[68Ga]‐HP‐DO3A‐nitroimidazole: a promising agent for PET detection of tumor hypoxia

The goal of this study is to evaluate a new ⁶⁸Ga‐based imaging agent for detecting tumor hypoxia using positron emission tomography (PET). The new hypoxia targeting agent reported here, [⁶⁸Ga]‐HP‐DO3A‐nitroimidazole ([⁶⁸Ga]‐HP‐DO3A‐NI), was constructed by linking a nitroimidazole moiety with the macrocyclic ligand component of ProHance®, HP‐DO3A. The hypoxia targeting capability of this agent was evaluated in A549 lung cancer cells in vitro and in SCID mice bearing subcutaneous A549 tumor xenografts. The cellular uptake assays showed that significantly more [⁶⁸Ga]‐HP‐DO3A‐NI accumulates in hypoxic tumor cells at 30, 60 and 120 min than in the same cells exposed to 21% O₂. The agent also accumulated in hypoxic tumors in vivo to give a tumor/muscle ratio (T/M) of 5.0 ± 1.2 (n = 3) as measured by PET at 2 h post‐injection (p.i.). This was further confirmed by ex vivo biodistribution data. In addition, [⁶⁸Ga]‐HP‐DO3A‐NI displayed very favorable pharmacokinetic properties, as it was cleared largely through the kidneys with little to no accumulation in liver, heart or lung (%ID/g < 0.5%) at 2 h p.i. The specificity of the agent for hypoxic tissues was further validated in a comparative study with a control compound, [⁶⁸Ga]‐HP‐DO3A, which lacks the nitroimidazole moiety, and by PET imaging of tumor‐bearing mice breathing air versus 100% O₂. Given the commercial availability of cGMP ⁶⁸Ge/⁶⁸Ga generators and the ease of ⁶⁸Ga labeling, the new agent could potentially be widely applied for imaging tumor hypoxia prior to radiation therapy. Copyright © 2015 John Wiley & Sons, Ltd.     

Spectroscopic,radiochemical, and theoretical studies of the Ga3+‐N‐2‐hydroxyethyl piperazine‐N′‐2‐ethanesulfonic acid (HEPES buffer) system: evidence for the formation of Ga3+‐ HEPES complexes in 68 Ga labeling reactions

Recent reports have claimed a superior performance of HEPES buffer in comparison to alternative buffer systems for ^67/68 Ga labeling in aqueous media. In this paper we report spectroscopic (¹H and ⁷¹ Ga NMR), radiochemical, mass spectrometry and theoretical modeling studies on the Ga³⁺/HEPES system (HEPES = N‐2‐hydroxyethylpiperazine‐N′‐2‐ethanesulfonic acid) performed with the aim of elucidating a potential contribution of HEPES in the ^68/67 Ga radiolabeling process. Our results demonstrate that HEPES acts as a weakly but competitive chelator of Ga³⁺ and that this interaction depends on the relative Ga³⁺: HEPES concentration. A by‐product formed in the labeling mixture has been identified as a [⁶⁸ Ga]Ga(HEPES) complex via chromatographic comparison with the nonradioactive analog. The formation of this complex was verified to compete with [⁶⁸ Ga]Ga(NOTA) complexation at low NOTA concentration. Putative chelation of Ga³⁺ by the hydroxyl and adjacent ring nitrogen of HEPES is proposed on the basis of ¹H NMR shifts induced by Ga³⁺ and theoretical modeling studies. Copyright © 2013 John Wiley & Sons, Ltd.     

Gallium(III) complexes of NOTA‐bis (phosphonate) conjugates as PET radiotracers for bone imaging

