Iron Availability within the Leaf Vasculature Determines the Magnitude of Iron Deficiency Responses in Source and Sink Tissues in Arabidopsis.

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.

Development and biodistribution studies of As-labeled trithiol RM2 bioconjugates for prostate cancer: Comparison of [As]As-trithiol-Ser-Ser-RM2 vs. [As]As-trithiol-Glu-Ser-RM2.

Introduction: Recent progress with the production of As (2.49 Mev β (64%), 3.33 Mev β (16%), 834 keV γ (81%), t: 26 h) and As (0.

A Third Generation Potentially Bifunctional Trithiol Chelate, Its Sb(III) Complex, and Selective Chelation of Radioantimony (Sb) from Its Sn Target.

The therapeutic potential of the Meitner-Auger- and conversion-electron emitting radionuclide Sb remains unexplored because of the difficulty of incorporating it into biologically targeted compounds. To address this challenge, we report the development of 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.

Recovery, recycling and re-irradiation of enriched Ru metal targets for cost effective production of Rh.

Rhodium-105 (0.567 MeV β, 319 keV γ, 35.4 h half-life) was produced by neutron irradiation of enriched Ru (>99%) over multiple decades.

Direct labeling of a somatostatin receptor antagonist via peptide cyclization with Re, Tc and Re metal centers: Radiochemistry and in vitro evaluation.

Introduction: With the long-term goal of developing a diagnostic (Tc) and therapeutic (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-Phe-c(DCys-Tyr-DTrp-Lys-Thr-Cys)-DTyr-NH (1) with Re (in Re-1), Tc (in [Tc]Tc-1) and Re (in [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 Tc-labeled glucoheptonate or [Re]ReOCl(PPh), yielding [Tc]Tc-1 or [Re]Re-1, respectively.

A New, Second Generation Trithiol Bifunctional Chelate for As: Trithiol(b)-(Ser)-RM2.

Trithiol chelates are suitable for labeling radioarsenic (As: 2.49 MeV β, 26 h; As: 0.683 MeV β, 38.

Development and Preclinical Evaluation of Tc- and Re-Labeled NOTA and NODAGA Bioconjugates Demonstrating Matched Pair Targeting of GRPR-Expressing Tumors.

Purpose: The goal of this work was to develop hydrophilic gastrin-releasing peptide receptor (GRPR)-targeting complexes of the general formula fac-[M(CO)(L)] [M = Re, Tc, Re; L: NOTA for 1, NODAGA for 2] conjugated to a powerful GRPR peptide antagonist (Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH) via a 6-aminohexanoic acid linker.

Procedures: Metallated-peptides were prepared employing the [M(OH)(CO)] [M = Re, Tc, Re] precursors. Re-1/2 complexes were characterized with HR-MS.

Development of resveratrol-conjugated gold nanoparticles: interrelationship of increased resveratrol corona on anti-tumor efficacy against breast, pancreatic and prostate cancers.

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. Resveratrol was used to reduce Au to Au 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.

Steric influence of salicylaldehyde-based Schiff base ligands on the formation of trans-[Re(PR)(Schiff base)] complexes.

Complexes of the type trans-[Re(PR)(Schiff base)] (R = ethyl and/or phenyl) 2-7 were prepared by the reaction of (nBuN)[ReOCl] with Hsalen or Hsalibn followed by addition of a tertiary phosphine. The trans-[Re(PR)(salen)] complexes 2-4 were stable in solution, whereas the trans-[Re(PR)(salibn)] complexes 6-7 were observed to convert to their corresponding cis-[ReO(PR)(salibn)] products through a process involving ligand dissociation, metal oxidation, and Schiff base ligand rearrangement. The conversion of the trans-[Re(PR)(salibn)] complexes is likely driven by steric interactions between the bulky backbone gem-dimethyl groups of the salibn ligand and the phosphine ligands.

Somatostatin receptor targeting with hydrophilic [Tc/Re]Tc/Re-tricarbonyl NODAGA and NOTA complexes.

Introduction: The aim of this work was to develop diagnostic (Tc) and therapeutic (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)(L-sst-ANT)] (M = Tc, Re), where L denotes NODAGA or NOTA and sst-ANT denotes the potent SSTR2 antagonist 4-NO-Phe-c(DCys-Tyr-DTrp-Lys-Thr-Cys)-DTyr-NH. Moreover, we assessed the in vivo properties of the Tc-complexes in an animal SSTR-tumor model.

Synthesis and evaluation of Re/Tc(I) complexes bearing a somatostatin receptor-targeting antagonist and labeled via a novel [N,S,O] clickable bifunctional chelating agent.

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-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)] and [Tc][Tc(CO)]. The chelator-peptide conjugation was performed via a Cu(I)-assisted click reaction of the alkyne-bearing chelator (2) with an azide-functionalized sst-ANT peptide (3), to yield NSO-sst-ANT (4).

