In the last two decades, a number of chelate strategies have been proposed for the fac-[MI(CO)3]+ (M = Re, 99mTc) 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. anionic) containing an aromatic amine in combination with monodentate pyridine analogs or imidazole were explored to determine the influence of the bidentate and monodentate ligands on the formation and stability of the respective complexes. The 2 + 1 complexes with Re and 99mTc were synthesized in two steps and characterized by standard radio/chemical methods. X-ray characterization and density functional theory analysis of the Re 2 + 1 complexes with the complete bidentate series with 4-dimethylaminopyridine were conducted, indicating enhanced ligand binding energies of the neutral over anionic ligands. In the 99mTc studies, anionic bidentate ligands had significantly higher formation yields of the 2 + 1 product, but neutral ligands appear to have increased stability in an amino acid challenge assay. Both bidentate series exhibited improved stability by increasing the basicity of the pyridine ligands.

Developing new strategies to rapidly incorporate the fac-[MI(CO)3]+ (M = Re, 99mTc) 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-[MI(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. A model amino acid (lysine) examined (1) amine conjugation of isothiocyanate-functionalized DPA followed by complexation with fac-[MI(CO)3]+ (postlabeling) and (2) complexation of fac-[MI(CO)3]+ with isothiocyanate-functionalized DPA followed by amine conjugation (prelabeling). Conducted with stable Re and radioactive 99mTc analogs, both strategies formed the product in good to excellent yields under macroscopic and radiotracer concentrations. A synthetic peptide (AE105) which targets an emerging biomarker in CaP prognosis, urokinase-type plasminogen activator receptor (uPAR), was also explored using the isothiocyanate-functionalized DPA strategy. In vitro PC-3 (uPAR+) cell uptake assays with the 99mTc-labeled peptide (8a) showed 4.2 ± 0.5% uptake at 4 h. In a murine model bearing PC-3 tumor xenografts, in vivo biodistribution of 8a led to favorable tumor uptake (3.7 ± 0.7% ID/g) at 4 h p.i. with relatively low accumulation (<2% ID/g) in normal organs not associated with normal peptide excretion. These results illustrate the promise of the isothiocyanate-functionalized approach for labeling amine containing biological targeting vectors with fac-[MI(CO)3]+.

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.

While a number of chelate strategies have been developed for the organometallic precursor fac-[MI(OH2)3(CO)3]+ (M = Re, 99mTc), 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-[MI(OH2)3(CO)3]+ has served as an essential scaffold for the development of new targeted 99mTc based radiopharmaceuticals due to its labile aquo ligands. However, the lipophilic nature of the fac-[MI(CO)3]+ core can influence the in vivo pharmacokinetics and biodistribution of the complexes. In an effort to understand and improve this behavior, monosubstituted pyridine ligands were used to assess the impact of donor nitrogen basicity on binding strength and stability of fac-[MI(CO)3]+ in a 2 + 1 labeling strategy. A series of Re and 99mTc complexes were synthesized with picolinic acid as a bidentate ligand and 4-substituted pyridine ligands. These complexes were designed to probe the effect of pKa from the monodentate pyridine ligand both at the macro scale and radiochemical concentrations. Comparison of X-ray structural data and radiochemical solution experiments clearly indicate an increase in overall yield and stability as pyridine basicity increased.

Isoxazole ring formation was examined as a potential Cu-free alternative click reaction to CuI-catalyzed alkyne/azide cycloaddition. The isoxazole reaction was explored at macroscopic and radiotracer concentrations with the fac-[MI(CO)3]+ (M = Re, 99mTc) 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-[MI(CO)3]+ complexes with a model nitrile oxide generator. Macroscale experiments, alkyne-functionalized chelates, or Re complexes indicate facile formation of the isoxazole ring. 99mTc experiments demonstrate efficient radiolabeling with click, then chelate; however, the chelate, then click approach led to faster product formation, but lower yields compared to the Re analogues.

The copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC) click reaction was used to incorporate alkyne-functionalized dipicolylamine (DPA) ligands (1 and 3) for fac-[MI(CO)3]+ (M = Re/99mTc) 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-[99mTcI(CO)3]+ complexes used in single photon emission computed tomography (SPECT) imaging studies with targeting biomolecules. The fac-[ReI(CO)3(3)] complex (4) was used for chemical characterization and X-ray crystal analysis prior to radiolabeling studies between 3 and fac-[99mTcI(OH2)3(CO)3]+. The corresponding 99mTc complex (4a) was obtained in high radiochemical yields, was stable in vitro for 24 h during amino acid challenge and serum stability assays, and showed increased hydrophilicity by log P analysis compared to an analogous complex with nonfunctionalized pyridine rings (2a). An α-MSH peptide functionalized with an azide was labeled with fac-[MI(CO)3]+ using both click, then chelate (CuAAC reaction with 1 or 3 followed by metal complexation) and chelate, then click (metal complexation of 1 and 3 followed by CuAAC with the peptide) strategies to assess the effects of CuAAC conditions on fac-[MI(CO)3]+ complexation within a peptide framework. The peptides from the click, then chelate strategy had different HPLC tR’s and in vitro stabilities compared to those from the chelate, then click strategy, suggesting nonspecific coordination of fac-[MI(CO)3]+ using this synthetic route. The fac-[MI(CO)3]+-complexed peptides from the chelate, then click strategy showed >90% stability during in vitro challenge conditions for 6 h, demonstrated high affinity and specificity for the melanocortin 1 receptor (MC1R) in IC50 analyses, and led to moderately high uptake in B16F10 melanoma cells. Log P analysis of the 99mTc-labeled peptides confirmed the enhanced hydrophilicity of the peptide bearing the novel, carboxylate-functionalized DPA chelate (10a′) compared to the peptide with the unmodified DPA chelate (9a′). In vivo biodistribution analysis of 9a′ and 10a′ showed moderate tumor uptake in a B16F10 melanoma xenograft mouse model with enhanced renal uptake and surprising intestinal uptake for 10a′ compared to predominantly hepatic accumulation for 9a′. These results, coupled with the versatility of CuAAC, suggests this novel, hydrophilic chelate can be incorporated into numerous biomolecules containing azides for generating targeted fac-[MI(CO)3]+ complexes in future studies.

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

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-[MI(OH2)3(CO)3]+ (M = Re, 99mTc). 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-[MI(OH2)3(CO)3]+ was reacted with the PMAA ligand “clicked” to the benzyl azide, 5, to yield two unique coordination species, fac-[MI(CO)3(O,Namine,Npy-5)], M = Re (8), 99mTc (8A), and fac-[MI(CO)3(Ntri,Namine,Npy-5)], M = Re (9), 99mTc (9A), where coordination is through the triazole (Ntri), central amine (Namine), pyridine (Npy), or carboxylate (O). Depending on the reaction pH, different ratios of complexes 8(A) and 9(A) were observed, but single species were obtained of (O,Namine,Npy) coordination, 8(A), in basic pHs (>9) and (Ntri,Namine,Npy) coordination, 9(A), in slightly acidic pHs (<4). In the chelate, then click approach, the (O,Namine,Npy) coordination of [MI(CO)3]+ was preorganized in the alkyne-functionalized fac-[MI(CO)3(O,Namine,Npy-3)], M = Re (6), 99mTc (6A), followed by standard CuI-catalyzed Huisgen “click” conditions at pH ≈ 7.4, where the (O,Namine,Npy) coordination mode remained unchanged upon formation of the triazole product in the clicked molecule. Despite the slow substitution kinetics of the low-spin d6 metal, the coordination modes (O,Namine,Npy) and (Ntri,Namine,Npy) were found to reversibly intraconvert between 8(A) and 9(A) based upon changes in pH that mirrored the (O,Namine,Npy) coordination in basic pHs and (Ntri,Namine,Npy) coordination in acidic pHs. Comparison of the Re and 99mTc analogs also revealed faster intraconversion between the coordination modes for 99mTc.

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 [MI(CO)3]+ (M = Re, 99mTc) systems for conjugating biologically active targeting molecules containing a thiol. In this strategy, a potent chelate system, 2,2′-dipicolylamine (DPA), for [MI(CO)3]+ was functionalized at the central amine with a terminal alkene linker that was explored with two synthetic approaches, click then chelate and chelate then click, to determine the flexibility and applicability of the thiol-ene click reaction to specifically incorporate ligand systems and metal complexes with a thiol containing molecule. In the click then chelate approach, the thiol-ene click reaction was carried out with the DPA chelate followed by complexation with [MI(CO)3]+. In the chelate then click approach, the alkene functionalized DPA chelate was first complexed with [MI(CO)3]+ followed by the conduction of the thiol-ene click reaction. Initial studies utilized benzyl mercaptan as a model thiol for both strategies to generate the identical product from either route to provide information on reactivity and product formation. DPA ligands functionalized with two unique linker systems (allyl and propyl allyl ether) were prepared to examine the effect of the proximity of the chelate or complex on the thiol-ene click reaction. Both the thiol-ene click and coordination reactions with Re, 99mTc were performed in moderate to high yields demonstrating the potential of the thiol-ene click reaction for [MI(CO)3]+ incorporation into thiol containing biomolecules.