Ligands with geminal bis(phosphonic acid) appended to 1,4,7‐triazacyclonone‐1,4‐diacetic acid fragment through acetamide (NOTAM^BP) or methylenephosphinate (NO2AP^BP) spacers designed for ⁶⁸Ga were prepared. Ga^III complexation is much faster for ligand with methylenephosphinate spacer than that with acetamide one, in both chemical (high reactant concentrations) and radiolabeling studies with no‐carrier‐added ⁶⁸Ga. For both ligands, formation of Ga^III complex was slower than that with NOTA owing to the strong out‐of‐cage binding of bis(phosphonate) group. Radiolabeling was efficient and fast only above 60 °C and in a narrow acidity region (pH ~3). At higher temperature, hydrolysis of amide bond of the carboxamide‐bis(phosphonate) conjugate was observed during complexation reaction leading to Ga–NOTA complex. In vitro sorption studies confirmed effective binding of the ⁶⁸Ga complexes to hydroxyapatite being comparable with that found for common bis(phosphonate) drugs such as pamindronate. Selective bone uptake was confirmed in healthy rats by biodistribution studies ex vivo and by positron emission tomography imaging in vivo. Bone uptake was very high, with SUV (standardized uptake value) of 6.19 ± 1.27 for [⁶⁸Ga]NO2AP^BP) at 60 min p.i., which is superior to uptake of ⁶⁸Ga–DOTA‐based bis(phosphonates) and [¹⁸F]NaF reported earlier (SUV of 4.63 ± 0.38 and SUV of 4.87 ± 0.32 for [⁶⁸Ga]DO3AP^BP and [¹⁸F]NaF, respectively, at 60 min p.i.). Coincidently, accumulation in soft tissue is generally low (e.g. for kidneys SUV of 0.26 ± 0.09 for [⁶⁸Ga]NO2AP^BP at 60 min p.i.), revealing the new ⁶⁸Ga complexes as ideal tracers for noninvasive, fast and quantitative imaging of calcified tissue and for metastatic lesions using PET or PET/CT. Copyright © 2014 John Wiley & Sons, Ltd.     

Bifunctional Gd(III) and Tb(III) chelates based on a pyridine–bis(iminodiacetate) platform,suitable optical probes and contrast agents for magnetic resonance imaging

To study the physicochemical properties of lanthanide complexes derived from a bifunctional chelating agent based on a PMN‐tetraacetic acid moiety {PMN‐tetraacetic acid (1): [2,6‐pyridinediylbis(methylene nitrilo)‐tetraacetic acid]}, 4‐carboxylic acid substituted pyridine derivative (2) was synthesized. This ligand forms heptadentate (N₃O₄) Ln(III) complexes (Ln = Gd, Eu, Tb), with two water molecules completing the inner coordination sphere of the metal. The parameters that govern the relaxivity of the Gd(III) complex and the luminescence of Eu(III) and Tb(III) complexes were obtained by ¹⁷O and ¹H NMR studies and time‐resolved fluorescence experiments, respectively. The gadolinium and terbium complexes show interesting properties either for MRI or FOR optical imaging; that is, for the Gd complex, a high proton relaxivity (r₁ = 6.4 s^?1 mm ^?1 at 20 MHz) with short water residence time (τ_M = 38.5 ns); for the Tb complex, a luminescence lifetime of 1.22 ms at room temperature and a luminescence quantum yield of 10%. The kinetic stability of these complexes toward blood protein, cation or bioactive oxyanion was also examined. The Gd(2)(H₂O)₂ complex does not interact with human serum albumin, but undergoes a transmetalation reaction with Zn(II) in a phosphate buffer solution (pH 7.4), rather similar to that of Gd–DTPA–BMA(H₂O). On the other hand, as observed for Eu and Tb complexes, these chelates do not form ternary complexes with bidentate anions such as l ‐lactate, citrate or carbonate. Finally, a phosphatidylserine‐specific hexapeptide (TLVSSL) was grafted on Gd or Tb chelates, and the Gd–peptide conjugate was used in vitro for targeting apoptotic cells. Copyright © 2014 John Wiley & Sons, Ltd.     

A novel PET tracer for the imaging of αvβ3 and αvβ5 integrins in experimental breast cancer bone metastases

The aim of this study was the evaluation of ⁶⁸Ga‐DOTA‐E‐[c(RGDfK)]₂ as a novel PET tracer to image αvβ3 and αvβ5 integrins. For this purpose, DOTA‐E‐[c(RGDfK)]₂ was labeled with ⁶⁸Ga, which was obtained from a ⁶⁸Ge/⁶⁸Ga generator, purified by solid‐phase extraction and the radiochemical purity analyzed by radio‐RP‐HPLC. ⁶⁸Ga‐DOTA‐E‐[c(RGDfK)]₂ was obtained reproducibly in radiochemical yields of 60 ± 6% and with an excellent radiochemical purity of >99%. In nude rats bearing bone metastases after injection of MDA‐MB‐231 human breast cancer cells, biodistribution studies were performed to evaluate the accumulation of the radiotracer in selected organs, blood and bone metastases 0.5, 1, 2 and 3 h post injection. A rapid uptake into the bone metastases and rapid blood clearance was observed, resulting in tumor–blood ratios of up to 26.6 (3 h post injection) and tumor–muscle ratios of up to 7.9 (3 h post injection). A blocking experiment with coinjected αvβ3/αvβ5 antagonist showed the tumor uptake to be receptor‐specific. In an initial in vivo micro PET evaluation of the tracer using the same animal model, the bone metastasis was clearly visualized. These results suggest that ⁶⁸Ga‐DOTA‐E‐[c(RGDfK)]₂ is a promising PET tracer suitable for the imaging of αvβ3 and αvβ5 integrins in bone metastases. This novel PET tracer should be further evaluated concerning its usefulness for early detection of bone metastases and monitoring treatment response of these lesions. Copyright © 2011 John Wiley & Sons, Ltd.     

