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Velaphi C Thipe,1,2 Kiandohkt Panjtan Amiri,3 Pierce Bloebaum,2,4 Alice Raphael Karikachery,2,5 Menka Khoobchandani,2,5 Kavita K Katti,2,5 Silvia S Jurisson,1,6 Kattesh V Katti2,4–71Department of Chemistry, University of Missouri, Columbia, MO 65201, USA; 2Institute of Green Nanotechnology, University of Missouri, Columbia, MO 65211, USA; 3Department of Physics, Washington University, St. Louis, MO 63130, USA; 4Department of Physics and Astronomy; 5Department of Radiology; 6University of Missouri Research Reactor, University of Missouri, Columbia, MO 65211, USA; 7Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO 65211, USABackground: As part of our continuing quest to enhance the efficacy of bioactive phytochemicals in cancer therapy, we report an innovative green nanotechnology approach toward the use of resveratrol for the production of biocompatible resveratrol-conjugated gold nanoparticles (Res-AuNPs). Our overarching aim is to exploit the inherent pro-apoptotic properties of gold nanoparticles (AuNPs) through synergistic anti-tumor characteristics of resveratrol, with the aim of developing a new class of green nanotechnology-based phytochemical-embedded AuNPs for applications in oncology.Method: Resveratrol was used to reduce Au3+, to Au0, for the synthesis of Res-AuNPs at room temperature and gum arabic (GA) was used to further encapsulate the nanoparticulate surface to increase the overall stability of the AuNPs. This comprehensive study involves the synthesis, full characterization and in vitro stability of Res-AuNPs in various biological media for their ultimate applications as anti-cancer agents against human breast (MDAMB-231), pancreatic (PANC-1) and prostate (PC-3) cancers.Results: This strategy to systematically increase the corona of resveratrol on AuNPs, in order to gain insights into the interrelationship of the phytochemical corona on the overall anti-tumor activities of Res-AuNPs, proved successful. The increased resveratrol corona on Res-AuNPs showed superior anti-cancer effects, attributed to an optimal cellular uptake after 24-hour incubation, while GA provided a protein matrix support for enhanced trans-resveratrol loading onto the surface of the AuNPs.Conclusion: The approach described in this study harnesses the benefits of nutraceuticals and nanoparticles toward the development of Res-AuNPs. We provide compelling evidence that the increased corona of resveratrol on AuNPs enhances the bioavailability of resveratrol so that therapeutically active species can be optimally available in vivo for applications in cancer therapy.Keywords: resveratrol, gold nanoparticles, nanotechnology, cancer therapy

Iron (Fe) uptake and translocation in plants are fine-tuned by complex mechanisms that are not yet fully understood. In Arabidopsis thaliana, local regulation of Fe homeostasis at the root level has been extensively studied and is better understood than the systemic shoot-to-root regulation. While the root system is solely a sink tissue that depends on photosynthates translocated from source tissues, the shoot system is a more complex tissue, where sink and source tissues occur synchronously. In this study, and to gain better insight into the Fe deficiency responses in leaves, we overexpressed Zinc/Iron-regulated transporter-like Protein (ZIP5), an Fe/Zn transporter, in phloem-loading cells (proSUC2::AtZIP5) and determined the timing of Fe deficiency responses in sink (young leaves and roots) and source tissues (leaves). Transgenic lines overexpressing ZIP5 in companion cells displayed increased sensitivity to Fe deficiency in root growth assays. Moreover, young leaves and roots (sink tissues) displayed either delayed or dampened transcriptional responses to Fe deficiency compared to wild-type (WT) plants. We also took advantage of the Arabidopsis mutant nas4x-1 to explore Fe transcriptional responses in the opposite scenario, where Fe is retained in the vasculature but in an unavailable and precipitated form. In contrast to proSUC2::AtZIP5 plants, nas4x-1 young leaves and roots displayed a robust and constitutive Fe deficiency response, while mature leaves showed a delayed and dampened Fe deficiency response compared to WT plants. Altogether, our data provide evidence suggesting that Fe sensing within leaves can also occur locally in a leaf-specific manner., (© The Author(s) 2022. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Recent progress with the production of 72 As (2.49 Mev β + max (64%), 3.33 Mev β + max (16%), 834 keV γ (81%), t 1/2 : 26 h) and 77 As (0.683 Mev β - max (97%), 239 keV γ (1.59%), t 1/2 : 38.8 h) has facilitated their evaluation as a potential "theranostic pair" for PET imaging and radiotherapy. Our 3rd generation trithiol chelate with two carboxylic acid groups was further developed as a bifunctional chelate for radioarsenic., Methods: The As complex with the trithiol chelate was synthesized and characterized. No carrier added (nca) [ 77 As][H 2 AsO 4 - ] was used for radiolabeling studies. The trithiol chelate was conjugated to the RM2 peptide ( D Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH 2 ) via solid phase peptide synthesis with two different linkers, Ser-Ser and Glu-Ser. The trithiol chelate and its RM2 bioconjugates were radiolabeled with nca 77 As, and the RM2 bioconjugates were compared in initial biodistribution studies., Results: The As diacid trithiol complex was characterized by 1 H NMR, 13 C NMR and HR-ESI-MS. The trithiol-RM2 precursor and As trithiol bioconjugates were characterized by HR-ESI-MS and/or LC-ESI-MS. Radiolabeling of the RM2 bioconjugates with 77 As resulted in over 85% radiochemical yield for [ 77 As]As-trithiol-Ser-Ser-RM2 ([ 77 As]8) and 90% for [ 77 As]As-trithiol-Glu-Ser-RM2 ([ 77 As]9). Both radiotracers demonstrated excellent in vitro stability (≥ 90% remaining intact through 24 h in PBS buffer) and were more hydrophilic than previous analogues based on log D 7.4 values. Biodistribution results of the two radiotracers in healthy CF-1 male mice demonstrated blockable pancreatic uptake at 1 h (82% for ([ 77 As]8 and 78% for [ 77 As]9) indicating specific gastrin-releasing peptide receptor (GRPR) uptake. The primary route of excretion was through the gastrointestinal system for both radiotracers., Conclusions: A new trithiol chelate with improved hydrophilicity was successfully conjugated to the RM2 peptide via two linkers, and high radiolabeling yield with nca 77 As was achieved. In vivo biodistribution studies with both radiotracers demonstrated blockable pancreatic uptake suggestive of specific receptor uptake., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The therapeutic potential of the Meitner-Auger- and conversion-electron emitting radionuclide 119 Sb remains unexplored because of the difficulty of incorporating it into biologically targeted compounds. To address this challenge, we report the development of 119 Sb production from electroplated tin cyclotron targets and its complexation by a novel trithiol chelate. The chelation reaction occurs in harsh solvent conditions even in the presence of large quantities of tin, which are necessary for production on small, low energy (16 MeV) cyclotrons. The 119 Sb-trithiol complex has high stability and can be purified by HPLC. The third generation trithiol chelate and the analogous stable nat Sb-trithiol compound were synthesized and characterized, including by single-crystal X-ray diffraction analyses.

Rhodium-105 (0.567 MeV β - , 319 keV γ, 35.4 h half-life) was produced by neutron irradiation of enriched 104 Ru (>99%) over multiple decades. A method is reported to recover the previously irradiated 104 Ru (trapped in HCl as RuO 4 2- ) as the metal. The 104 Ru was recovered in >93% yield and >98% enrichment. Neutron re-irradiation of the recycled 104 Ru produced 105 Rh, which was successfully radiolabeled with tetrathioethers in high yield. This recovery and recycling method for enriched 104 Ru makes 105 Rh production and utilization economical., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Trithiol chelates are suitable for labeling radioarsenic ( 72 As: 2.49 MeV β + , 26 h; 77 As: 0.683 MeV β - , 38.8 h) to form potential theranostic radiopharmaceuticals for positron emission tomography (PET) imaging and therapy. A trithiol(b)-(Ser) 2 -RM2 bioconjugate and its arsenic complex were synthesized and characterized. The trithiol(b)-(Ser) 2 -RM2 bioconjugate was radiolabeled with no-carrier-added 77 As in over 95% radiochemical yield and was stable for over 48 h, and in vitro IC 50 cell binding studies of [ 77 As]As-trithiol(b)-(Ser) 2 -RM2 in PC-3 cells demonstrated high affinity for the gastrin-releasing peptide (GRP) receptor (low nanomolar range). Limited biodistribution studies in normal mice were performed with HPLC purified 77 As-trithiol(b)-(Ser) 2 -RM2 demonstrating both pancreatic uptake and hepatobiliary clearance.

