Development of Ac-doped biocompatible nanoparticles for targeted alpha therapy.

Targeted alpha therapy (TAT) relies on chemical affinity or active targeting using radioimmunoconjugates as strategies to deliver α-emitting radionuclides to cancerous tissue. These strategies can be affected by transmetalation of the parent radionuclide by competing ions in vivo and the bond-breaking recoil energy of decay daughters. The retention of α-emitting radionuclides and the dose delivered to cancer cells are influenced by these processes.

Elucidating the coordination chemistry of the radium ion for targeted alpha therapy.

The coordination chemistry of Ra is poorly defined, hampering efforts to design effective chelators for Ra-based targeted alpha therapy. Here, we report the complexation thermodynamics of Ra with the biomedically-relevant chelators DOTA and macropa. Our work reveals the highest affinity chelator to date for Ra and advances our understanding of key factors underlying complex stability and selectivity for this underexplored ion.

Applications of machine learning in acute care research.

Artificial intelligence has been successfully applied to numerous health care and non-health care-related applications and its use in emergency medicine has been expanding. Among its advantages are its speed in decision making and the opportunity for rapid, actionable deduction from unstructured data with that increases with access to larger volumes of data. Artificial intelligence algorithms are currently being applied to enable faster prognosis and diagnosis of diseases and to improve patient outcomes.

Influence of bidentate ligand donor types on the formation and stability in 2 + 1 fac-[M(CO)] (M = Re, Tc) complexes.

In the last two decades, a number of chelate strategies have been proposed for the fac-[M(CO)] (M = Re, Tc) core in radiopharmaceutical applications. However, the development of new ligands/complexes with improved function and in vivo performance has been limited in recent years. Expanding on our previous studies using the 2 + 1 labeling strategy, a series of bidentate ligands (neutral vs.

Recovery of rhodium with a novel soft donor ligand using solvent extraction techniques in chloride media.

Rhodium remains a high value platinum group metal that has key applications in electronics, catalysts, and batteries. To provide a useful tool for Rh isolation, a novel tridentate ligand utilizing soft N and S donors was designed to specifically extract Rh. The synthesis, complexation kinetics, and liquid-liquid extraction studies were performed to explore the overall process and recovery of Rh from chloride media.

Isothiocyanate-Functionalized Bifunctional Chelates and fac-[M(I)(CO)3](+) (M = Re, (99m)Tc) Complexes for Targeting uPAR in Prostate Cancer.

Developing new strategies to rapidly incorporate the fac-[M(I)(CO)3](+) (M = Re, (99m)Tc) core into biological targeting vectors in radiopharmaceuticals continues to expand as molecules become more complex and as efforts to minimize nonspecific binding increase. This work examines a novel isothiocyanate-functionalized bifunctional chelate based on 2,2'-dipicolylamine (DPA) specifically designed for complexing the fac-[M(I)(CO)3](+) core. Two strategies (postlabeling and prelabeling) were explored using the isothiocyanate-functionalized DPA to determine the effectiveness of assembly on the overall yield and purity of the complex with amine containing biomolecules.

Influence of functionalized pyridine ligands on the radio/chemical behavior of [M(I)(CO)3](+) (M = Re and (99m)Tc) 2 + 1 complexes.

While a number of chelate strategies have been developed for the organometallic precursor fac-[M(I)(OH2)3(CO)3](+) (M = Re, (99m)Tc), a unique challenge has been to improve the overall function and performance of these complexes for in vivo and in vitro applications. Since its discovery, fac-[M(I)(OH2)3(CO)3](+) has served as an essential scaffold for the development of new targeted (99m)Tc based radiopharmaceuticals due to its labile aquo ligands. However, the lipophilic nature of the fac-[M(I)(CO)3](+) core can influence the in vivo pharmacokinetics and biodistribution of the complexes.

Re and (99m)Tc complexes of BodP3--multi-modality imaging probes.

A fluorescent tridentate phosphine, BodP3 (2), forms rhenium complexes which effectively image cancer cells. Related technetium analogues are also readily prepared and have potential as dual SPECT/fluorescent biological probes.

