Development and evaluation of a 166holmium labelled porphyrin complex as a possible therapeutic agent

Porphyrins are interesting derivatives with low toxicity, tumor avidity and rapid wash-out suggested as potential radiopharmaceuticals in radiolabeled form. In this work, [¹⁶⁶Ho] labeled 5,10,15,20-tetrakis(phenyl) porphyrin ([¹⁶⁶Ho]-TPP) was prepared using [¹⁶⁶Ho]HoCl₃ and 5,10,15,20-tetrakis(phenyl)porphyrin (H₂TPP) for 12 h at 50 °C (radiochemical purity: >95 ± 2 % ITLC, >99 ± 0.5 % HPLC, specific activity: 0.9–1.1 GBq/mmol). Stability of the complex was checked in final formulation and human serum for 48 h. The partition coefficient was calculated for the compound (log P = 2.01). The biodistribution of the labeled compound in vital organs of wild-type rats was studied using scarification studies and SPECT. A detailed comparative pharmacokinetic study performed for ¹⁶⁶Ho cation and [¹⁶⁶Ho]-TPP performed up to 24 h. The complex is mostly washed out from the circulation through kidneys and in less extends from the liver. The kidney:blood, kidney:liver and kidney:muscle ratios 4 h post injection were 14, 3.6 and 7.38 respectively.     

Preparation, nano purification, quality control and labeling optimization of [64Cu]-5,10,15,20-tetrakis (penta fluoro phenyl) porphyrin complex as a possible imaging agent

Cu-64 was produced via the ⁶⁸Zn (p,αn)⁶⁴Cu nuclear reaction (≈200 mCi, >95 % chemical yield at 180 μA for 1.1 h irradiation, (radionuclidic purity >96 %, copper-67 as impurity) followed by purification with amino functionalized nano magnetic oxide, Fe₃O₄ aiming to remove trace amount of heavy metal ions from aqueous media due to achieve ultra pure [⁶⁴Cu] CuCl₂ for labeling step. [⁶⁴Cu] labeled 5,10,15,20-tetrakis(penta fluoro phenyl) porphyrin ([⁶⁴Cu]-TFPP) was prepared using freshly prepared [⁶⁴Cu] CuCl₂ (Cu-64; T _1/2 = 12.7 h) and 5,10,15,20-tetrakis(penta fluoro phenyl)porphyrin (H₂TFPP) for 60 min at 100 °C under reflux condition (radiochemical purity: >97 % ITLC, >98 % HPLC, specific activity: 14–16 GBq/mmol). Stability of the complex was checked in final formulation and human serum for 24 h. The partition coefficient was calculated for the compound (log P = 0.73). The biodistribution of the labeled compound in vital organs of wild-type rats was studied using scarification studies and PET imaging up in 2 and 4 h after injection. A detailed comparative pharmacokinetic study performed for ⁶⁴Cu cation and [⁶⁴Cu]-TFPP. The complex is mostly washed out from the circulation through kidneys and liver and can be an interesting tumor imaging/targeting agent due to high specific uptake and rapid excretion through the urinary tract.     

Radiosynthesis and biodistribution studies of [62Zn/62Cu]–plerixafor complex as a novel in vivo PET generator for chemokine receptor imaging

In order to develop a possible C-X-C chemokine receptor type 4 (CXCR4) imaging agent for oncological scintigraphy, [⁶²Zn]labeled 1,1′-[1,4-phenylenebis(methylene)]bis-1,4,8,11-tetraazacyclotetradecane ([⁶²Zn]-AMD3100) was prepared using in-house made [⁶²Zn]ZnCl₂ and AMD-3100 for 1 h at 50 °C (radiochemical purity: >97 % ITLC, >96 % HPLC, specific activity: 20–22 GBq/mmol) in acetate buffer. The complex showed highly hydrophilic properties (log P = ?1.114). Stability of the complex was checked in presence of human serum (37 °C) and in final formulation for 1 day. The biodistribution of the labeled compound in vital organs of wild-type Sprague–Dawdley rats were determined and compared with that of free Zn²⁺ cation up to 6 h. Co-incidence imaging of the complex was consistent with the distribution data up to 3 h. The complex can be a possible in vivo generator compound for PET imaging in CXCR4 positive tumors.     