Gadolinium‐containing magnetic resonance contrast media: investigation on the possible transchelation of Gd3+ to the glycosaminoglycan heparin

Retention of gadolinium (Gd) in biological tissues is considered an important cofactor in the development of nephrogenic systemic fibrosis (NSF). Research on this issue has so far focused on the stability of Gd‐based contrast media (GdCM) and a possible release of Gd³⁺ from the complex. No studies have investigated competing chelators that may occur in vivo. We performed proton T₁‐relaxometry in solutions of nine approved GdCM and the macromolecular chelator heparin (250 000 IU per 10 ml) without and with addition of ZnCl₂. For the three linear, nonspecific GdCM complexes, Omniscan®, OptiMARK® and Magnevist®, 2 h of incubation in heparin at 37 °C in the presence of 2.0 mm ZnCl₂ led to an increase in T₁‐relaxivity by a factor of 7.7, 5.6 and 5.1, respectively. For the three macrocyclic complexes, Gadovist®, Dotarem® and Prohance®, only a minor increase in T₁‐relaxivity by a factor of 1.5, 1.6 and 1.7 was found, respectively. Without addition of ZnCl₂, no difference between the two GdCM groups was observed (factors of 1.4, 1.2, 1.1, 1.3, 1.5 and 1.4, respectively). The increase in T₁‐relaxivities observed for linear GdCM complexes may be attributable to partial transchelation with formation of a macromolecular Gd–heparin complex. For comparison, mixing of GdCl₃ and heparin results in a 8.7‐fold higher T₁‐relaxivity compared with a solution of GdCl₃ in water. Heparin is a glycosaminoglycan (GAG) and as such occurs in the human body as a component of the extracellular matrix. GAGs generally are known to be strong chelators. Gd³⁺ released from chelates of GdCM might be complexed by GAGs in vivo, which would explain their retention in biological tissues. Plasma GAG levels are elevated in end‐stage renal disease; hence, our results might contribute to the elucidation of NSF. Copyright © 2012 John Wiley & Sons, Ltd.     

Development and Evaluation of User-Friendly Single Vial DOTA-Peptide Kit Formulations,Specifically Designed for Radiolabelling with <Superscript>68</Superscript>Ga from a Tin Dioxide <Superscript>68</Superscript>Ge/<Superscript>68</Superscript>Ga Generator

Purpose

This study was aimed to develop single vial 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-peptide kits to be used with fractionated eluates from a SnO₂-based ⁶⁸Ge/⁶⁸Ga generator.

Procedures

Kits were formulated with 35 μg DOTA-Tyr³-Thre⁸-octreotide, DOTA-[Tyr³]-octreotide and DOTA-[NaI³]-octreotide (DOTATATE, DOTATOC and DOTANOC) and sodium acetate powder, vacuum-dried and stored at ?20 °C for up to 12 months. Labelling of the kits was carried out with 2 ml ⁶⁸Ga eluate. Comparative labelling was carried out using aqueous DOTA-peptide stock solutions kept frozen at ?20 °C for up to 12 months.

Results

The quality of the kits was found to be suitable over a 1-year storage period (pH, sterility, endotoxin content, radiolabelling efficiency and radiochemical yields of ⁶⁸Ga-labelled DOTA-peptides). Radiochemical yields ranged from 73 to 83 %, while those obtained from stock solutions from 64 to 79 %. No significant decline in kit labelling yields was observed over a 12-month storage period.

Conclusion

The single vial kit formulations met the quality release specifications for human administration and appear to be highly advantageous over using peptide stock solutions in terms of stability and user-friendliness.

     

Cation exchange synthesis of CuInxGa1−xSe2 nanowires and their implementation in photovoltaic devices

CuIn_xGa_1−xSe₂ (CIGS) nanowires were synthesized for the first time through an in situ cation exchange reaction by using CuInSe₂ (CIS) nanowires as a template material and Ga-OLA complexes as the Ga source. These CIGS nanowires maintain nearly the same morphology as CIS nanowires, and the Ga/In ratio can be controlled through adjusting the concentration of Ga-OLA complexes. The characteristics of adjustable band gap and highly effective light-absorbances have been achieved for these CIGS nanowires. The light-absorbing layer in photovoltaic devices (PVs) can be assembled by employing CIGS nanowires as a solar-energy material for enhancing the photovoltaic response. The highest power conversion efficiency of solar thin film semiconductors is more than 20%, achieved by the Cu(In_xGa_1−x)Se₂ (CIGS) thin-film solar cells. Therefore, these CIGS nanowires have a great potential to be utilized as light absorber materials for high efficiency single nanowire solar cells and to generate bulk heterojunction devices.