Rhenium and technetium bi- and tricarbonyl complexes in a new strategy for biomolecule incorporation using click chemistry.

A versatile strategy to prepare fac-[M(I)(CO)3](+) and cis-[M(I)(CO)2](+) (M = Re, (99m)Tc) complexes was developed using Huisgen click chemistry and monodentate phosphine ligands to readily incorporate biomolecules and tailor the chemical properties.

Clickable, hydrophilic ligand for fac-[M(I)(CO)3](+) (M = Re/(99m)Tc) applied in an S-functionalized α-MSH peptide.

The copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) click reaction was used to incorporate alkyne-functionalized dipicolylamine (DPA) ligands (1 and 3) for fac-[M(I)(CO)3](+) (M = Re/(99m)Tc) complexation into an α-melanocyte stimulating hormone (α-MSH) peptide analogue. A novel DPA ligand with carboxylate substitutions on the pyridyl rings (3) was designed to increase the hydrophilicity and to decrease in vivo hepatobiliary retention of fac-[(99m)Tc(I)(CO)3](+) complexes used in single photon emission computed tomography (SPECT) imaging studies with targeting biomolecules. The fac-[Re(I)(CO)3(3)] complex (4) was used for chemical characterization and X-ray crystal analysis prior to radiolabeling studies between 3 and fac-[(99m)Tc(I)(OH2)3(CO)3](+).

99mTc-labeled cystine knot peptide targeting integrin αvβ6 for tumor SPECT imaging.

Integrin αvβ6 is overexpressed in a variety of cancers, and its expression is often associated with poor prognosis. Therefore, there is a need to develop affinity reagents for noninvasive imaging of integrin αvβ6 expression since it may provide early cancer diagnosis, more accurate prognosis, and better treatment planning. We recently engineered and validated highly stable cystine knot peptides that selectively bind integrin αvβ6 with no cross-reactivity to integrins αvβ5, α5β1, or αvβ3, also known to be overexpressed in many cancers.

Cu-free 1,3-dipolar cycloaddition click reactions to form isoxazole linkers in chelating ligands for fac-[M(I)(CO)3]+ centers (M = Re, 99mTc).

Isoxazole ring formation was examined as a potential Cu-free alternative click reaction to Cu(I)-catalyzed alkyne/azide cycloaddition. The isoxazole reaction was explored at macroscopic and radiotracer concentrations with the fac-[M(I)(CO)3](+) (M = Re, (99m)Tc) core for use as a noncoordinating linker strategy between covalently linked molecules. Two click assembly methods (click, then chelate and chelate, then click) were examined to determine the feasibility of isoxazole ring formation with either alkyne-functionalized tridentate chelates or their respective fac-[M(I)(CO)3](+) complexes with a model nitrile oxide generator.

pH-controlled coordination mode rearrangements of "clickable" Huisgen-based multidentate ligands with [M(I)(CO)3]+ (M = Re, (99m)Tc).

The viability of the Huisgen cycloaddition reaction for clickable radiopharmaceutical probes was explored with an alkyne-functionalized 2-[(pyridin-2-ylmethyl)amino]acetic acid (PMAA) ligand system, 3, and fac-[M(I)(OH2)3(CO)3](+) (M = Re, (99m)Tc). Two synthetic strategies, (1) click, then chelate and (2) chelate, then click, were investigated to determine the impact of assembly order on the reactivity of the system. In the click, then chelate approach, fac-[M(I)(OH2)3(CO)3](+) was reacted with the PMAA ligand "clicked" to the benzyl azide, 5, to yield two unique coordination species, fac-[M(I)(CO)3(O,N(amine),N(py)-5)], M = Re (8), (99m)Tc (8A), and fac-[M(I)(CO)3(N(tri),N(amine),N(py)-5)], M = Re (9), (99m)Tc (9A), where coordination is through the triazole (N(tri)), central amine (N(amine)), pyridine (N(py)), or carboxylate (O).

