysAlisPro Software system, version 1.171.39.46
O.V Dolomanov, L.J. Bourhis, R.J. Gildea, J.A.K. Howard, H. Puschmann, OLEX2: a complete structure solution, refinement and analysis program, J. Appl. Cryst. 42, 339-341 (2009),https://doi.org/10.1107/S0021889808042726.
G.M. Sheldrick, Crystal structurerefinement with SHELXL, Acta Crystallogr. Sect. C: Struct. Chem. 71, 3-8 (2015), https://doi.org/10.1107/S2053229614024218.
A.L. Spek, Structure validation in chemical crystallography, Acta Cryst. D: Struct. Biol. 65, 148-155 (2009), https://doi.org/10.1107/S090744490804362X.
G. Habarurema, J. Mukiza, T.I.A. Gerber, T. Mukabagorora, E.C. Hosten, R. Betz, Imidazolidine ligands and their coordination behaviour towards the fac-[Re(CO)₃]⁺ core: Unusual synthetic route, spectroscopic and X-Ray crystallographic characterization, J. Organomet. Chem. 906, 121033 (2020), https://doi.org/10.1016/j.jorganchem.2019.121033.
J. Mukiza, E.C. Hosten, T.I.A. Gerber, Dimeric rhenium(IV) and monomeric rhenium(I) and (V) complexes of orotic acid, Polyhedron 98, 251-258 (2015), https://doi.org/10.1016/j.poly.2015.06.006.
J. Mukiza, T.I.A. Gerber, E. Hosten, Coordination of Bidentate Aroylhydrazone-Based N,N-Donor Ligands to the fac-[Re(CO)₃]⁺ Core, J. Chem. Crystallogr. 44, 368-375 (2014), https://doi.org/10.1007/s10870-014-0524-4.
P. Lu, Y. Wu, H. Kang, H. Wei, H. Liubd, M. Fang, What can pK_a and NBO charges of the ligands tell us about the water and thermal stability of metal organic frameworks? J. Mater. Chem. A, 2 16250–16267 (2014),https://doi.org/10.1039/C4TA03154G.
T. Li, X. H. Huang, Y. F. Zhao, H. H. Li, S. T. Wu and C. C. Huang, An unusual double T5(2) water tape trapped in silver(I) coordination polymer hosts: influence of the solvent on the assembly of Ag(I)-4,4′-bipyridine chains with trans-cyclohexanedicarboxylate and their luminescent properties, Dalton Trans. 41, 12872–12881 (2012), https://doi.org/10.1039/C2DT31847D.
L.N. Dong, Y. Tian, X. Li and Y. Jiang, 3-D frameworks assembled by lanthanide dimers with 1,4-cyclohexanedicarboxylic acid and 1,10-phenanthroline via hydrogen bonds and π–π stacking interactions, J. Coord. Chem. 63, 2088–2096 (2010), https://doi.org/10.1080/00958972.2010.498911.
K. P. Rao, A. Thirumurugan, C. N. R. Rao, Lamellar and Three-Dimensional Hybrid Compounds Formed by Cyclohexene- and Cyclohexanedicarboxylates of Pb, La, and Cd, Chem. Eur. J. 13, 3193–3201 (2007), https://doi.org/10.1002/chem.200600966.
V.Y. Kukushki, Metal-ion mediated deoxygenation of sulfoxides, Coord. Chem. Rev. 139, 375-407 (1995), https://doi.org/10.1016/0010-8545(94)01116-S.
A. Boulay, M. Artigau, Y. Coulais, C. Picard, B. Mestre-Voegtl, E. Benoist, First dinuclear Re/Tc complex as a potential bimodal Optical/SPECT molecular imaging agent, Dalton Trans. 40, 6206–6209 (2011), https://doi.org/10.1039/C0DT01397H.
F. Alison, C. Auzanneau, V. Le Morvan, C. Galaup, S.G. Hannah, L. Marty, A. Boulay, M. Artigau, B. Mestre-Voegtlé, N. Leygue, C. Picard, Y. Coulais, J. Robert, E. Benoist, A functionalized heterobimetallic ^99mTc/Re complex as a potential dual-modality imaging probe: synthesis, photophysical properties, cytotoxicity and cellular imaging investigations, Dalton Trans. 43, 439–450 (2014), https://doi.org/10.1039/C3DT51968F.
C. Mamat, C. Jentschel, M. Köckerling, J. Steinbach, Strategic Evaluation of the Traceless Staudinger Ligation for Radiolabeling with the Tricarbonyl Core, Molecules26, 6629 (2021), https://doi.org/10.3390/molecules26216629.

Schemes 1 and 2 are available in the Supplementary Files section

No competing interests reported.