CuIn_xGa_1−xSe₂ (CIGS) nanowires were synthesized for the first time through an in situ cation exchange reaction by using CuInSe₂ (CIS) nanowires as a template material and Ga-OLA complexes as the Ga source.     

Four- and five-coordinate nickel(ii) complexes bearing new diphosphine–phosphonite and triphosphine–phosphite ligands: catalysts for N-alkylation of amines

The reaction of Ph₂PCH₂OH with PhPCl₂ and PCl₃ in the presence of Et₃N afforded new phosphonite compounds PhP(OCH₂PPh₂)₂1 and P(OCH₂PPh₂)₃2, respectively. The reaction between 1 and [NiCl₂(DME)] in dichloromethane gave the five-coordinate complex [NiCl₂(1-κ³P,P,P)] 3. Conversely, 1 reacts with [NiCl₂(DME)] in the presence of NH₄PF₆ in dichloromethane to yield the four coordinate ionic complex [NiCl(1-κ³P,P,P)][PF₆] 4. The reactions between 1, [NiCl₂(DME)] and KPF₆ in the presence of RNC (R = Xylyl, ^tBu and ⁱPr) in dichloromethane yielded the five coordinate monocationic [NiCl(1-κ³P,P,P)(RNC)][PF₆] (R = Xylyl) and dicationic [Ni(1-κ³P,P,P)(RNC)₂][PF₆]₂ (R = ^tBu and ⁱPr) complexes, respectively. The analogous reaction of 2 with [NiCl₂(DME)] in the presence of KPF₆ gave complex [NiCl(2-κ⁴P,P,P,P)][PF₆], 8. The structures of all complexes were determined by single crystal X-ray diffraction studies and supported by spectroscopic methods. To demonstrate their catalytic application, N-alkylation reactions between primary aryl amines, benzyl and 4-methoxy benzyl alcohols were found to proceed smoothly in the presence of 2.5 mol% of complexes bearing ligand 1 and <0.5 mmol of KOBu^t in toluene at 140 °C. The C–N coupled products were formed in very good yields. Its substrate scope includes sterically encumbered, heterocyclic amines and aliphatic alcohol.

A series of nickel(ii) complexes supported by the new tridentate P3 and tetradentate P4 ligands act efficiently as catalysts for the N-alkylation of primary amines with alcohols.     

Synthesis,characterization and olefin polymerization behaviors of phenylene-bridged bis-β-carbonylenamine binuclear titanium complexes

Binuclear and multinuclear complexes have attracted much attention due to their unique catalytic performances for olefin polymerization compared with their mononuclear counterparts. In this work, a series of phenyl-bridged bis-β-carbonylenamine [O⁻NS^R] (R = alkyl or phenyl) tridentate ligands and their binuclear titanium complexes (Ti²L₁–Ti²L₅) were synthesized and characterized by ¹H NMR, ¹³C NMR, FTIR and elemental analysis. The molecular structure of ligand L₂ (R = ⁿPr) and its corresponding Ti complex Ti²L₂ were further investigated by single-crystal X-ray diffraction, which showed that each titanium coordinated with six atoms to form a distorted octahedral configuration along with the conversion of the ligand from β-carbonylenamine to β-imino enol form. Under the activation of MMAO, these complexes catalyzed ethylene polymerization and ethylene/α-olefin copolymerization with extremely high activity (over 10⁶ g mol (Ti)⁻¹ h⁻¹ atm⁻¹) to produce high molecular weight polyethylene. At the same time, wider polydispersity as compared with the mononuclear counterpart TiL₆ was observed, indicating that two active catalytic centers may be present, consistent with the asymmetrical crystal structure of the binuclear titanium complex. Furthermore, these complexes possessed better thermal stability than their mononuclear analogues. Compared with the complexes bearing alkylthio sidearms, the complex Ti²L₅ bearing a phenylthio sidearm exhibited higher catalytic activity towards ethylene polymerization and produced polyethylene with much higher molecular weight, but with an appreciably lower 1-hexene incorporation ratio. Nevertheless, these bis-β-carbonylenamine-derived binuclear titanium complexes showed much higher ethylene/1-hexene copolymerization activity and 1-hexene incorporation ratios as compared with the methylene-bridged bis-salicylaldiminato binuclear titanium complexes, and the molecular weight and 1-hexene incorporation ratio could be flexibly tuned by the initial feed of α-olefin commoners and catalyst structures.