Introduction: With the long-term goal of developing a diagnostic ( 99m Tc) and therapeutic ( 186 Re) agent pair for targeting somatostatin receptor (SSTR)-positive neuroendocrine tumors (NETs), we developed novel metal-cyclized peptides through direct labeling of the potent SSTR2 antagonist Ac-4-NO 2 -Phe-c(DCys-Tyr-DTrp-Lys-Thr-Cys)-DTyr-NH 2 (1) with Re (in Re-1), 99m Tc (in [ 99m Tc]Tc-1) and 186 Re (in [ 186 Re]Re-1)., Methods: Re-1 was characterized by LC-ESI-MS and HR-ESI-MS and was tested for receptor affinity in SSTR-expressing cells (AR42J). Radiolabeling of the peptide was achieved via ligand exchange from 99m Tc-labeled glucoheptonate or [ 186 Re]ReOCl 3 (PPh 3 ) 2 , yielding [ 99m Tc]Tc-1 or [ 186 Re]Re-1, respectively. In vitro stability of [ 99m Tc]Tc-1/[ 186 Re]Re-1 in PBS (10 mM) at pH 7.4 and 37 °C was determined by HPLC analysis. Moreover, [ 99m Tc]Tc-1 stability was tested in cysteine (1 mM) and rat serum under the same conditions., Results: Re-1 consisted of two isomers, confirmed by LC-ESI-MS, with good SSTR2 affinity (IC 50  = 43 ± 6 nM). Optimization of the 99m Tc labeling through varying reaction parameters such as pH, reaction time, and Sn 2+ and ligand concentrations resulted in high radiochemical yield (RCY ≥92%). Similarly, [ 186 Re]Re-1 was prepared in reasonable RCY (≥50%). Both 99m Tc/ 186 Re-tracers consisted of two product isomers as identified by HPLC co-injection with Re-1. While [ 99m Tc]Tc-1 was sufficiently stable in vitro (≥71% intact through 4 h in PBS, cysteine and rat serum), [ 186 Re]Re-1 exhibited more moderate in vitro stability (58% intact after 1 h in PBS)., Conclusions: Novel 99m Tc/ 186 Re-cyclized SSTR2 antagonist peptides were synthesized and characterized using the Re-cyclized analogue as a reference. Due to the nanomolar SSTR2 affinity of Re-1 and good in vitro stability of [ 99m Tc]Tc-1, the latter shows early promise for development as a radiodiagnostic agent for SSTR-expressing NETs., Advances in Knowledge and Implications for Patient Care: The 99m Tc-cyclized complex showed promising in vitro properties, and future in vivo studies will determine the potential for translating such a design into the human clinic., Competing Interests: 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., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: The goal of this work was to develop hydrophilic gastrin-releasing peptide receptor (GRPR)-targeting complexes of the general formula fac-[M(CO) 3 (L)] + [M =  nat Re, 99m Tc, 186 Re; L: NOTA for 1, NODAGA for 2] conjugated to a powerful GRPR peptide antagonist ( D Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH 2 ) via a 6-aminohexanoic acid linker., Procedures: Metallated-peptides were prepared employing the [M(OH 2 ) 3 (CO) 3 ] + [M = Re, 99m Tc, 186 Re] precursors. Re-1/2 complexes were characterized with HR-MS. IC 50 studies were performed for peptides 1/2 and their respective Re-1/2 complexes in a binding assay utilizing GRPR-expressing human PC-3 prostate cancer cells and [ 125 I]I-Tyr 4 -BBN as the competing ligand. The 99m Tc/ 186 Re-complexes were identified by HPLC co-injection with their Re-analogues. All tracers were challenged in vitro at 37 °C against cysteine/histidine (phosphate-buffered saline 10 mM, pH 7.4) and rat serum. Biodistribution and micro-SPECT/CT imaging of [ 99m Tc]Tc-1/2 and [ 186 Re]Re-2 were performed in PC-3 tumor-bearing ICR SCID mice., Results: High in vitro receptor affinity (IC 50 2-3 nM) was demonstrated for all compounds. The 99m Tc/ 186 Re-tracers were found to be hydrophilic (log D 7.4  ≤ - 1.35) and highly stable. Biodistribution in PC-3 xenografted mice revealed good tumor uptake (%ID/g at 1 h: 4.3 ± 0.7 for [ 99m Tc]Tc-1, 8.3 ± 0.9 for [ 99m Tc]Tc-2 and 4.2 ± 0.8 for [ 186 Re]Re-2) with moderate retention over 24 h. Rapid renal clearance was observed for [ 99m Tc]Tc-2 and [ 186 Re]Re-2 (> 84 % at 4 h), indicating favorable pharmacokinetics. Micro-SPECT/CT images for the 99m Tc-tracers clearly visualized PC-3 tumors in agreement with the biodistribution data and with superior imaging properties found for [ 99m Tc]Tc-2., Conclusions: [ 99m Tc]Tc-2 shows promise for further development as a GRPR-imaging agent. [ 186 Re]Re-2 demonstrated very similar in vivo behavior to [ 99m Tc]Tc-2, and further studies are therefore justified to explore the theranostic potential of our approach for targeting of GRPR-positive cancers.

Complexes of the type trans-[Re(PR 3 ) 2 (Schiff base)] + (R = ethyl and/or phenyl) 2-7 were prepared by the reaction of (nBu 4 N)[ReOCl 4 ] with H 2 sal 2 en or H 2 sal 2 ibn followed by addition of a tertiary phosphine. The trans-[Re(PR 3 ) 2 (sal 2 en)] + complexes 2-4 were stable in solution, whereas the trans-[Re(PR 3 ) 2 (sal 2 ibn)] + complexes 6-7 were observed to convert to their corresponding cis-[ReO(PR 3 )(sal 2 ibn)] + products through a process involving ligand dissociation, metal oxidation, and Schiff base ligand rearrangement. The conversion of the trans-[Re(PR 3 ) 2 (sal 2 ibn)] + complexes is likely driven by steric interactions between the bulky backbone gem-dimethyl groups of the sal 2 ibn ligand and the phosphine ligands. These complexes were isolated and characterized by 1 H and 13 C NMR, FT-IR spectroscopy, cyclic voltammetry, and single crystal X-ray diffraction. The results reported herein provide insight into the factors that drive trans-[Re(PR 3 ) 2 (Schiff base)] + complex formation. This will aid in the development of novel 186/188 Re therapeutic agents and the design of novel bifunctional N 2 O 2 Schiff base ligands.