Preparation and preliminary evaluation of [<Superscript>67</Superscript>Ga]-tetra phenyl porphyrin complexes as possible imaging agents

[⁶⁷Ga]labeled tetraphenyl porphyrin ([⁶⁷Ga]-TPP) was prepared using freshly prepared [⁶⁷Ga]GaCl₃ and tetraphenyl porphyrin (TPPH₂) for 30–60 min at 25 °C (radiochemical purity: >97 ± 1% ITLC, >98 ± 0.5% HPLC, specific activity: 13–14 GBq/mmol). Stability of the complex was checked in final formulation and human serum for 24 h. The partition coefficient was calculated for the compound (log P 1.89). The biodistribution of the labeled compound in vital organs of wild-type rats was studied using scarification studies and SPECT imaging up to 24 h. A detailed comparative pharmacokinetic study performed for ⁶⁷Ga cation and [⁶⁷Ga]-TPP. The complex is mostly washed out from the circulation through kidneys and can be an interesting tumor imaging/targeting agent due to low liver uptake and rapid excretion through the urinary tract.     

The first example of Diels-Alder cycloaddition of ortho-xylylenes to meso-tetraarylporphyrins containing electron-deficient β,β-double bonds

β-Nitro-5,10,15,20-tetraphenylporphyrin and its zinc complex, or 2,7-dinitro-5,10,15,20-tetraphenylporphyrin, react with 1,3-dihydrobenzo[c]thiophene 2,2-dioxide in refluxing 1,2,4-trichlorobenzene, giving rise to chlorins, bacteriochlorins or isobacteriochlorins. The products obtained are attractive intermediates for further functionalization of porphyrins and may be of potential use as sensitizers in photodynamic therapy.     

New mixed rare earth double-decker complexes with octyloxynaphthyl-porphyrinato and phenylthio-naphthalocyaninato ligands – preparation and spectroscopic characterization

Eight new (porphyrinato)(naphthalocyaninato) rare earth(III) double-decker complexes M^III(TONPP)[Nc(PhS)₈] [M = La, Pr, Nd, Sm, Eu, Gd, Tb, and Dy; TONPP = 5,10,15,20-tetrakis(4-octyloxynaphthyl) porphyrin; Nc(PhS)₈ = 3,4,12,13,21,22,30,31-octa(phenylthio)-2,3-naphthalocyanine] have been prepared and characterized by spectroscopic methods. The UV–vis absorption spectra depend on the central rare earth ionic size, suggesting that all the transitions involve molecular orbitals with contribution from both porphyrin and naphthalocyanine ligands. The IR and Raman spectra of these double-decker compounds were systemically investigated, showing that the electron hole in these mixed double-deckers is mainly localized at the naphthalocyanine ring. Their sandwich nature was also characterized by MS, EA, and ¹H NMR techniques.     

Quantitative analysis of neodymium, uranium, and palladium in nitric acid solution by reflection absorption spectrophotometry

Quantitative analysis of Nd, U, or Pd in 3 mol dm^?3 (M) HNO₃ was performed by reflection absorption spectrophotometry at ultraviolet–visible–near-infrared (UV/Vis/NIR) region. A sample chamber with optics for reflection measurement was designed and attached to a UV/Vis/NIR spectrophotometer by optical fibers. The reflection absorbance showed linear relations with concentrations of Nd, U, and Pd at the absorbance region less than 0.1. The quantitative analysis was found to be possible for 3 M HNO₃ solutions containing [Nd] ~0.2 M, [U] ~0.04 M, or [Pd] ~0.01 M.     

Porphyrins. 14. Synthesis and properties of 1-substituted derivatives of 5,10,15,20-tetraphenylporphyrin

The Vilsmeier formylatlon of the cobalt complex of 5,10,15,20-tetraphenylporphyrin was realized, and its intermediate salt with the dimethylformamide-POC1₃ complex was isolated; demetallation of the latter gave 1-formyl-5,10,15,20-tetraphenylporphyrin. Formyltetraphenylporphyrin oxime and its 0-acetyl derivative and 1-cyano-5,10,15, 20-tetraphenylporphyrin were synthesized. The Wittig reaction with formylporphyrin and its copper and cobalt complexes with methoxycarbonylmethinyltriphenylphosphorane and diethylamidocarbonylmethinylhexamethyltriamidophosphorane was realized, and conditions that affect the ratios of the Z and E isomers of the acrylic derivatives obtained were studied.See [1] for Communication 13.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 59–64, January, 1982.The authors sincerely thank L. B. Lazukova and A. M. Shul'ge for recording the PMR spectra, V. P. Suboch for recording the mass spectra, and I. I. Mizrakhfor providing us with a sample of phosphorane B.     