Phenyl-bridged bis-β-carbonylenamine binuclear titanium complexes were synthesized, characterized and used to catalyze ethylene (co)polymerization with extremely high activity.     

The pH sensitivity of –NH exchange in LnDOTA–tetraamide complexes varies with amide substituent

The amide proton exchange rates in various lanthanide(III) DOTA–tetraamide complexes were investigated by CEST as a function of variable chemical structures and charges on the amide substituents. Comparisons were made between YbDOTA–(gly)₄^? (Yb‐1), YbDOTA–(NHCH₂PO₃)₄^5? (Yb‐2) and YbDOTA–(NHCH₂PO₃Et₂)₄³⁺ (Yb‐3). The general shapes of the CEST vs pH profiles were similar for the three complexes but they showed maximum CEST intensities at different pH values, pH 8.3, 8.8 and 6.9 for Yb‐1, Yb‐2 and Yb‐3, respectively. This indicates that a more negatively charged substituent on the amide helps stabilize the partial positive charge on the amide nitrogen and consequently more base is required to catalyze proton exchange. The chemical shifts of the –NH protons in Yb‐1 and Yb‐2 were similar (?17 ppm) while the –NH proton in Yb‐3 was at ?13 ppm. This shows that the crystal field produced by the amide oxygen donor atoms in Yb‐3 is substantially weaker than that in the other two complexes. In an effort to expand the useful range of pH values that might be measured using these complexes as CEST agents, the shapes of the CEST vs pH curves were also determined for two thulium(III) complexes with much larger hyperfine shifted –NH proton resonances. The ratio of CEST from –NH exchange in Tm‐1 compared with CEST from –NH exchange in Tm‐3 was found to be linear over an extended pH range, from 6.3 to 7.4. This demonstrates a potential advantage of using mixtures of lanthanide(III) DOTA–tetraamides for mapping tissue pH by use of ratiometric CEST imaging. Copyright © 2011 John Wiley & Sons, Ltd.     

[<Superscript>68</Superscript>Ga]PSMA-HBED-CC Uptake in Osteolytic,Osteoblastic, and Bone Marrow Metastases of Prostate Cancer Patients

Purpose

The aim of this study was to evaluate potential differences in “Glu-NH-CO-NH-Lys” radio-labeled with [⁶⁸Ga]gallium N,N-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N-diacetic acid ([⁶⁸Ga]PSMA-HBED-CC) uptake in osteolytic, osteoblastic, mixed, and bone marrow metastases in prostate cancer (PC) patients.

Procedures

This retrospective study was approved by the local ethics committee. Patients who received [⁶⁸Ga]PSMA-HBED-CC positron emission tomography/computed tomography ([⁶⁸Ga]PSMA-PET/CT) with at least one positive bone metastasis were included in this study. Only patients who have not received systemic therapy for their PC were included. Bone metastases had to be confirmed by at least one other imaging modality or follow-up investigation. The maximum standardized uptake value (SUV_max) and mean Hounsfield units (HU_mean) of each metastasis were measured. Based on CT, each metastasis was classified as osteolytic (OL), osteoblastic (OB), bone marrow (BM), or mixed (M).

Results

One hundred fifty-four bone metastases in 30 patients were evaluated. Eighty out of 154 (51.9%) metastases were classified as OB, 21/154 (13.6%) as OL, 23/154 (14.9%) as M, and 30/154 (19.5%) as BM. The SUV_max for the different types of metastases were 10.6 ± 7.07 (OB), 24.0 ± 19.3 (OL), 16.0 ± 21.0 (M), and 14.7 ± 9.9 (BM). The SUV_max of OB vs. OL and OB vs. BM metastases differed significantly (p ≤ 0.025). A significant negative correlation between HU_mean and SUV_max (r = ?0.23, p < 0.05) was measured.

Conclusions

[⁶⁸Ga]PSMA-HBED-CC uptake is higher in osteolytic and bone marrow metastases compared to osteoblastic metastases. Information derived from [⁶⁸Ga]PSMA-PET and CT complement each other for the reliable diagnosis of the different types of bone metastases in PC patients.