Introduction: The aim of this work was to develop diagnostic ( 99m Tc) and therapeutic ( 186 Re) agents for targeting somatostatin receptor (SSTR)-positive neuroendocrine tumors (NETs). In this regard, we evaluated in vitro complexes of the general formula [M(CO) 3 (L-sst 2 -ANT)] (M =  99m Tc, 186 Re), where L denotes NODAGA or NOTA and sst 2 -ANT denotes the potent SSTR2 antagonist 4-NO 2 -Phe-c(DCys-Tyr-DTrp-Lys-Thr-Cys)-DTyr-NH 2 . Moreover, we assessed the in vivo properties of the 99m Tc-complexes in an animal SSTR-tumor model., Methods: The [ 99m Tc]/[ 186 Re][Tc/Re(OH 2 ) 3 (CO) 3 ] + precursors were utilized to prepare the 99m Tc/ 186 Re-complexes, which were identified by HPLC co-injection with their nat Re analogues. The tracers were challenged in vitro at 37 °C against cysteine and histidine in phosphate-buffered saline (pH 7.4) and in rat serum. Biodistribution and micro-SPECT/CT imaging studies of the 99m Tc-tracers were performed in AR42J tumor-bearing female ICR SCID mice., Results: The 99m Tc-complexes were prepared in high radiochemical yield (RCY > 90%, by HPLC), with lower RCY (≤30%) obtained for 186 Re-complexes. Tracers remained intact in vitro and displayed low non-specific binding (10-25%) to rat serum proteins. Biodistribution of [ 99m Tc]Tc-NODAGA-sst 2 -ANT revealed low tumor uptake (2.78 ± 0.27 %ID/g) at 1 h, while high tumor uptake (16.70 ± 3.32 %ID/g) was found for [ 99m Tc]Tc-NOTA-sst 2 -ANT. Moderate to low tumor retention was observed for both tracers after 4 and 24 h. Tumor uptake for [ 99m Tc]Tc-NOTA-sst 2 -ANT was receptor-mediated, as demonstrated by parallel SSTR blocking studies. Rapid renal clearance was observed for both tracers, and SPECT/CT images clearly delineated the tumors, in agreement with the biodistribution data., Conclusions: The [ 99m Tc]Tc-NOTA-sst 2 -ANT complex demonstrated high tumor uptake and rapid clearance in a SSTR-tumor mouse model, showing potential for further development., Advances in Knowledge and Implications for Patient Care: Preclinical data support the feasibility of the [ 99m Tc]Tc/[ 186 Re]Re-NOTA/NODAGA labeling strategy for use in the development of theranostic radiopharmaceuticals for translation into the human clinic for targeting of SSTR-expressing NETs., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The somatostatin receptor subtype 2 (SSTR2) is often highly expressed on neuroendocrine tumors (NETs), making it a popular in vivo target for diagnostic and therapeutic approaches aimed toward management of NETs. In this work, an antagonist peptide (sst 2 -ANT) with high affinity for SSTR2 was modified at the N-terminus with a novel [N,S,O] bifunctional chelator (2) designed for tridentate chelation of rhenium(I) and technetium(I) tricarbonyl cores, [Re(CO) 3 ] + and [ 99m Tc][Tc(CO) 3 ] + . The chelator-peptide conjugation was performed via a Cu(I)-assisted click reaction of the alkyne-bearing chelator (2) with an azide-functionalized sst 2 -ANT peptide (3), to yield NSO-sst 2 -ANT (4). Two synthetic methods were used to prepare Re-4 at the macroscopic scale, which differed based on the relative timing of the click conjugation to the [Re(CO) 3 ] + complexation by 2. The resulting products demonstrated the expected molecular mass and nanomolar in vitro SSTR2 affinity (IC 50 values under 30 nM, AR42J cells, [ 125 I]iodo-Tyr 11 -somatostatin-14 radioligand standard). However, a difference in their HPLC retention times suggested a difference in metal coordination modes, which was attributed to a competing N-triazole donor ligand formed during click conjugation. Surprisingly, the radiotracer scale reaction of [ 99m Tc][Tc(OH 2 ) 3 (CO) 3 ] + ( 99m Tc; t ½  = 6 h, 141 keV γ) with 4 formed a third product, distinct from the Re analogues, making this one of the unusual cases in which Re and Tc chemistries are not well matched. Nevertheless, the [ 99m Tc]Tc-4 product demonstrated excellent in vitro stability to challenges by cysteine and histidine (≥98% intact through 24 h), along with 75% stability in mouse serum through 4 h. In vivo biodistribution and microSPECT/CT imaging studies performed in AR42J tumor-bearing mice revealed improved clearance of this radiotracer in comparison to a similar [ 99m Tc][Tc(CO) 3 ]-labeled sst 2 -ANT derivative previously studied. Yet despite having adequate tumor uptake at 1 h (4.9% ID/g), tumor uptake was not blocked by co-administration of a receptor-saturating dose of SS-14. Aimed toward realignment of the Re and Tc product structures, future efforts should include distancing the alkyne group from the intended donor atoms of the chelator, to reduce the coordination options available to the [M(CO) 3 ] + core (M = Re, 99m Tc) by disfavoring involvement of the N-triazole., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Positron-emitting 72 As is the PET imaging counterpart for beta-emitting 77 As. Its parent, no carrier added (n.c.a.) 72 Se, was produced for a 72 Se/ 72 As generator by irradiating an enriched 7 °Ge metal-graphite target via the 70 Ge(α, 2 n) 72 Se reaction. Target dissolution used a fast, environmentally friendly method with 93% radioactivity recovery. Chromatographic parameters of the 72 Se/ 72 As generator were evaluated, the eluted n.c.a. 72 As was characterized with a phantom imaging study, and the previously reported trithiol and aryl-dithiol ligand systems were radiolabeled with the separated n.c.a. 72 As in high yield., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

With the long-term goal of developing theranostic agents for applications in nuclear medicine, in this work we evaluated the well-known NOTA and NODAGA chelators as bifunctional chelators (BFCs) for the [ 99m Tc/ 186 Re]Tc/Re-tricarbonyl core. In particular, we report model complexes of the general formula fac-[M(L)(CO) 3 ] + (M = Re, 99m Tc, 186 Re) where L denotes NOTA-Pyr (1) or NODAGA-Pyr (2), which are derived from conjugation of NOTA/NODAGA with pyrrolidine (Pyr). Further, as proof-of-principle, we synthesized the peptide bioconjugate NODAGA-sst 2 -ANT (3) and explored its complexation with the fac-[Re(CO) 3 ] + and fac-[ 99m Tc][Tc(CO) 3 ] + cores; sst 2 -ANT denotes the somatostatin receptor (SSTR) antagonist 4-NO 2 -Phe-c(DCys-Tyr-DTrp-Lys-Thr-Cys)-DTyr-NH 2 . Rhenium complexes Re-1 through Re-3 were synthesized and characterized spectroscopically, and receptor binding affinity was demonstrated for Re-3 in SSTR-expressing cells (AR42J, IC 50 = 91 nM). Radiolabeled complexes [ 99m Tc]Tc/[ 186 Re]Re-1/2 and [ 99m Tc]Tc-3 were prepared in high radiochemical yield (>90%, determined by radio-HPLC) by reacting [ 99m Tc]/[ 186 Re][Tc/Re(OH 2 ) 3 (CO) 3 ] + with 1-3 and correlated well with the respective Re-1 through Re-3 standards in comparative HPLC studies. All radiotracers remained intact through 24 h ( 99m Tc-labeled complexes) or 48 h ( 186 Re-labeled complexes) against 1 mM l-histidine and 1 mM l-cysteine (pH 7.4, 37 °C). Similarly, rat serum stability studies displayed no decomposition and low nonspecific binding of 9-24% through 4 h. Biodistribution of [ 99m Tc]Tc-3 in healthy CF-1 mice demonstrated a favorable pharmacokinetic profile. Rapid clearance was observed within 1 h post-injection, predominantly via the renal system (82% of the injected dose was excreted in urine by 1 h), with low kidney retention (% ID/g: 11 at 1 h, 5 at 4 h, and 1 at 24 h) and low nonspecific uptake in other organs/tissues. Our findings establish NOTA and NODAGA as outstanding BFCs for the fac-[M(CO) 3 ] + core in the design and development of organometallic radiopharmaceuticals. Future in vivo studies of [ 99m Tc]Tc- and [ 186 Re]Re-tricarbonyl complexes of NODAGA/NOTA-biomolecule conjugates will further probe the potential of these chelates for nuclear medicine applications in diagnostic imaging and targeted radiotherapy, respectively.

Rhenium, the third-row congener of technetium, is often used to develop the macroscopic chemistry of potential 99m Tc diagnostic radiopharmaceuticals. The rhenium analogues to 99m Tc-furifosmin are being developed for potential radiotherapy of multidrug-resistant tumors. Complexes of the form trans-[M III (PR 3 ) 2 (N 2 O 2 -Schiff base)] + are of interest for the potential imaging and treatment of multidrug-resistant tumors. Reaction of the tetradentate Schiff ligand 4,4'-[(1 E,1' E)-[ethane-1,2-diylbis(azanylylidene)]bis(methanylylidene)]bis(2,2,5,5-tetramethyl-2,5-dihydrofuran-3-ol) (tmf 2 enH 2 ) with the M(V) starting materials ( nBu 4 N)[TcOCl 4 ] and ( nBu 4 N)[ReOCl 4 ] gave the monomeric products trans-[TcOCl(tmf 2 en)] and trans-[ReOCl(tmf 2 en)], respectively. Reduction of in situ formed trans-[ReOCl(tmf 2 en)] by various tertiary phosphines yielded disubstitued Re(III) products of the general type trans-[Re III (PR 3 ) 2 (tmf 2 en)] + . The rhenium(III) compounds were found to be water-soluble and stable in aqueous solution. Reversible Re III /Re IV and Re III /Re II redox processes were observed at about 0.8-0.9 and -0.65 to -0.8 V, respectively, for each of the rhenium(III) species. Reaction of in situ formed trans-TcOCl(tmf 2 en) with triethylphosphine yielded the reduced, disubstituted trans-[Tc(PEt 3 ) 2 (tmf 2 en)]PF 6 . A reversible Tc III /Tc II redox couple was observed for the technetium(III) species, about 200 mV less negative than their rhenium(III) analogues, in addition to an irreversible Tc III /Tc IV process. All compounds were characterized using conventional spectroscopic techniques, single-crystal X-ray crystallography, and cyclic voltammetry.

The OLIGOPEPTIDE TRANSPORTER 3 (OPT3) has recently been identified as a component of the systemic network mediating iron (Fe) deficiency responses in Arabidopsis. Reduced expression of OPT3 induces an over accumulation of Fe in roots and leaves, due in part by an elevated expression of the IRON-REGULATED TRANSPORTER 1. Here we show however, that opt3 leaves display a transcriptional program consistent with an Fe overload, suggesting that Fe excess is properly sensed in opt3 leaves and that the OPT3-mediated shoot-to-root signaling is critical to prevent a systemic Fe overload. We also took advantage of the tissue-specific localization of OPT3, together with other Fe-responsive genes, to determine the timing and location of early transcriptional events during Fe limitation and resupply. Our results show that the leaf vasculature responds more rapidly than roots to both Fe deprivation and resupply, suggesting that the leaf vasculature is within the first tissues that sense and respond to changes in Fe availability. Our data highlight the importance of the leaf vasculature in Fe homeostasis by sensing changes in apoplastic levels of Fe coming through the xylem and relaying this information back to roots via the phloem to regulate Fe uptake at the root level., (© 2018 John Wiley & Sons Ltd.)