Photo-initiated thiol-ene click reactions as a potential strategy for incorporation of [M(I)(CO)3]+ (M = Re, (99m)Tc) complexes.

Click reactions offer a rapid technique to covalently assemble two molecules. In radiopharmaceutical construction, these reactions can be utilized to combine a radioactive metal complex with a biological targeting molecule to yield a potent tool for imaging or therapy applications. The photo-initiated radical thiol-ene click reaction between a thiol and an alkene was examined for the incorporation of [M(I)(CO)3](+) (M = Re, (99m)Tc) systems for conjugating biologically active targeting molecules containing a thiol.

Targeting prostate cancer cells with PSMA inhibitor-guided gold nanoparticles.

Prostate-specific membrane antigen (PSMA) is a notable biomarker for diagnostic and therapeutic applications in prostate cancer. Gold nanoparticles (AuNPs) provide an attractive nanomaterial platform for combining a variety of targeting, imaging, and cytotoxic agents into a unified device for biomedical research. In this study, we present the generation and evaluation of the first AuNP system functionalized with a small molecule phosphoramidate peptidomimetic inhibitor for the targeted delivery to PSMA-expressing prostate cancer cells.

Novel, cysteine-modified chelation strategy for the incorporation of [M(I)(CO)(3)](+) (M = Re, (99m)Tc) in an α-MSH peptide.

Engineering peptide-based targeting agents with residues for site-specific and stable complexation of radionuclides is a highly desirable strategy for producing diagnostic and therapeutic agents for cancer and other diseases. In this report, a model N-S-N(Py) ligand (3) and a cysteine-derived α-melanocyte stimulating hormone (α-MSH) peptide (6) were used as novel demonstrations of a widely applicable chelation strategy for incorporation of the [M(I)(CO)(3)](+) (M = Re, (99m)Tc) core into peptide-based molecules for radiopharmaceutical applications. The structural details of the core ligand-metal complexes as model systems were demonstrated by full chemical characterization of fac-[Re(I)(CO)(3)(N,S,N(Py)-3)](+) (4) and comparative high-performance liquid chromatography (HPLC) analysis between 4 and [(99m)Tc(I)(CO)(3)(N,S,N(Py)-3)](+) (4a).

PSMA-targeted SPECT agents: mode of binding effect on in vitro performance.

Background: The enzyme-biomarker prostate-specific membrane antigen (PSMA) is an active target for imaging and therapeutic applications for prostate cancer. The internalization of PSMA has been shown to vary with inhibitors' mode of binding: irreversible, slowly reversible, and reversible.

Methods: In the present study, PSMA-targeted clickable derivatives of an irreversible phosphoramidate inhibitor DBCO-PEG(4) -CTT-54 (IC(50) = 1.

A phosphoramidate-based prostate-specific membrane antigen-targeted SPECT agent.

Background: Prostate-specific membrane antigen (PSMA) remains an active target for imaging and therapeutic applications for prostate cancer.

Methods: In the present study, an irreversible phosphoramidate inhibitor, CTT-54 (IC50 = 14 nM), has been modified to deliver 99mTc-(CO)3-DTPA as a SPECT imaging payload to PSMA+ cells in vivo and in vitro. Percent uptake, competitive binding, and internalization will evaluate the imaging agent in vitro.

The hydrazide/hydrazone click reaction as a biomolecule labeling strategy for M(CO)3 (M = Re, (99m)Tc) radiopharmaceuticals.

Facile reactivity of hydrazides and aldehydes was explored as potential coupling partners for incorporation into M(CO)(3) (M = Re, (99m)Tc) based radiopharmaceuticals. Both 'click, then chelate' and 'prelabel, then click' synthetic routes produced identical products in high yields and lacked metal-hydrazide/-hydrazone interactions, highlighting the potential of this click strategy.

Investigation of mixed oxidation state cyanide-bridged Re(V)oxo (acac(2)en/pn) and Re(I)(bipy)(CO)3 complexes.