     

Small animal PET for the evaluation of an animal model of genital infection

Background: [¹⁸F]‐FDG is a widely used tracer for the non‐invasive evaluation of hypermetabolic processes like cancer and inflammation. However, [¹⁸F]‐FDG is considered inaccurate for the diagnosis of urinary tract and genital infections because of its urinary excretion. Since the 1970s, Gallium scintigraphy is a well established test that has been used for the evaluation of inflammation and infection in human patients. Aim: The aim of this study was to assess the feasibility of ⁶⁸Ga‐Chloride small animal PET for the analysis of an animal model of genital infection, induced after the vaginal inoculum of Chlamydia muridarum. Material and methods: Thirty mice were infected by placing 15 μl of sucrose phosphate glutamic acid (SPG) 10⁷ inclusion forming units of C. muridarum into the vaginal vault. As controls of inflammation, three animals were challenged with 15 μl of SPG and one healthy animal was used to assess the tracer biodistribution. Four animals died during the experiment. Eleven animals were evaluated with ⁶⁸Ga‐Chloride small animal PET (GE, eXplore Vista) 3–5, 10–12, 17–19 days after infection, as well as three controls of inflammation and one healthy animal. Infection was monitored by obtaining cervical‐vaginal swabs from all the animals on the day of each PET procedure. Moreover, five groups of three animals each were killed at 6, 13, 20, 27 and 34 days after infection were studied. Results: ⁶⁸Ga‐PET turned out positive in all the infected animals, concordantly to data obtained by the cervical swabs and by the ex vivo analysis. The tumour‐to‐background ratio (TBR) decreased over time as the inflammation tended to naturally extinguish. The controls showed a slightly increased uptake of tracer due to the aseptic inflammation caused by SPG and frequent cervical swabs. The healthy control did not show any pelvic uptake. Conclusion: ⁶⁸Ga‐Chloride is a promising tracer for the assessment of genital infection in a mouse animal model.     

Improving PET Quantification of Small Animal [<Superscript>68</Superscript>Ga]DOTA-Labeled PET/CT Studies by Using a CT-Based Positron Range Correction

Purpose

Image quality of positron emission tomography (PET) tracers that emits high-energy positrons, such as Ga-68, Rb-82, or I-124, is significantly affected by positron range (PR) effects. PR effects are especially important in small animal PET studies, since they can limit spatial resolution and quantitative accuracy of the images. Since generators accessibility has made Ga-68 tracers wide available, the aim of this study is to show how the quantitative results of [⁶⁸Ga]DOTA-labeled PET/X-ray computed tomography (CT) imaging of neuroendocrine tumors in mice can be improved using positron range correction (PRC).

Procedures

Eighteen scans in 12 mice were evaluated, with three different models of tumors: PC12, AR42J, and meningiomas. In addition, three different [⁶⁸Ga]DOTA-labeled radiotracers were used to evaluate the PRC with different tracer distributions: [⁶⁸Ga]DOTANOC, [⁶⁸Ga]DOTATOC, and [⁶⁸Ga]DOTATATE. Two PRC methods were evaluated: a tissue-dependent (TD-PRC) and a tissue-dependent spatially-variant correction (TDSV-PRC). Taking a region in the liver as reference, the tissue-to-liver ratio values for tumor tissue (TLR_tumor), lung (TLR_lung), and necrotic areas within the tumors (TLR_necrotic) and their respective relative variations (ΔTLR) were evaluated.

Results

All TLR values in the PRC images were significantly different (p?<?0.05) than the ones from non-PRC images. The relative differences of the tumor TLR values, respect to the case with no PRC, were ΔTLR_tumor 87?±?41 % (TD-PRC) and 85?±?46 % (TDSV-PRC). TLR_lung decreased when applying PRC, being this effect more remarkable for the TDSV-PRC method, with relative differences respect to no PRC: ΔTLR_lung?=???45?±?24 (TD-PRC), ??55?±?18 (TDSV-PRC). TLR_necrotic values also decreased when using PRC, with more noticeable differences for TD-PRC: ΔTLR_necrotic?=???52?±?6 (TD-PRC), ??48?±?8 (TDSV-PRC).

Conclusion

The PRC methods proposed provide a significant quantitative improvement in [⁶⁸Ga]DOTA-labeled PET/CT imaging of mice with neuroendocrine tumors, hence demonstrating that these techniques could also ameliorate the deleterious effect of the positron range in clinical PET imaging.