Preparation and the biodistribution study of [131I]-5,10,15,20-tetrakis(4-hydroxyphenyl)porphyrin and 5-(4-aminophenyl)-10,15,20-triphenylporphyrin

[¹³¹I]-5,10,15,20-tetrakis(4-hydroxyphenyl)porphyrin and [¹³¹I]-5-(4-aminophenyl)-10,15,20-triphenylporphyrin (¹³¹I-TPPOH and ¹³¹I-TPPNH₂) were prepared and their biodistribution properties were evaluated in normal Kunming (KM) mice and SMMC-7721 tumor-bearing BALB/c mice. The optimized labeling yields were 98 and 96 % for ¹³¹I-TPPOH and ¹³¹I-TPPNH₂, respectively. They were stable in vitro saline and in vivo. Both compounds had a specific affinity to liver and lung, and mainly metabolized through liver. They showed a time-dependent accumulation and retainable characteristics in SMMC-7721 tumor. These results supported their potential value for targeted tumor therapy agents.     

Effect of the nature of the tetrapyrrole macrocycle on the transmetallation of Zn2+ and Cd2+ porphyrins with PdCl2 in dimethylformamide

Transmetallation of zinc (Zn²⁺) and cadmium (Cd²⁺) complexes of 5,10,15,20-tetraphenylporphin, 5,10,15,20-tetra(4-chlorophenyl)porphyrin, 5,10,15,20-tetra(4-methoxyphenyl)porphyrin, tetrabenzoporphyrin, and octaphenyltetraazaporphyrin with PdCl₂ in DMF was studied by spectrophotometry. The influence of the nature of the tetrapyrrole macrocycle on the reactivity of Zn²⁺ porphyrins toward palladium chloride in boiling DMF was established. Palladium(II) complexes of 5,10,15,20-tetraphenylporphyrin, 5,10,15,20-tetra(4-chlorophenyl)porphyrin, 5,10,15,20-tetra(4-methoxyphenylporphyrin), and tetrabenzoporphyrin were prepared and identified.     

Synthesis and properties of ms- and β-substituted Pt(II) and Pt(IV) tetraphenylporphyrinates

The interaction of 5,10,15,20-tetraphenylporphyrin, 5,10,15,20-tetra-(4-chlorophenyl)porphyrin, 2-bromo-5,10,15,20-tetraphenylporphyrin, and 2,3,12,13-tetrabromo-5,10,15,20-tetraphenylporphyrin with platinum(II) chloride in boiling phenol has been studied. The corresponding platinum(II) porphyrinates have been synthesized; their subsequent treatment with bromine in chloroform resulted in platinum(IV) porphyrinates. The Pt(II) and Pt(IV)(Br)₂ porphyrinates have been identified by elemental analysis, electron absorption, IR, and ¹H NMR spectroscopy.     

Synthesis,structure, magnetic and catalytic behavior of a dinuclear copper(II) complex with triazendio ligands

A dinuclear copper(II) complex [Cu₂L₄] has been prepared by the reaction of CuCl₂·2H₂O and 1-[(2-iodo)benzene]-3-[benzothiazole] triazene (HL). The complex has been characterized by X-ray crystallography and by physico-chemical and spectroscopic methods. In the solid state, there is a significant antiferromagnetic coupling between the copper(II) centers with a coupling constant (J) of ??558 cm^?1. In homogeneous solution, the complex shows electrocatalytic activities for hydrogen generation from both acetic acid and neutral buffer with a turnover frequency of 50 mol of H₂ per mole of catalyst per hour (mol H₂/mol catalyst/h) at an overpotential (OP) of 941.6 mV, and 502 mol H₂/mol catalyst/h at an OP of 836.7 mV.     

Preparation,molecular modeling and biodistribution of 99mTc-phytochlorin complex

Phytochlorin [21H, 23H-Porphine-7-propanoicacid, 3-carboxy-5-(carboxymethyl)13-ethenyl-18-ethyl-7,8-dihydro-2,8,12,17-tetramethyl-,(7S,8S)] was labeled with ^99mTc and the factors affecting the labeling yield of ^99mTc-phytochlorin complex were studied in details. At pH 10, ^99mTc-phytochlorin complex was obtained with a high radiochemical yield of 98.4 ± 0.6 % by adding ^99mTc to 100 mg phytochlorin in the presence of 75 μg SnCl₂·2H₂O after 30 min reaction time. The molecular modeling study showed that the structure of ^99mTc-phytochlorin complex presents nearly linear HO–Tc–OH unit with an angle of 179.27° and a coplanar Tc(N1N2N3N4) unit. Biodistribution of ^99mTc-phytochlorin complex in tumor bearing mice showed high T/NT ratio (T/NT = 3.65 at 90 min post injection). This preclinical study showed that ^99mTc-phytochlorin complex is a potential selective radiotracer for solid tumor imaging and afford it as a new radiopharmaceutical suitable to proceed through the clinical trials for tumor imaging.     