ManuscriptSIApril.docx
Scheme1.png
Scheme 1. Aqueous synthesis of monomeric rhenium and technetium complexes of pyrimidine-4,6-dicarboxylic acid (H₂pmdc) based on the fac-[M(CO)₃]⁺ core.
Scheme2.png
Scheme 2. Aqueous synthesis of dimeric rhenium complex (4) and its homologous heterobimetallic rhenium and technetium-99m complex (5) of pyrimidine-4,6-dicarboxylic acid (H₂pmdc) based on the fac-[M(CO)₃]⁺ core.

Download PDF

Version 1

posted

You are reading this latest preprint version

Monomeric and dimeric complexes of pyrimidine-4,6-dicarboxylic acid with organometallic fac-[M(CO)₃]⁺ (M = Re and ^99mTc) core as radiopharmaceutical probes

Status:

Version 1

Abstract

Figures

1. Introduction

2. Experimental

2.1. Materials and instrumentation

2.2. Synthesis of [Re(CO)₃(OH₂)(Hpmdc)] (1)

2.3. Synthesis of [^99mTc(CO)₃(OH₂)(Hpmdc)] (2)

2.4. Synthesis of [Re(CO)₃(OH₂)(etpmdc)] (3)

2.5. Synthesis of (Et₃NH)₂[(µ-pmdc)₂(Re(CO)₃)₂] (4)

2.6. Synthesis of [(µ-pmdc)₂(Re(CO)₃)(^99mTc(CO)₃)]²⁻ (5)

3. Results and discussion

3.1. Synthesis of [Re(CO)₃(OH₂)(Hpmdc)] (1), [^99mTc(CO)₃(OH₂)(Hpmdc)] (2) and [Re(CO)₃(OH₂)(etpmdc)] (3)

3.2. Synthesis of (Et₃NH)₂[(µ-pmdc)₂(Re(CO)₃)₂ (4) and [(µ-pmdc)₂(Re(CO)₃)(^99mTc(CO)₃)]²⁻ (5)

4. Conclusion

Declarations

Declaration of Competing Interest

Author Contribution

Acknowledgement

References

Schemes

Additional Declarations

Supplementary Files

Status:

Version 1

Monomeric and dimeric complexes of pyrimidine-4,6-dicarboxylic acid with organometallic fac-[M(CO)3]+ (M = Re and 99mTc) core as radiopharmaceutical probes

Status:

Version 1

Abstract

Figures

1. Introduction

2. Experimental

2.1. Materials and instrumentation

2.2. Synthesis of [Re(CO)3(OH2)(Hpmdc)] (1)

2.3. Synthesis of [99mTc(CO)3(OH2)(Hpmdc)] (2)

2.4. Synthesis of [Re(CO)3(OH2)(etpmdc)] (3)

2.5. Synthesis of (Et3NH)2[(µ-pmdc)2(Re(CO)3)2] (4)

2.6. Synthesis of [(µ-pmdc)2(Re(CO)3)(99mTc(CO)3)]2− (5)

3. Results and discussion

3.1. Synthesis of [Re(CO)3(OH2)(Hpmdc)] (1), [99mTc(CO)3(OH2)(Hpmdc)] (2) and [Re(CO)3(OH2)(etpmdc)] (3)

3.2. Synthesis of (Et3NH)2[(µ-pmdc)2(Re(CO)3)2 (4) and [(µ-pmdc)2(Re(CO)3)(99mTc(CO)3)]2− (5)

4. Conclusion

Declarations

Declaration of Competing Interest

Author Contribution

Acknowledgement

References

Schemes

Additional Declarations

Supplementary Files

Status:

Version 1

Monomeric and dimeric complexes of pyrimidine-4,6-dicarboxylic acid with organometallic fac-[M(CO)₃]⁺ (M = Re and ^99mTc) core as radiopharmaceutical probes

2.2. Synthesis of [Re(CO)₃(OH₂)(Hpmdc)] (1)

2.3. Synthesis of [^99mTc(CO)₃(OH₂)(Hpmdc)] (2)

2.4. Synthesis of [Re(CO)₃(OH₂)(etpmdc)] (3)

2.5. Synthesis of (Et₃NH)₂[(µ-pmdc)₂(Re(CO)₃)₂] (4)

2.6. Synthesis of [(µ-pmdc)₂(Re(CO)₃)(^99mTc(CO)₃)]²⁻ (5)

3.1. Synthesis of [Re(CO)₃(OH₂)(Hpmdc)] (1), [^99mTc(CO)₃(OH₂)(Hpmdc)] (2) and [Re(CO)₃(OH₂)(etpmdc)] (3)

3.2. Synthesis of (Et₃NH)₂[(µ-pmdc)₂(Re(CO)₃)₂ (4) and [(µ-pmdc)₂(Re(CO)₃)(^99mTc(CO)₃)]²⁻ (5)