     

Gallium Nitrate Is Efficacious in Murine Models of Tuberculosis and Inhibits Key Bacterial Fe-Dependent Enzymes

Acquiring iron (Fe) is critical to the metabolism and growth of Mycobacterium tuberculosis. Disruption of Fe metabolism is a potential approach for novel antituberculous therapy. Gallium (Ga) has many similarities to Fe. Biological systems are often unable to distinguish Ga³⁺ from Fe³⁺. Unlike Fe³⁺, Ga³⁺ cannot be physiologically reduced to Ga²⁺. Thus, substituting Ga for Fe in the active site of enzymes may render them nonfunctional. We previously showed that Ga inhibits growth of M. tuberculosis in broth and within cultured human macrophages. We now report that Ga(NO₃)₃ shows efficacy in murine tuberculosis models. BALB/c SCID mice were infected intratracheally with M. tuberculosis, following which they received daily intraperitoneal saline, Ga(NO₃)₃, or NaNO₃. All mice receiving saline or NaNO₃ died. All Ga(NO₃)₃-treated mice survived. M. tuberculosis CFU in the lungs, liver, and spleen of the NaNO₃-treated or saline-treated mice were significantly higher than those in Ga-treated mice. When BALB/c mice were substituted for BALB/c SCID mice as a chronic (nonlethal) infection model, Ga(NO₃)₃ treatment significantly decreased lung CFU. To assess the mechanism(s) whereby Ga inhibits bacterial growth, the effect of Ga on M. tuberculosis ribonucleotide reductase (RR) (a key enzyme in DNA replication) and aconitase activities was assessed. Ga decreased M. tuberculosis RR activity by 50 to 60%, but no additional decrease in RR activity was seen at Ga concentrations that completely inhibited mycobacterial growth. Ga decreased aconitase activity by 90%. Ga(NO₃)₃ shows efficacy in murine M. tuberculosis infection and leads to a decrease in activity of Fe-dependent enzymes. Additional work is warranted to further define Ga''s mechanism of action and to optimize delivery forms for possible therapeutic uses in humans.     

Improving T1 and T2 magnetic resonance imaging contrast agents through the conjugation of an esteramide dendrimer to high‐water‐coordination Gd(III) hydroxypyridinone complexes

Commercial gadolinium magnetic resonance imaging (MRI) contrast agents are limited by low relaxivity (r₁) and coordination to only a single water molecule (q = 1). Consequently, gram quantities of these agents must be injected to obtain sufficient diagnostic contrast. In this study, MRI contrast agents for T₁ and T₂ relaxivity were synthesized using hydroxypyridinone and terephthalamide chelators with mesityl and 1,4,7‐triazacyclononane capping moieties. When covalently conjugated to a highly biocompatible esteramide dendrimer, T₂ relaxation rates up to 52 m m ^?1 s^?1 and T₁ relaxation rates up to 31 m m ^?1 s^?1 per gadolinium were observed under clinically relevant conditions. These values are believed to be brought about by using a dendritic macromolecule to decrease the molecular tumbling time of the small molecule complexes. These agents also show high aqueous solubility and low toxicity in vitro. In this study we report six new compounds: three discrete complexes and three dendrimer conjugates. Copyright © 2012 John Wiley & Sons, Ltd.     

PET/CT to detect adverse reactions to metal debris in patients with metal‐on‐metal hip arthroplasty: an exploratory prospective study

Metal‐on‐metal (MoM) bearings in total hip arthroplasties and hip resurfacing arthroplasties have recently shown a new type of complication: adverse reactions to metal debris (ARMD). ARMD is characterized by local severe inflammation and tissue necrosis leading to implant failures. The gluteal muscle region is important for the patient outcome after revision surgery. This prospective positron emission tomography/computed tomography (PET/CT) study was undertaken to evaluate the characteristics of 2‐deoxy‐2‐[¹⁸F]fluoro‐d ‐glucose ([¹⁸F]FDG) and [⁶⁸Ga]Gallium citrate ([⁶⁸Ga]Citrate) PET/CT in ARMD patients. [¹⁸F]FDG and [⁶⁸Ga]Citrate PET/CT were performed in 18 hip arthroplasty patients: 12 ARMD patients (with 16 MoM hips) and six arthroplasty controls without ARMD. Tracer uptake was evaluated visually, and maximum standardized uptake (SUV_max) was measured in the gluteal muscle region. ARMD severity was graded by metal artefact reduction sequence‐magnetic resonance imaging (MARS‐MRI). Periprosthetic [¹⁸F]FDG uptake was observed in 15 of 16 hips, [⁶⁸Ga]Citrate uptake in three of 16 hips, respectively. The distribution of tracer uptake resembled infection in three hips. In the gluteal muscle region, the SUV_max of [¹⁸F]FDG was significantly greater in hips with moderate and severe ARMD compared with the controls (P = 0·009 for [¹⁸F]FDG and P = 0·217 for [⁶⁸Ga]Citrate). In patients who needed revision surgery, an intraoperative finding of gluteal muscle necrosis was associated with increased local SUV_max as detected by preoperative [¹⁸F]FDG (P = 0·039), but not by [⁶⁸Ga]Citrate (P = 0·301). In conclusion, the inflammatory reaction to metal debris in hip arthroplasty patients is best visualized with [¹⁸F]FDG.     