A series of cyanide-bridged complexes that combine a low-valent photoacceptor rhenium(I) metal center with an electroactive midvalent rhenium(V) complex were prepared. The synthesis involved the preparation of novel asymmetric rhenium(V) oxo compounds, cis-Re(V)O(CN)(acac(2)en) (1) and cis-Re(V)O(CN)(acac(2)pn) (2), formed by reacting trans-[Re(V)O(OH(2))(acac(2)en)]Cl or trans-Re(V)O(acac(2)pn)Cl with [NBu(4)][CN]. The μ-bridged cyanide mixed-oxidation Re(V)-Re(I) complexes were prepared by incubating the asymmetric complexes, 1 or 2, with fac-[Re(I)(bipy)(CO)(3)][OTf] to yield cis-[Re(V)O(acac(2)en)(μ-CN-1κC:2κN)-fac-Re(I)(bipy)(CO)(3)][PF(6)] (3) and [cis-Re(V)O(acac(2)pn)(μ-CN-1κC:2κN)-fac-Re(I)(bipy)(CO)(3)][PF(6)] (4), respectively.

"Click" labeling strategy for M(CO)(3) (M = Re, (99m)Tc) prostate cancer targeted flutamide agents.

Two distinct "click" chemistry labeling approaches were investigated with dipyridylamine alkyne derivatives and M(CO)(3)(+) (M = Re, (99m)Tc). The triazole ring was found uncoordinated and was incorporated into the preparation of a crossover androgen receptor targeting inhibitor for prostate cancer.

Investigation of the coordination interactions of S-(pyridin-2-ylmethyl)-L-cysteine ligands with M(CO)(3)(+) (M = Re, (99m)Tc).

Development of new ligands for fac-M(OH(2))(3)(CO)(3)(+) (M = Re, (99m)Tc) led the investigation with S-(pyridin-2-ylmethyl)-l-cysteine, 1. The ligand 1 has potential to coordinate with the metal through three different tridentate modes: tripodal through cysteine (O,N,S) and two linear involving the S-pyridyl and cysteine (O,S,N(Py), N,S,N(Py)). From the reaction with 1, two species were observed in the (1)H NMR, where the primary product was the linear fac-Re(N,S,N(Py)-1)(CO)(3)(+), 2a, complex.

Synthesis and characterization of nonsteroidal-linked M(CO)(3)+ (M = 99mTc, Re) compounds based on the androgen receptor targeting molecule flutamide.

Androgen receptors are overexpressed in most primary and metastatic prostate cancers. A series of single photon emission computed tomography imaging agents (SPECT) utilizing the organometallic radioactive imaging species, fac-99mTc(OH(2))(3)(CO)(3)+, were prepared on the basis of the structure of Flutamide, a potent nonsteroidal antiandrogen prostate cancer drug. Novel bifunctional chelate-linked Flutamide analogues were prepared using a newly developed universal alkylating reagent, 2-bromo-N-[4-nitro-3-(trifluoromethyl)phenyl]-acetamide, 1.

Experiences with carotid endarterectomy at Sree Chitra Tirunal Institute.

Background: Atherosclerotic carotid artery disease poses a grave threat to cerebral circulation, leading to a stroke with its devastating sequelae, if left untreated. Carotid endarterectomy has a proven track record with compelling evidence in stroke prevention.

Objectives: a) To confirm that carotid endarterectomy (CEA) is safe and effective in preventing stroke at both short and long term.

Metal-assisted in situ formation of a tridentate acetylacetone ligand for complexation of fac-Re(CO)3+ for radiopharmaceutical applications.

Reaction of [NEt4]2[ReBr3(CO)3] with 2,4-pentanedione (acac) yields a complex of the type fac-Re(acac)(OH2)(CO)3 (1) under aqueous conditions. 1 was further reacted with a monodentate ligand (pyridine) to yield a fac-Re(acac)(pyridine)(CO)3 complex (2). Complex 1 was found to react with primary amines to generate a Schiff base (imine) in aqueous solutions.