Synthesis of [64Cu]DOTA-ADIBON3-Ala-PEG28-A20FMDV2 via copper-free click chemistry for PET imaging of integrin αvβ6

Catalyst-free click reactions are effective chemical tools for synthesis of radiometal-based radiopharmaceuticals offering advantages towards preparation of non-toxic agents with high specific activity. In the present study the radiotracer [⁶⁴Cu]DOTA-ADIBON₃-Ala-PEG₂₈-A20FMDV2, [⁶⁴Cu]3, was synthesized for positron emission tomography imaging of integrin α_vβ₆ expressing tumors via a strain-promoted click reaction using both a “pre-click” and “post-click” approaches. The radiotracer, prepared in >99 % radiochemical yield, was evaluated in vitro (64.6 ± 2.8 % binding to α_vβ₆-positive cells vs. <5 % to α_vβ₆-negative cells) and in vivo (α_vβ₆-positive tumor uptake: 1.52 ± 0.16 % ID/g, 24 h p.i.). While the high initial renal uptake (76.2 ± 10.7 % ID/g at 1 h p.i.) was comparable to a previously reported radiotracer, [⁶⁴Cu]DOTA-PEG₂₈-A20FMDV2, [⁶⁴Cu]3 showed notably improved renal clearance (11.3 ± 2.5 % ID/g at 24 h p.i.). Thus, the introduction of a chelator-strained alkyne system resulted in improved pharmacokinetics for the present radiotracer, highlighting the attractive prospects of strain-promoted click-based preparations in the construction of radiometalated bioconjugates for targeted molecular imaging and therapy.     

Novel 99mTc labeled σ receptor ligand as a potential tumor imaging agent

A novel ^99mTc labeled complex, [N-[2-((2-oxo-2-(4-(3-phenylpropyl)piperazin-1-yl)ethyl) (2-mercaptoethyl)amino)acetyl]-2-aminoethanethiolato]Technetium(V) oxide (PPPE-MAMA’-^99mTcO) ([ ^99m Tc]-2) has been designed and prepared based on the integrated approach. The corresponding rhenium complex (PPPE-MAMA’-ReO)(Re-2) has been prepared and characterized. In vitro competition binding assays show moderate affinity of Re-2 towards σ₁ and σ₂ receptors with K _i values of 8.67 ± 0.07 and 5.71 ± 1.88 μmol, respectively. Planar images obtained at 0.5 h, 4 h, 20 h after i.v. injection indicate the accumulation of [ ^99m Tc]-2 in MCF-7 human breast tumor bearing mice at 20 h. Furthermore, the accumulation of [ ^99m Tc]-2 has been inhibited at 20 h after co-injection of [ ^99m Tc]-2 plus haloperidol (1 mg/kg). Biodistribution studies of [ ^99m Tc]-2 display an in vivo tumor uptake of 0.14% ± 0.01% ID/g at 24 h post i.v. injection with a tumor/muscle ratio of 6.02 ± 0.87. The above results suggest that [ ^99m Tc]-2, derived from a previously published lead compound, retains certain tumor uptake and affinity for σ receptors. [ ^99m Tc]-2 may be used as a basis for further structural modifications to develop tumor imaging agents with high affinity for σ receptors.     

Visible Light Photocatalytic Activity of Porphyrin Tin(IV) Sensitized TiO2 Nanoparticles for the Degradation of 4-Nitrophenol and Methyl Orange