NOTA and NODAGA [Tc]Tc- and [Re]Re-Tricarbonyl Complexes: Radiochemistry and First Example of a [Tc]Tc-NODAGA Somatostatin Receptor-Targeting Bioconjugate.

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 [Tc/Re]Tc/Re-tricarbonyl core. In particular, we report model complexes of the general formula fac-[M(L)(CO)] (M = Re, Tc, 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-ANT (3) and explored its complexation with the fac-[Re(CO)] and fac-[Tc][Tc(CO)] cores; sst-ANT denotes the somatostatin receptor (SSTR) antagonist 4-NO-Phe-c(DCys-Tyr-DTrp-Lys-Thr-Cys)-DTyr-NH.

Evaluation of Se/As generator and production of Se for supplying As as a potential PET imaging radionuclide.

Positron-emitting As is the PET imaging counterpart for beta-emitting As. Its parent, no carrier added (n.c.

Technetium and Rhenium Schiff Base Compounds for Nuclear Medicine: Syntheses of Rhenium Analogues to Tc-Furifosmin.

Rhenium, the third-row congener of technetium, is often used to develop the macroscopic chemistry of potential Tc diagnostic radiopharmaceuticals. The rhenium analogues to Tc-furifosmin are being developed for potential radiotherapy of multidrug-resistant tumors. Complexes of the form trans-[M(PR)(NO-Schiff base)] are of interest for the potential imaging and treatment of multidrug-resistant tumors.

A trithiol bifunctional chelate for As: A matched pair theranostic complex with high in vivo stability.

Introduction: Trithiol chelates are suitable for labeling radioarsenic (As: 2.49 MeV β, 26 h; As: 0.683 MeV β, 38.

Changes in iron availability in Arabidopsis are rapidly sensed in the leaf vasculature and impaired sensing leads to opposite transcriptional programs in leaves and roots.

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.

Pertechnetate-Induced Addition of Sulfide in Small Olefinic Acids: Formation of [TcO(dimercaptosuccinate)] and [TcO(mercaptosuccinate)] Analogues.

Technetium-99 (Tc) is important to the nuclear fuel cycle as a long-lived radionuclide produced in ∼6% fission yield from U or Pu. In its most common chemical form, namely, pertechnetate (TcO), it is environmentally mobile. In situ hydrogen sulfide reduction of pertechnetate has been proposed as a potential method to immobilize environmental TcO that has entered the environment.

Chemistry and radiochemistry of As, Re and Rh isotopes relevant to radiopharmaceutical applications: high specific activity radionuclides for imaging and treatment.

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.

In vivo transport of three radioactive [F]-fluorinated deoxysucrose analogs by the maize sucrose transporter ZmSUT1.

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 [F] at the C-6' position within the fructosyl moiety of sucrose did not affect sucrose transport by the maize (Zea mays) ZmSUT1 protein.

Bulk production and evaluation of high specific activity Re for cancer therapy using enriched WO targets in a proton beam.

Introduction: Rhenium-186g (t = 3.72 d) is a β emitting isotope suitable for theranostic applications. Current production methods rely on reactor production by way of the reaction Re(n,γ)Re, which results in low specific activities limiting its use for cancer therapy.

Synthesis and evaluation of a Tc tricarbonyl-labeled somatostatin receptor-targeting antagonist peptide for imaging of neuroendocrine tumors.

Introduction: A somatostatin receptor (SSTR)-targeting antagonist peptide (sst-ANT) was radiolabeled with Tc tricarbonyl via a tridentate [N,S,N]-type ligand (L) to develop a radiodiagnostic agent, TcL-sst-ANT, for imaging of SSTR-expressing neuroendocrine tumors.

Methods: Receptor affinity was assessed in vitro with the nonradioactive analogue, ReL-sst-ANT, via a challenge experiment in AR42J cells with I-SS-14 as the competing radioligand. Preparation of TcL-sst-ANT was achieved via reaction of [Tc(CO)(HO)] with L-sst-ANT.

Monooxorhenium(V) complexes with 222-NS MAMA ligands for bifunctional chelator agents: Syntheses and preliminary in vivo evaluation.

Introduction: Targeted radiotherapy using the bifunctional chelate approach with 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) were synthesized, complexed with rhenium, radiolabeled with Tc and Re (carrier added and no carrier added), and evaluated in initial biological distribution studies.

Dithiol Aryl Arsenic Compounds as Potential Diagnostic and Therapeutic Radiopharmaceuticals.

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.

Deuteron irradiation of W and WO3 for production of high specific activity (186)Re: Challenges associated with thick target preparation.

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.

Accelerator-based production of the (99m)Tc-(186)Re diagnostic-therapeutic pair using metal disulfide targets (MoS2, WS2, OsS2).

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.