Introduction: Trithiol chelates are suitable for labeling radioarsenic ( 72 As: 2.49 MeV β + , 26 h; 77 As: 0.683 MeV β - , 38.8 h) to form potential theranostic radiopharmaceuticals for PET imaging and therapy. To investigate the in vivo stability of trithiol chelates complexed with no carrier added (nca) radioarsenic, a bifunctional trithiol chelate was developed, and conjugated to bombesin(7-14)NH 2 as a model peptide., Methods: A trithiol-BBN(7-14)NH 2 bioconjugate and its arsenic complex were synthesized and characterized. The trithiol-BBN(7-14)NH 2 conjugate was radiolabeled with 77 As, its in vitro stability assessed, and biodistribution studies were performed in CF-1 normal mice of free [ 77 As]arsenate and 77 As-trithiol- BBN(7-14)NH 2 ., Results: The trithiol-BBN(7-14)NH 2 conjugate, its precursors and its As-trithiol-BBN(7-14)NH 2 complex were fully characterized. Radiolabeling studies with nca 77 As resulted in over 90% radiochemical yield of 77 As-trithiol-BBN, which was stable for over 48 h. Biodistribution studies were performed with both free [ 77 As]arsenate and Sep-Pak® purified 77 As-trithiol-BBN(7-14)NH 2 . Compared to the fast renal clearance of free [ 77 As]arsenate, 77 As-trithiol-BBN(7-14)NH 2 demonstrated increased retention with clearance mainly through the hepatobiliary system, consistent with the lipophilicity of the 77 As-trithiol-BBN(714)NH 2 complex., Conclusion: The combined in vitro stability of 77 As-trithiol-BBN(7-14)NH 2 and the biodistribution results demonstrate its high in vivo stability, making the trithiol a promising platform for developing radioarsenic-based theranostic radiopharmaceuticals., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Technetium-99 ( 99 Tc) is important to the nuclear fuel cycle as a long-lived radionuclide produced in ∼6% fission yield from 235 U or 239 Pu. In its most common chemical form, namely, pertechnetate ( 99 TcO 4 - ), it is environmentally mobile. In situ hydrogen sulfide reduction of pertechnetate has been proposed as a potential method to immobilize environmental 99 TcO 4 - that has entered the environment. Reactions of 99 TcO 4 - with sulfide in solution result in the precipitation of Tc 2 S 7 except when olefinic acids, specifically fumaric or maleic acid, are present; a water-soluble 99 Tc species forms. NMR ( 1 H, 13 C, and 2D methods) and X-ray absorption spectroscopy [XAS; near-edge (XANES) and extended fine structure (EXAFS)] studies indicate that sulfide adds across the olefinic bond to generate mercaptosuccinic acid (H 3 MSA) and/or dimercaptosuccinic acid (H 4 DMSA), which then chelate(s) the 99 Tc to form [ 99 TcO(MSA) 2 ] 3- , [ 99 TcO(DMSA) 2 ] 5- , or potentially [ 99 TcO(MSA)(DMSA)] 4- . 2D NMR methods allowed identification of the products by comparison to 99 Tc and nonradioactive rhenium standards. The rhenium standards allowed further identification by electrospray ionization mass spectrometry. 99 TcO 4 - is essential to the reaction because no sulfide addition occurs in its absence, as determined by NMR. Computational studies were performed to investigate the structures and stabilities of the potential products. Because olefinic acid is a component of the naturally occurring humic and fulvic acids found in soils and groundwater, the viability of in situ hydrogen sulfide reduction of environmental 99 TcO 4 - as an immobilization method is evaluated.

The chemistry and radiochemistry of high specific activity radioisotopes of arsenic, rhenium and rhodium are reviewed with emphasis on University of Missouri activities over the past several decades, and includes recent results. The nuclear facilities at the University of Missouri (10 MW research reactor and 16.5 MeV GE PETtrace cyclotron) allow research and development into novel theranostic radionuclides. The production, separation, enriched target recovery, radiochemistry, and chelation chemistry of 72,77 As, 186,188 Re and 105 Rh are discussed.

Introduction: Rhenium-186g (t 1/2 = 3.72 d) is a β - emitting isotope suitable for theranostic applications. Current production methods rely on reactor production by way of the reaction 185 Re(n,γ) 186g Re, which results in low specific activities limiting its use for cancer therapy. Production via charged particle activation of enriched 186 W results in a 186g Re product with a higher specific activity, allowing it to be used more broadly for targeted radiotherapy applications. This targets the unmet clinical need for more efficient radiotherapeutics., Methods: A target consisting of highly enriched, pressed 186 WO 3 was irradiated with protons at the Los Alamos National Laboratory Isotope Production Facility (LANL-IPF) to evaluate 186g Re product yield and quality. LANL-IPF was operated in a dedicated nominal 40 MeV mode. Alkaline dissolution followed by anion exchange chromatography was used to isolate 186g Re from the target material. Phantom and radiolabeling studies were conducted with the produced 186g Re activity., Results: A 186g Re batch yield of 1.38 ± 0.09 MBq/μAh or 384.9 ± 27.3 MBq/C was obtained after 16.5 h in a 205 μA average/230μA maximum current proton beam. The chemical recovery yield was 93% and radiolabeling was achieved with efficiencies ranging from 60-80%. True specific activity of 186g Re at EOB was determined via ICP-AES and amounted to 0.788 ± 0.089 GBq/μg (0.146 ± 0.017 GBq/nmol), which is approximately seven times higher than the product obtained from neutron capture in a reactor. Phantom studies show similar imaging quality to the gold standard 99m Tc., Conclusions: We report a preliminary study of the large-scale production and novel anion exchange based chemical recovery of high specific activity 186g Re from enriched 186 WO 3 targets in a high-intensity proton beam with exceptional chemical recovery and radiochemical purity., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Sucrose transporter (SUT) proteins translocate sucrose across cell membranes; however, mechanistic aspects of sucrose binding by SUTs are not well resolved. Specific hydroxyl groups in sucrose participate in hydrogen bonding with SUT proteins. We previously reported that substituting a radioactive fluorine-18 [ 18 F] at the C-6' position within the fructosyl moiety of sucrose did not affect sucrose transport by the maize (Zea mays) ZmSUT1 protein. To determine how 18 F substitution of hydroxyl groups at two other positions within sucrose, the C-1' in the fructosyl moiety or the C-6 in the glucosyl moiety, impact sucrose transport, we synthesized 1'-[F 18 ]fluoro-1'-deoxysucrose and 6-[F 18 ]fluoro-6-deoxysucrose ([ 18 F]FDS) analogs. Each [ 18 F]FDS derivative was independently introduced into wild-type or sut1 mutant plants, which are defective in sucrose phloem loading. All three (1'-, 6'-, and 6-) [ 18 F]FDS derivatives were efficiently and equally translocated, similarly to carbon-14 [ 14 C]-labeled sucrose. Hence, individually replacing the hydroxyl groups at these positions within sucrose does not interfere with substrate recognition, binding, or membrane transport processes, and hydroxyl groups at these three positions are not essential for hydrogen bonding between sucrose and ZmSUT1. [ 18 F]FDS imaging afforded several advantages compared to [ 14 C]-sucrose detection. We calculated that 1'-[ 18 F]FDS was transported at approximately a rate of 0.90 ± 0.15 m.h-1 in wild-type leaves, and at 0.68 ± 0.25 m.h-1 in sut1 mutant leaves. Collectively, our data indicated that [ 18 F]FDS analogs are valuable tools to probe sucrose-SUT interactions and to monitor sucrose transport in plants., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Introduction: A somatostatin receptor (SSTR)-targeting antagonist peptide (sst 2 -ANT) was radiolabeled with 99m Tc tricarbonyl via a tridentate [N,S,N]-type ligand (L) to develop a radiodiagnostic agent, 99m TcL-sst 2 -ANT, for imaging of SSTR-expressing neuroendocrine tumors., Methods: Receptor affinity was assessed in vitro with the nonradioactive analogue, ReL-sst 2 -ANT, via a challenge experiment in AR42J cells with 125 I-SS-14 as the competing radioligand. Preparation of 99m TcL-sst 2 -ANT was achieved via reaction of [ 99m Tc(CO) 3 (H 2 O) 3 ] + with L-sst 2 -ANT. To test the stability of the radiolabeled complex, challenge experiments were performed in phosphate-buffered saline solutions containing cysteine or histidine and also in mouse serum. Biodistribution and micro-SPECT/CT imaging studies were performed in AR42J tumor-bearing female ICR SCID mice., Results: The half maximal inhibitory concentration (IC 50 value) of ReL-sst 2 -ANT in AR42J cells was 15nM. Preparation of 99m TcL-sst 2 -ANT was achieved with ≥97% radiochemical yield (RCY) and was verified by HPLC co-elution with the ReL-sst 2 -ANT analogue. The radiolabeled complex remained intact for up to 24h in high concentration solutions of cysteine and histidine at 37°C. Furthermore, the radiotracer was 90% stable for 1h at 37°C in mouse serum. Micro-SPECT/CT images showed clear uptake in tumors and were supported by the biodistribution data, in which the 3.2% ID/g tumor uptake at 4h was significantly blocked by co-administration of nonradioactive SS-14., Conclusions: A [ 99m Tc(CO) 3 (N,S,N)] + chelate was employed for radiolabeling of an SSTR-targeting antagonist peptide. Synthesis of 99m TcL-sst 2 -ANT was achieved in high RCY, and the resulting complex displayed high in vitro stability. Somatostatin receptor affinity was retained in both cells and in tumor-bearing mice, where the complex successfully targeted SSTR-positive tumors via a receptor-mediated process. Advances in Knowledge and Implications for Patient Care. This first 99m Tc-tricarbonyl-labeled SSTR antagonist peptide showed promising in vivo tumor targeting in mice. Future studies may lead to translation of a similar design into the clinic., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Introduction: Targeted radiotherapy using the bifunctional chelate approach with 186/188 Re(V) is challenging because of the susceptibility of monooxorhenium(V)-based complexes to oxidize in vivo at high dilution. A monoamine-monoamide dithiol (MAMA)-based bifunctional chelating agent was evaluated with both rhenium and technetium to determine its utility for in vivo applications., Methods: A 222-MAMA chelator, 222-MAMA(N-6-Ahx-OEt) bifunctional chelator, and 222-MAMA(N-6-Ahx-BBN(7-14)NH 2 ) were synthesized, complexed with rhenium, radiolabeled with 99m Tc and 186 Re (carrier added and no carrier added), and evaluated in initial biological distribution studies., Results: An IC 50 value of 2.0±0.7nM for nat ReO-222-MAMA(N-6-Ahx-BBN(7-14)NH 2 ) compared to [ 125 I]-Tyr 4 -BBN(NH 2 ) was determined through competitive cell binding assays with PC-3 tumor cells. In vivo evaluation of the no-carrier added 99m Tc-222-N 2 S 2 (N-6-Ahx-BBN(7-14)NH 2 ) complex showed little gastric uptake and blockable pancreatic uptake in normal mice., Conclusions: The 186 ReO-222-N 2 S 2 (N-6-Ahx-BBN(7-14)NH 2 ) complex showed stability in biological media, which indicates that the 222-N 2 S 2 chelator is appropriate for chelating 186/188 Re in radiopharmaceuticals involving peptides. Additionally, the in vitro cell studies showed that the ReO-222-N 2 S 2 (N-6-Ahx-BBN(7-14)NH 2 ) complex (macroscopically) bound to PC3-tumor cell surface receptors with high affinity. The 99m Tc analog was stable in vivo and exhibited pancreatic uptake in mice that was blockable, indicating BB2r targeting., (Copyright © 2016 Elsevier Inc. All rights reserved.)