A stable metalloporphyrin sensitized TiO₂ (Degussa P25) photocatalyst was prepared by using trans-dihydroxo[5,10,15,20-tetraphenylporphyrin]tin(IV) (SnP) as a sensitizer in a simple impregnation process. The solid diffuse reflectance ultraviolet-visible (UV-vis) spectrum of the SnP sensitized TiO₂ photocatalyst (SnP-TiO₂) indicated that there existed interaction between SnP and TiO₂. It was found that SnP-TiO₂ exhibited an enhanced visible light photocatalytic activity as compared with that over P25 for the degradation of 4-nitrophenol (4-NP) and methyl orange (MO) in aqueous solutions. The mechanism exploration showed that the degradation of MO and 4-NP experienced two different ways, that is, MO was photodegraded by reactive oxygen species and 4-NP was directly photodegraded by the excited state of SnP. Furthermore, it was found that the loading content of SnP had an important influence on the photocatalytic activity of TiO₂. The maximum photocatalytic efficiency was achieved when the contents of SnP were 25 mg and 30 mg per gram TiO₂ for MO and 4-NP, respectively. Importantly, SnP-TiO₂ was particularly stable and the photocatalytic activity was hardly decreased after being recycled seven times in the presence of oxygen, which could be attributed to the easy reductive regeneration of SnP.     

A perspective on <Superscript>99m</Superscript>Tc and <Superscript>125/131</Superscript>I labeled receptor targeted compounds and their in vitro/in vivo affinities

A novel quinoline derivative, 2,2′-[(5-chloro-8-hydroxyquinoline-7-yl) methylazanediyl] diacetic acid (CHQMADA) was labeled with ^99mTc using SnCl₂·2H₂O as a reducing agent to give a complex with a labeling yield 94 %. Also [^99mTc(H₂O)₃(CO)₃]⁺ was prepared by heating at 100 °C for 30 min using 2 mg CHQMADA at pH 8 to give a labeling yield >99 %. ^99mTc-(CO)₃ CHQMADA and ^99mTc-Sn(II)-CHQMADA showed tissue uptake (target to non target T/NT = 6.80 ± 0.22) and (T/NT = 5.65 ± 0.34) respectively in Escherichia coli induced infection, which is higher than the commercially available ^99mTc-ciprofloxacin (T/NT = 3.80 ± 0.80). In conclusion, both complexes were able to differentiate between septic and aseptic inflammation with superiority of [^99mTc-(CO)₃ CHQMADA].     

Porphyrins and their derivatives: XXV. Reaction of 2-formyl-5,10,15,20-tetraphenylporphyrin with diazomethane

2-Formyl-5,10,15,20-tetraphenylporphyrin and its copper and zinc complexes react with diazomethane in a mixture chloroform-alcohol providing the corresponding 2-acetyl-and 2-acetonyl derivatives. In a pure chloroform main product of diazomethane reaction with 2-formyl-5,10,15,20-tetraphenylporphyrin is 2-acetyl-5,10,15,20-tetraphenylcyclopropa[b]chlorin.     

Source tracing of chromium-, manganese-, nickel- and zinc-containing particles (PM<Subscript>10</Subscript>) by micro-PIXE spectrum

Due to the interesting anti-proliferative properties of gallium-thiosemicarbazone complexes, the production of [⁶⁷Ga]labeled 2-acetylpyridine 4,4-dimethyl thiosemicarbazone (APTSM₂) was investigated. The freshly prepared [⁶⁷Ga]GaCl₃ was mixed with 2-acetylpyridine 4,4-dimethyl thiosemicarbazone for 60 minutes at 90 °C to yield [⁶⁷Ga]APTSM₂ with a radiochemical yield of more than 98%. Radio-thin-layer-chromatography (RTLC) showed a radiochemical purity of more than 99%. A specific activity of about 370–740 MBq/mmol (10–20 Ci/mmol) was obtained. The stability of the final product was checked in the absence and presence of human serum at 37 °C. The partition coefficient of the final complex was also determined. The biodistribution of the labeled compound in normal rats was compared with that of free Ga³⁺ cation up to 22 hours.     

Radiosynthesis and biological evaluation of 166Ho labeled methoxylated porphyrins as possible therapeutic agents

¹⁶⁶Ho labeled 5,10,15,20-tetrakis(3,4-dimethoxyphenyl) porphyrin, and 5,10,15,20-tetrakis(3,4,5-trimethoxyphenyl) porphyrin ([¹⁶⁶Ho]–TDMPP and [¹⁶⁶Ho]–TTMPP respectively) were prepared with acceptable radiochemical purity and specific activities. Stability and partition coefficient of the complexes were determined in the final formulations and biodistribution studies in mouse demonstrated high accumulation of [¹⁶⁶Ho]–TDMPP in the lung and liver and less excretion through the kidney. while [¹⁶⁶Ho]–TTMPP was mostly excreted into intestines and kidneys while lungs were a minor accumulation site. In contrast to other reported radiolanthanide labeled porphyrins these two complexes showed less liver accumulation. Further investigation of their potential therapeutic properties is of interest.