Molecularly engineered electroplex emission for an efficient near-infrared light-emitting electrochemical cell (NIR-LEC)

Electroplex emission is rarely seen in ruthenium polypyridyl complexes, and there have been no reports from light-emitting electrochemical cells (LECs) to date. Here, for the first time, near-infrared (NIR) emission via the electroplex mechanism in a LEC based on a new blend of ruthenium polypyridyl complexes is described. The key factor in the design of the new complexes is the 0.4 V decrease in the oxidation half-potential of Ru(ii)/Ru(iii) in [Ru(DPCO)(bpy)₂]ClO₄ (DPCO = diphenylcarbazone, bpy = 2,2 bipyridine), which is about one-third of the value for benchmark [Ru(bpy)₃](ClO₄)₂, as well as the long lifetime of excited states of 350–450 ns. The LEC based on the new blend with a narrow band gap (≈1.0 eV) of a Ru(DPCO) complex and Ru(bpy)₃²⁺ can produce an electroluminescence spectrum centred at about 700 nm, which extends to the NIR region with a high external quantum efficiency (EQE) of 0.93% at a very low turn-on voltage of 2.6 V. In particular, the very simple LEC structure was constructed from indium tin oxide (anode)/Ru(DPCO):Ru(bpy)₃²⁺/Ga:In (cathode), avoiding any polymer or transporting materials, as well as replacing Al or Au by a molten alloy cathode. This system has promising applications in the production of LECs via microcontact or inkjet printing.

Electroplex emission is rarely seen in ruthenium polypyridyl complexes, and there have been no reports from light-emitting electrochemical cells (LECs) to date. Here, near-infrared (NIR) emission via the electroplex mechanism in a LEC was reported.     

Preliminary PET/CT Imaging with Somatostatin Analogs [<Superscript>68</Superscript>Ga]DOTAGA-TATE and [<Superscript>68</Superscript>Ga]DOTAGA-TOC

Purpose

Somatostatin receptor positron emission tomography/X-ray computed tomography (SSTR-PET/CT) is a well-established technique for staging and detection of neuroendocrine tumors (NETs). Ga-68-labeled DOTA-conjugated octreotide analogs are the privileged radiotracers for diagnosis and therapeutic monitoring of NETs. Hence, we were interested in assessing the influence of promising, newer variant DOTAGA on the hydrophilicity, pharmacokinetics, and lesion pick-up of somatostatin analogs. Herein, the potential of ([⁶⁸Ga]DOTAGA, Tyr³, Thr⁸) octreotide ([⁶⁸Ga]DOTAGA-TATE) and ([⁶⁸Ga]DOTAGA, Tyr³) octreotide ([⁶⁸Ga]DOTAGA-TOC) as NET imaging agents has been investigated.

Procedures

Amenability of [⁶⁸Ga]DOTAGA-(TATE/TOC) to kit-type formulation has been demonstrated. Biodistribution studies were carried out in normal rats at 1 h post-injection (p.i.). [⁶⁸Ga]DOTAGA-(TATE/TOC) PET/CT scans were carried out in patients (70–170 MBq, 1 h p.i.) with histologically confirmed well-differentiated NETs.

Results

[⁶⁸Ga]DOTAGA-TATE exhibited hydrophilicity similar to [⁶⁸Ga]DOTA-TATE (log P = ?3.51 vs ?3.69) whereas [⁶⁸Ga]DOTAGA-TOC was more hydrophilic than [⁶⁸Ga]DOTA-TOC (log P = ?3.27 vs ?2.93). [⁶⁸Ga]DOTAGA-TATE and [⁶⁸Ga]DOTA-TATE showed almost identical blood and kidney uptake in normal rats whereas significantly fast clearance (p < 0.05) of [⁶⁸Ga]DOTAGA-TATE was observed from other non-specific organs (liver, lungs, spleen, intestine). [⁶⁸Ga]DOTAGA-TOC also demonstrated rapid clearance from blood and kidneys (p < 0.05) in comparison to [⁶⁸Ga]DOTA-TOC. The metastatic lesions in NET patients were well identified by [⁶⁸Ga]DOTAGA-TATE and [⁶⁸Ga]DOTAGA-TOC.

Conclusion

The phenomenal analogy was observed between [⁶⁸Ga]DOTAGA-TATE and [⁶⁸Ga]DOTA-TATE as well as between [⁶⁸Ga]DOTAGA-TOC and [⁶⁸Ga]DOTA-TOC in biodistribution studies in rats. The good lesion detection ability of the two radiotracers indicates their potential as NET imaging radiotracers.