This investigation evaluated target fabrication and beam parameters for scale-up production of high specific activity (186)Re using deuteron irradiation of enriched (186)W via the (186)W(d,2n)(186)Re reaction. Thick W and WO3 targets were prepared, characterized and evaluated in deuteron irradiations. Full-thickness targets, as determined using SRIM, were prepared by uniaxially pressing powdered natural abundance W and WO3, or 96.86% enriched (186)W, into Al target supports. Alternatively, thick targets were prepared by pressing (186)W between two layers of graphite powder or by placing pre-sintered (1105°C, 12h) natural abundance WO3 pellets into an Al target support. Assessments of structural integrity were made on each target prepared. Prior to irradiation, material composition analyses were conducted using SEM, XRD, and Raman spectroscopy. Within a minimum of 24h post irradiation, gamma-ray spectroscopy was performed on all targets to assess production yields and radionuclidic byproducts. Problems were encountered with the structural integrity of some pressed W and WO3 pellets before and during irradiation, and target material characterization results could be correlated with the structural integrity of the pressed target pellets. Under the conditions studied, the findings suggest that all WO3 targets prepared and studied were unacceptable. By contrast, (186)W metal was found to be a viable target material for (186)Re production. Thick targets prepared with powdered (186)W pressed between layers of graphite provided a particularly robust target configuration., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Arsenic-72 ((72)As) and (77)As have nuclear properties useful for positron emission tomography (PET) and radiotherapy, respectively. The thiophilic nature of arsenic led to the evaluation of dithioarylarsines for potential use in radiopharmaceuticals. Several dithioarylarsines were synthesized from their arylarsonic acids and dithiols and were fully characterized by NMR, ESI-MS, and X-ray crystallography. This chemistry was translated to the no-carrier-added (nca) (77)As level. Because arsenic was available at the nca nanomolar level only as [(77)As]arsenate, this required addition of an aryl group directly to the As to form the [(77)As]arylarsonic acid. The [(77)As]arsenate was reduced from (77)As (V) to (77)As (III), and a modified Bart reaction was used to incorporate the aryl ring onto the (77)As, which was followed by dithiol addition. Various modifications and optimizations resulted in 95% radiochemical yield of nca [(77)As]p-ethoxyphenyl-1,2-ethanedithiolatoarsine.

Novel, natural abundance metal disulfide targets were irradiated for 1h with a 10µA proton beam in a small, medical cyclotron. Osmium disulfide was synthesized by simple distillation and precipitation methods while MoS2 and WS2 were commercially available. The targets dissolved under mild conditions and were analyzed by γ-spectroscopy. Production rates and potential applications are discussed, including target recovery and recycling schemes for OsS2 and WS2., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Similarity between the Ga(+) ion and the Fe(3+) ion allows for partial replacement of Fe(3+) ions with Ga(3+) ions in the Fe(iii) crystallographic positions in Prussian blue (PB) to form various solid solutions KGaxFe1-x[Fe(CN)6] (0 < x < 1). Such solid solutions possess very high thermodynamic stability as expected from the parent PB structure. Consequently, a simple one-step (68)Ga-labeling method was developed for preparing a single-phase nanoparticulate bimodal PET/MRI imaging agent based on the PB structural platform. Unlike the typical (68)Ga-labelling reaction based on metal complexation, this novel chelator-free (68)Ga-labeling reaction was shown to be kinetically fast under the acidic conditions. The Ga(3+) ion does not hydrolyze, and affords the (68)Ga-labelled PB nanoparticles, which are easy to purify and have extremely high stability against radionuclidic leaching in aqueous solution.

Introduction: Arsenic-72 ((72)As; 2.49MeV β(+), 26h) and (77)As (0.683MeV β(-), 38.8h) have nuclear properties useful for positron emission tomography (PET) and radiotherapy applications, respectively. Their half-lives are sufficiently long for targeting tumors with antibodies, as well as peptides. Potential radiopharmaceuticals based on radioarsenic require development of suitable bifunctional chelates for stable conjugation of arsenic to vectors under in vivo conditions at high dilution., Methods: The thiophilic nature of arsenic led to the synthesis and characterization of a simple trithiol ligand and its arsenic complex, and radiolabeling studies at the no carrier added (NCA) (77)As level., Results: (1)H- and (13)C-NMR spectroscopy, electrospray ionization mass spectrometry (ESI-MS), and single crystal X-ray diffraction were used to characterize the trithiol ligand and its arsenic(III) complex. Radiotracer studies with no carrier added (NCA) (77)As resulted in high radiolabeling yields (>96%) with high in vitro stability., Conclusions: The high yield and stability of a single NCA (77)As trithiol complex indicates that this framework is suitable for developing matched pair agents for non-invasive in vivo PET imaging and radiotherapy of tumors with (72,77)As. This is the first reported chelate developed for NCA radioarsenic and studies are underway for developing a trithiol bifunctional chelate conjugated to a targeting vector, such as a peptide or monoclonal antibody., (Copyright © 2016 Elsevier Inc. All rights reserved.)

A simple column chromatographic method was developed to isolate (77)As (94±6% (EtOH/HCl); 74±11 (MeOH)) from germanium for potential use in radioimmunotherapy. The separation of arsenic from germanium was based on their relative affinities for different chromatographic materials in aqueous and organic environments. Using an organic or mixed mobile phase, germanium was selectively retained on a silica gel column as germanate, while arsenic was eluted from the column as arsenate. Subsequently, enriched (76)Ge (98±2) was recovered for reuse by elution with aqueous solution (neutral to basic). Greater than 98% radiolabeling yield of a (77)As-trithiol was observed from methanol separated [(77)As]arsenate [17]., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Radiolabeled proteolytic degradation-resistant somatostatin analogues have been of long-standing interest as cancer imaging and radiotherapy agents for targeting somatostatin receptor-positive tumors. Our interest in developing (186)Re- and (188)Re-based therapeutic radiopharmaceuticals led to investigation of a new Re(V)-cyclized octreotide analogue, Re(V)-cyclized, thiolated-DPhe(1)-Cys(2)-Tyr(3)-DTrp(4)-Lys(5)-Thr(6)-Cys(7)-Thr(OH)(8) (Re-SDPhe-TATE) using both experimental and quantum chemical methods. The metal is directly coordinated to SDPhe-TATE through cyclization of the peptide around the [ReO](3+) core. Upon complexation, four isomers were observed; the isolated/semi-isolated isomers exhibited different somatostatin receptor (sstr) binding affinities, 0.13 to 1.5 μM, in rat pancreatic tumor cells. Two-dimensional NMR experiments and electronic structure calculations were employed to elucidate the structural differences among the different isomers. According to NMR studies, the metal is coordinated to three thiolates and the backbone amide of Cys(2) in isomers 1 and 4, whereas the metal is coordinated to three thiolates and the backbone amide of Tyr(3) in isomer 2. Quantum chemical methods clarified the stereochemistry of Re-SDPhe-TATE and the possible peptide arrangements around the [ReO](3+) core. The re-cyclization reaction was translated to the (99m)Tc radiotracer level with four isomers observed on complexation with comparable HPLC retention times as the Re-SDPhe-TATE isomers. About 85% total (99m)Tc labeling yield was achieved by ligand exchange from (99m)Tc-glucoheptonate at 60 °C for an hour. About 100% and 51% of (99m)Tc(V)-cyclized SDPhe-TATE remained intact in phosphate buffered saline and 1 mM cysteine solution under physiological conditions at 6 h, respectively.

Sugars produced from photosynthesis in leaves are transported through the phloem tissues within veins and delivered to non-photosynthetic organs, such as roots, stems, flowers, and seeds, to support their growth and/or storage of carbohydrates. However, because the phloem is located internally within the veins, it is difficult to access and to study the dynamics of sugar transport. Radioactive tracers have been extensively used to study vascular transport in plants and have provided great insights into transport dynamics. To better study sucrose partitioning in vivo, a novel radioactive analog of sucrose was synthesized through a completely chemical synthesis route by substituting fluorine-18 (half-life 110 min) at the 6' position to generate 6'-deoxy-6'[(18)F]fluorosucrose ((18)FS). This radiotracer was then used to compare sucrose transport between wild-type maize plants and mutant plants lacking the Sucrose transporter1 (Sut1) gene, which has been shown to function in sucrose phloem loading. Our results demonstrate that (18)FS is transported in vivo, with the wild-type plants showing a greater rate of transport down the leaf blade than the sut1 mutant plants. A similar transport pattern was also observed for universally labeled [U-(14)C]sucrose ([U-(14)C]suc). Our findings support the proposed sucrose phloem loading function of the Sut1 gene in maize, and additionally demonstrate that the (18)FS analog is a valuable, new tool that offers imaging advantages over [U-(14)C]suc for studying phloem transport in plants.

Plants and seeds are the main dietary sources of zinc, iron, manganese, and copper, but are also the main entry point for toxic elements such as cadmium into the food chain. We report here that an Arabidopsis oligopeptide transporter mutant, opt3-2, over-accumulates cadmium (Cd) in seeds and roots but, unexpectedly, under-accumulates Cd in leaves. The cadmium distribution in opt3-2 differs from iron, zinc, and manganese, suggesting a metal-specific mechanism for metal partitioning within the plant. The opt3-2 mutant constitutively up-regulates the Fe/Zn/Cd transporter IRT1 and FRO2 in roots, indicative of an iron-deficiency response. No genetic mutants that impair the shoot-to-root signaling of iron status in leaves have been identified. Interestingly, shoot-specific expression of OPT3 rescues the Cd sensitivity and complements the aberrant expression of IRT1 in opt3-2 roots, suggesting that OPT3 is required to relay the iron status from leaves to roots. OPT3 expression was found in the vasculature with preferential expression in the phloem at the plasma membrane. Using radioisotope experiments, we found that mobilization of Fe from leaves is severely affected in opt3-2, suggesting that Fe mobilization out of leaves is required for proper trace-metal homeostasis. When expressed in yeast, OPT3 does not localize to the plasma membrane, precluding the identification of the OPT3 substrate. Our in planta results show that OPT3 is important for leaf phloem-loading of iron and plays a key role regulating Fe, Zn, and Cd distribution within the plant. Furthermore, ferric chelate reductase activity analyses provide evidence that iron is not the sole signal transferred from leaves to roots in leaf iron status signaling., (© The Author 2014. Published by Oxford University Press on behalf of CSPB and IPPE, SIBS, CAS.)

An anion exchange method was developed to separate selenium and arsenic for potential utility in a (72)Se/(72)As generator. The separation of the daughter (72)As from the (72)Se parent is based on the relative acid-base behavior of the two oxo-anions in their highest oxidation states. At pH 1.5, selenate is retained on strongly basic anion exchange resin as HSeO4(-) and SeO4(2-), while neutral arsenic acid, H3AsO4, is eluted., (Copyright © 2014 Elsevier B.V. All rights reserved.)

A laboratory discussion worksheet and its answer key provide instructors and students a discussion model to further the students' understanding of chemical kinetics. This discussion worksheet includes a section for students to augment their previous knowledge about chemical kinetics measurements, an initial check on students' understanding of basic concepts, a group participation model where students work on solving complex-conceptual problems, and a conclusion to help students connect this discussion to their laboratory or lecture class. Additionally, the worksheet has a detailed solution to a more advanced problem to help students understand how the concepts they have put together relate to problems they will encounter during later formal assessments.

Reaction of (Bu4N)[ReOCl4] with the tetradentate Schiff base ligand α,α'-[(1,1-dimethylethylene)dinitrilo]di-o-cresol (sal2ibnH2) yields cis-[Re(V)OCl(sal2ibn)], which quickly forms trans-[μ-O(Re(V)O(sal2ibn))2] in solution. The dinuclear complex can also be isolated by the addition of base (Et3N) to the reaction mixture. Conversely, the mononuclear complex can be trapped as cis-[Re(V)O(NCS)(sal2ibn)] by addition of (Bu4N)SCN to the reaction mixture. Reduction of cis-[Re(V)O(NCS)sal2ibn] with triphenylphosphine gives the rare trans-[Re(III)(NCS)(PPh3)(sal2ibn)] and unique μ-oxo Re(IV) dimer trans-[μ-O(Re(IV)(NCS)(sal2ibn))2]. All of the complexes were characterized by (1)H and (13)C NMR, FT-IR spectroscopy, electrospray ionization mass spectrometry (ESI-MS), cyclic voltammetry and single crystal X-ray diffraction.

A variety of method and basis set combinations has been evaluated for monooxorhenium(V) complexes with N, O, P, S, Cl, and Se donor atoms. The geometries and energies obtained are compared to both high-level computations and literature structures. These calculations show that the PBE0 method outperforms the B3LYP method with respect to both structure and energetics. The combination of 6-31G** basis set on the nonmetal atoms and LANL2TZ effective core potential on the rhenium center gives reliable equilibrium structures with minimal computational resources for both model and literature compounds. Single-point energy calculations at the PBE0/LANL2TZ,6-311+G* level of theory are recommended for energetics.

Radiometals play an important role in diagnostic and therapeutic radiopharmaceuticals. This field of radiochemistry is multidisciplinary, involving radiometal production, separation of the radiometal from its target, chelate design for complexing the radiometal in a biologically stable environment, specific targeting of the radiometal to its in vivo site, and nuclear imaging and/or radiotherapy applications of the resultant radiopharmaceutical. The critical importance of inorganic chemistry in the design and application of radiometal-containing imaging and therapy agents is described from a historical perspective to future directions.

2-[2-benzothiazoylmethyl)thio]-benzenamine, which was first reported in 1898, was isolated from the reaction of bromoacetyl bromide and 2-aminothiophenol [1]. The product crystallized from an aqueous methanol solution of the reaction mixture to which nickel(II) acetate had been added. 2-[(2-benzothiazolylmethyl)thio]-benzenamine crystallized in the monoclinic system, in space group C2/c, with cell dimensions of a = 27.392 (19) Å, b = 4.730 (3) Å, and c = 23.686 (16) Å, β = 122.465 (6)°, V = 2589(3) Å(3), Z = 8 and refined to R = 0.0343 and R(w) = 0.0844. Crystallization from methanol yielded the product as the hydrobromide salt in the monoclinic space group Cc, with cell dimensions of a = 10.488 (3) Å, b = 33.404 (9) Å, c = 5.2578 (14) Å, β = 116.769(2)°, V = 1644.7(8) Å(3), Z = 4 and refined to R = 0.0296 and R(w) = 0.0600. Mass spectral and NMR analyses confirmed that the bulk and crystalline compound were all 2-[(2-benzothiazolylmethyl)thio]-benzenamine.

Selenium-72 production by the proton bombardment of a natural NaBr target has been successfully demonstrated at the Los Alamos National Laboratory Isotope Production Facility (LANL-IPF). Arsenic-72 (half life 26 h) is a medium-lived positron emitting radionuclide with the major advantage of being formed as the daughter of another "generator" radioisotope (Se-72, 8.5 d). A (72)Se/(72)As generator would be the preferred mechanism for clinical utilization of (72)As for positron emission tomography (PET). No portable (72)Se/(72)As generator system has been demonstrated for convenient, repeated (72)As elution ("milking"). In this work, we describe (72)Se production and recovery from irradiated NaBr targets using a 100 MeV proton beam. We also introduce an (72)As generator principle based on (72)Se chelation followed by liquid-liquid extraction, which will be transferred to a solid-phase sorption/elution system., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The therapeutic efficacies of radiolabeled biotin, pretargeted by monoclonal antibody (mAb)-streptavidin fusion protein CC49 scFvSA, were compared to those of radiolabeled mAb CC49, using the three radiolanthanides in an animal model of human colon cancer. The purpose of the present study was to compare antibody pretargeting to conventional radioimmunotherapy using (149)Pm, (166)Ho, or (177)Lu. Nude mice bearing LS174T colon tumors were injected sequentially with CC49 scFvSA, the blood clearing agent biotin-GalNAc(16), and (149)Pm-, (166)Ho-, or (177)Lu-DOTA-biotin. Tumor-bearing mice were alternatively administered (149)Pm-, (166)Ho-, or (177)Lu-MeO-DOTA-CC49. Therapy with pretargeted (149)Pm-,(166)Ho-, and (177)Lu-DOTA-biotin increased the median time of progression to a 1 g tumor to 50, 41, and 50 days post-treatment, respectively. Therapy with (149)Pm-,(166)Ho-, and (177)Lu-MeO-DOTA-CC49 increased the median time to progression to 53, 24, and 67 days post-treatment, respectively. In contrast, saline controls showed a median time to progression of 13 days postinjection. Treatment with pretargeted (149)Pm-, (166)Ho-, and (177)Lu-biotin or (149)Pm-, (166)Ho-, and (177)Lu-CC49 increased tumor doubling time to 18-36 days, compared to 3 days for saline controls. Among treated mice, 23% survived >84 days post-therapy, and 11% survived 6 months, but controls survived <29 days. Long-term survivors showed tumor growth inhibition or partial regression, extensive necrosis in residual masses, and no evidence of nontarget tissue toxicity at necropsy. Both pretargeted and conventional RIT demonstrated considerable efficacy in an extremely aggressive animal model of cancer. Our results identified (177)Lu as an optimal radiolanthanide for future evaluation of these agents in toxicity and multiple-dose therapy studies.

A new tumor-seeking tridentate topology consisting of a phosphino dithioether ((HOCH(2))(2)PCH(2)CH(2)S(CH(2))(n)CH(2)SR; PS(2)) ligand framework for the production of kinetically inert and in vivo stable facial [(99m)Tc(CO)(3)(PS(2))](+) or [Re(CO)(3)(PS(2))](+) is described. The X-ray crystal structure of fac-Re(CO)(3)(PS(2))PF(6) is reported. The bioconjugation strategies for incorporating bombesin (BBN) peptides on to the PS(2) tripodal framework and, thereby, de novo designing of GRP receptor-seeking Tc(PS(2)-BBN)(CO)(3) are developed., (© 2011 American Chemical Society)

Introduction: To probe the interplay between radiotracer stability and somatostatin receptor affinity, Tyr(3)-octreotate and six variations of its peptide sequence, for which the Re-cyclized products were previously reported, were radiolabeled with (99m)Tc and investigated for their in vitro stability., Methods: Radiolabeling of the peptides was effected by ligand exchange from (99m)Tc-glucoheptonate, and the desired products were purified by radio-RP-HPLC. The in vitro stability in phosphate buffered saline, mouse serum and cysteine solutions at physiological temperature and pH for all seven (99m)Tc-cyclized peptides was determined by radio-RP-HPLC and radio-TLC. Normal CF-1 mouse biodistribution studies were performed for three of the (99m)Tc-cyclized peptides., Results: Based on the fully characterized Re-cyclized peptide analogues, four (99m)Tc-coordination motifs were proposed for the (99m)Tc-cyclized peptides. Technetium-99m-cyclized Tyr(3)-octreotate derivatives with N(2)S(2) metal coordination modes and large metal ring sizes were susceptible to oxidation and loss of (99m)Tc in the form of (99m)TcO(4)(-), as evidenced by their instability in the various solutions under physiological conditions (15-58% intact at 24 h). As anticipated, the addition of a third cysteine to the sequence stabilized the (99m)Tc metal coordination, and peptides with NS(3) coordination modes remained >85% intact out to 24 h. No significant differences were observed in the biodistribution studies performed with three peptides of varying stabilities., Conclusions: Improvements in stability were not sufficient to outweigh the low somatostatin receptor affinity for the peptides in this study. Further improvements in the peptide sequence and/or metal coordination are needed to result in a radiodiagnostic/radiotherapeutic pair for targeting the somatostatin receptor., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Reactions of Re(V), tetradentate Schiff base complexes with tertiary phosphines have previously yielded both rearranged Re(V) and reduced Re(III) complexes. To further understand this chemistry, the rigid diiminediphenol (N(2)O(2)) Schiff base ligand sal(2)phen (N,N'-o-phenylenebis(salicylaldimine)) was reacted with (n-Bu(4)N)[ReOCl(4)] to yield trans-[ReOCl(sal(2)phen)] (1). On reaction with triphenylphosphine (PPh(3)), a rearranged Re(V) product cis-[ReO(PPh(3))(sal(2)phen*)]PF(6) (2), in which one of the imines was reduced to an amine during the reaction, and the reduced Re(III) products trans-[ReCl(PPh(3))(sal(2)phen)] (4) and trans-[Re(PPh(3))(2)(sal(2)phen)](+) (5) were isolated. Reaction of sal(2)phen with [ReCl(3)(PPh(3))(2)(CH(3)CN)] resulted in the isolation of [ReCl(2)(PPh(3))(2)(salphen)] (3). The compounds were characterized using standard spectroscopic methods, elemental analyses and single crystal X-ray crystallography.

Introduction: Tetradentate acyclic and macrocyclic diphosphine ligands (P(2)N(2) and P(2)S(2)) have been synthesized and characterized as potential chelates for Rh(III)., Methods: The coordination complexes [RhCl(2)(L1)]Cl, trans-[RhCl(2)(L2)]PF(6), [Ni(L2)](PF(6))(2), [Ni(L3)](PF(6))(2), [RhCl(2)(L4)]PF(6) and [RhCl(2)(L5)]PF(6) have been synthesized and characterized. In addition, radiochemistry studies of the (105)Rh complexes with the ligands N,N'-bis[2-(diphenylphosphino)phenyl]-1,3-diaminopropane (L1), 4,8-diphenyl-1,11-diaza-4,8-diphosphaundecane (L2), 5,9-diphenyl-5,9-diphospha-2,12-dithiatridecane (L3) and 1,4,8,11-tetraphenyl-4,8-diphospha-1,11-dithiaundecane (L4) are reported, including normal mouse biodistributions of (105)Rh-L2., Results: trans-[RhCl(2)(L2)]PF(6) crystallized in the monoclinic space group P2(1)/c with a = 9.9353(5) Å, b = 9.0929(5) Å, c = 28.689(1) Å, β = 93.1400(10) deg, Z = 4, R = 0.037 and R(w) = 0.053. [Ni(L2)](PF(6))(2) crystallized in the monoclinic space group P2(1)/c with a = 11.9665(6) Å, b = 14.8903(7) Å, c = 31.148(1) Å, β = 91.587(1) deg, Z = 8, R = 0.056 and R(w) = 0.083. μ-O(2)SO(2)-[Ni(L5)](2)(PF(6))(2), an unusual sulfate-bridged Ni(II) dimer, crystallized in the triclinic space group P1 bar with a = 15.179(2) Å, b = 15.514(2) Å, c = 16.128(2) Å, α = 105.280(7) deg, β = 113.074(6) deg, γ = 101.657(8) deg, Z = 2, R = 0.050 and R(w) = 0.072., Conclusions: Phosphine-containing ligands allowed for lower temperatures and lower ethanol concentrations in the formulations for (105)Rh(L) complexation, but at the expense of higher ligand concentrations., (Copyright © 2011 Elsevier Inc. All rights reserved.)

(103)Rhodium(III) complexes derived from seven acyclic tetradentate N(2)S(2) ligands (one diaminedithiol and six diaminedithioether ligands) have been synthesized and characterized. Structural variations in the ligand include the length of carbon backbone between the coordinating atoms (222; 232; 323; 333), the presence or absence of gem-dimethyl groups α to sulfur, and the nature of the organic moiety on the sulfurs (hydrogen, p-methoxybenzyl and methyl). For each ligand, the formation of cis and/or trans dichloro isomeric complexes was assessed. Two complexes have been further characterized by single crystal X-ray diffraction. Preparation of the (103)Rhodium(III) complexes was conducted and overall radiochemical yields, in vitro stability and log D(7.4) values were measured. From these studies, the ligand with the 232 chain length, gem-dimethyl groups and the methyl thioether (L4) emerged as a preferred ligand for formation of rhodium complexes with trans geometry and highest radiochemical yields.

Unlabelled: Gastrin-releasing peptide receptors (GRPr) are a member of the bombesin (BBN) receptor family. GRPr are expressed in high numbers on specific human cancers, including human prostate cancer. Therefore, copper-64 ((64)Cu) radiolabeled BBN(7-14)NH(2) conjugates could have potential for diagnosis of human prostate cancer via positron-emission tomography (PET). The aim of this study was to produce [(64)Cu-NO2A-(X)-BBN(7-14)NH(2)] conjugates for prostate cancer imaging, where X=pharmacokinetic modifier (beta-alanine, 5-aminovaleric acid, 6-aminohexanoic acid, 8-aminooctanoic acid, 9-aminonanoic acid or para-aminobenzoic acid) and NO2A=1,4,7-triazacyclononane-1,4-diacetic acid [a derivative of NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid)]., Methods: [(X)-BBN(7-14)NH(2)] Conjugates were synthesized by solid-phase peptide synthesis (SPPS), after which NOTA was added via manual conjugation. The new peptide conjugates were radiolabeled with (64)Cu radionuclide. The receptor-binding affinity was determined in human prostate PC-3 cells, and tumor-targeting efficacy was determined in PC-3 tumor-bearing severely combined immunodeficient (SCID) mice. Whole-body maximum intensity microPET/CT images of PC-3 tumor-bearing SCID mice were obtained 18 h postinjection (pi)., Results: Competitive binding assays in PC-3 cells indicated high receptor-binding affinity for the [NO2A-(X)-BBN(7-14)NH(2)] and [(nat)Cu-NO2A-(X)-BBN(7-14)NH(2)] conjugates. In vivo biodistribution studies of the [(64)Cu-NO2A-(X)-BBN(7-14)NH(2)] conjugates at 1, 4 and 24 h pi showed very high uptake of the tracer in GRPr-positive tissue with little accumulation and retention in nontarget tissues. High-quality, high-contrast microPET images were obtained, with xenografted tumors being clearly visible at 18 h pi., Conclusions: NO2A chelator sufficiently stabilizes copper(II) radiometal under in vivo conditions, producing conjugates with very high uptake and retention in targeted GRPr. Preclinical evaluation of these new peptide conjugates in tumor-bearing mice provides some impetus for clinical evaluation in human patients., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Introduction: Development of radiolabeled octreotide analogues is of interest for targeting somatostatin receptor (SSTR)-positive tumors for diagnostic and therapeutic purposes. We are investigating a direct labeling approach for incorporation of a Re ion into octreotide analogues, where the peptide sequences are cyclized via coordination to Re rather than through a disulfide bridge., Methods: Various octreotide analogue sequences and coordination systems (e.g., S(2)N(2) and S(3)N) were synthesized and cyclized with nonradioactive Re. In vitro competitive binding assays with (111)In-DOTA-Tyr(3)-octreotide in AR42J rat pancreatic tumor cells yielded IC(50) values as a measure of SSTR affinity of the Re-cyclized analogues. Three-dimensional structures of Re-cyclized Tyr(3)-octreotate and its disulfide-bridged analogue were calculated from two-dimensional NMR experiments to visualize the effect of metal cyclization on the analogue's pharmacophore., Results: Only two of the 11 Re-cyclized analogues investigated showed moderate in vitro binding affinity toward somatostatin subtype 2 receptors. Three-dimensional molecular structures of Re- and disulfide-cyclized Tyr(3)-octreotate were calculated, and both of their pharmacophore turns appear to be very similar with minor differences due to metal coordination to the amide nitrogen of one of the pharmacophore amino acids., Conclusions: Various Re-cyclized analogues were developed and analogue 4 had moderate affinity toward somatostatin subtype 2 receptors. In vitro stable studies that are in progress showed stable radiometal cyclization of octreotide analogues via NS(3) and N(2)S(2) coordination forming five- and six-membered chelate rings. In vivo biodistribution studies are underway of (99m)Tc-cyclized analogue 4., (Copyright 2010 Elsevier Inc. All rights reserved.)

Introduction: A variety of (bis)thiosemicarbazone-based ligand systems have been investigated as chelating agents for Au(III) complexes with potential radiotherapeutic applications. Ligand systems containing an ethyl, propyl or butyl backbone between the two imine N donors have been synthesized to evaluate chelate ring size effects on the resultant Au(III) complex stability at the macroscopic and radiotracer levels., Methods: The Au(III) complexes were synthesized and characterized by NMR, electrospray ionization mass spectra, elemental analysis and X-ray crystallography. The (198)Au complexes were evaluated in vitro at the tracer level for stability in phosphate-buffered saline at pH 7.4 and 37 degrees C. One of these complexes [(198)Au(3,4-HxTSE)] showed high in vitro stability and was further evaluated in vivo in normal mice., Results: [Au(ATSM)]AuCl(4).2CH(3)OH, (ATSM=diacetyl-bis(N(4)-methylthiosemicarbazone)) H(14)C(8)N(6)O(2)S(2)Cl(4)Au(2).2CH(3)OH, crystallized from methanol in the monoclinic space group P21/n with a=14.7293(13) A, b=7.7432(7) A, c=20.4363(18) A, beta=100.140(2) degrees, V=2294.4 (4) A(3), Z=4; [Au(3,4-HxTSE)]Cl.CH(3)CH(2)OH/AuCl(2), (3,4-HxTSE=3,4-hexanedione-bis(N(4)-ethylthiosemicarbazone)) H(26)C(13.6)N(6)O(0.8)S(2)Cl(1.2)Au(1.2), crystallized from ethanol in the monoclinic space group P21/c with a=10.1990(10) A, b=13.8833(14) A, c=15.1752(15) A, beta=99.353(2) degrees , V=2120.2 (4) A(3), Z=4., Conclusions: These studies revealed poor stability of the [(198)Au][Au(3,4-HxTSE)](+) complex; however, crystal structure data suggest potential alterations to the ligand backbone may increase stability., (Copyright 2010 Elsevier Inc. All rights reserved.)

The development of receptor-targeting radiopharmaceuticals commonly involves the use of peptides, antibodies or small molecules. Resulting from the numerous modifications that can be made to these basic targeting agents, research in this field often generates a series of compounds as potential ligands for in vivo investigation. However, measuring each variant of a series in vivo can be both costly and time-consuming. Therefore, a number of in vitro assays, to study interactions between the targeted receptor and the ligands of interest, are frequently used to quickly and inexpensively narrow the field and identify a lead compound(s) for further investigation. For example, in saturation binding studies, the amount of radioligand required to saturate the receptors is measured and analyzed to determine the radioligand equilibrium dissociation constant (Kd), a useful gauge of the receptor binding affinity of a radioligand. In competitive binding experiments, a ligand of interest competes for available receptor sites with a standard radioligand of known high receptor affinity. Competition data are analyzed to yield another indicator of receptor affinity, called an IC50 value, which can be used to rank the relative receptor binding affinities for a series of ligands. In internalization and efflux studies, the rate and extent of receptor-mediated radioligand taken into and subsequently released from cells is measured, providing insight into cellular uptake and retention of the radioligand. Individually or taken together, these in vitro receptor binding assays are useful tools in radiopharmaceutical development.