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–NPy 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 [MI(CO)3]+ (M = Re, 99mTc) 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-[ReI(CO)3(N,S,NPy-3)]+ (4) and comparative high-performance liquid chromatography (HPLC) analysis between 4 and [99mTcI(CO)3(N,S,NPy-3)]+ (4a). The α-MSH analogue bearing the N–S–NPy chelate on a modified cysteine residue (6) was generated and complexed with [MI(CO)3]+ to confirm the chelation strategy’s utility when applied in a peptide-based targeting agent. Characterization of the ReI(CO)3-6 peptide conjugate (7) confirmed the efficient incorporation of the metal center, and the 99mTcI(CO)3-6 analogue (7a) was explored as a potential single photon emission computed tomography (SPECT) compound for imaging the melanocortin 1 receptor (MC1R) in melanoma. Peptide 7a showed excellent radiolabeling yields and in vitro stability during amino acid challenge and serum stability assays. In vitro B16F10 melanoma cell uptake of 7a reached a modest value of 2.3 ± 0.08% of applied activity at 2 h at 37 °C, while this uptake was significantly reduced by coincubation with a nonlabeled α-MSH analogue, NAPamide (3.2 μM) (P < 0.05). In vivo SPECT/X-ray computed tomography (SPECT/CT) imaging and biodistribution of 7a were evaluated in a B16F10 melanoma xenografted mouse model. SPECT/CT imaging clearly visualized the tumor at 1 h post injection (p.i.) with high tumor-to-background contrast. Blocking studies with coinjected NAPamide (10 mg per kg of mouse body weight) confirmed the in vivo specificity of 7a for MC1R-positive tumors. Biodistribution results with 7a yielded a moderate tumor uptake of 1.20 ± 0.09 percentage of the injected radioactive dose per gram of tissue (% ID/g) at 1 h p.i. Relatively high uptake of 7a was also seen in the kidneys and liver at 1 h p.i. (6.55 ± 0.36% ID/g and 4.44 ± 0.17% ID/g, respectively), although reduced kidney uptake was seen at 4 h p.i. (3.20 ± 0.48% ID/g). These results demonstrate the utility of the novel [MI(CO)3]+ chelation strategy when applied in a targeting peptide.

Facile reactivity of hydrazides and aldehydes was explored as potential coupling partners for incorporation into M(CO)3 (M = Re, 99mTc) 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.

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-ReVO(CN)(acac2en) (1) and cis-ReVO(CN)(acac2pn) (2), formed by reacting trans-[ReVO(OH2)(acac2en)]Cl or trans-ReVO(acac2pn)Cl with [NBu4][CN]. The μ-bridged cyanide mixed-oxidation ReV–ReI complexes were prepared by incubating the asymmetric complexes, 1 or 2, with fac-[ReI(bipy)(CO)3][OTf] to yield cis-[ReVO(acac2en)(μ-CN-1κC:2κN)-fac-ReI(bipy)(CO)3][PF6] (3) and [cis-ReVO(acac2pn)(μ-CN-1κC:2κN)-fac-ReI(bipy)(CO)3][PF6] (4), respectively.

The fac-Re(OH2)3(CO)3+ moiety was investigated with a known bidentate ligand, acetylactone (acac) and amine based ligands in a 2 + 1 and tridentate approach. In the 2 + 1 approach, the fac-Re(CO)3(acac)(OH2) was reacted with ethylamine to yield the monomer version fac-Re(CO)3(acac)(NH2Et), 1. Based on the Schiff base condensation of a ketone and a primary amine, a tridentate ligand approach for fac-Re(OH2)3(CO)3+ utilizing the reactivity of acac and diamine ligands (1,2 ethylene, 1,3 propylene, 1,4 butylene) was explored in a didactic manner: 1) an in situ ligand synthesis approach reacting fac-Re(CO)3(acac)(OH2) with the diamine (2 + 2 = 3) or 2) direct complexation of fac-Re(OH2)3(CO)3+ with the prepared ligand. The results observed with rhenium complexes were characterized by standard chemical analysis and X-ray analysis.The fac-Re(CO)3+ moiety was investigated with a known bidentate ligand, acetylacetone (acac) to generate fac-Re(CO)3(acac)(OH2) followed by the introduction of amine based ligands in a 2 + 1 and tridentate approach.Research Highlights► Denticity of amine based ligands impacts the type of complex observed. ► Re(CO)3(acac) with amine donors can form 2 + 1 or tridentate complexes. ► Amines coordination vs. Schiff base condensation.

The fac-M(CO)3+ (M = Re, 99mTc) moiety was investigated with a known bidentate ligand, acetylacetone (acac) and imidazole based ligands in a 2 + 1 and tridentate approach. In the 2 + 1 approach, the fac-Re(CO)3(acac)(OH2) was reacted with imidazole or 1-methylimidazole to yield a unique anionic μ-bridging imidazol-1-ide dimer fac-[(imidazol-1-ide)-bis-(fac-acetylacetonatotricarbonylrhenium (I)], 1, or the monomer version fac-M(CO)3(acac)(1-methylimidazole), 2, respectively. Based on the Schiff base condensation of a ketone and a primary amine, a tridentate ligand approach for fac-M(OH2)3(CO)3+ utilizing the reactivity of acac and histamine was explored in a didactic manner: (1) an in situ ligand synthesis approach reacting fac-M(CO)3(acac)(OH2) with histamine (2 + 2 = 3) that led to the formation of an unexpected dimer μ-acachistimine, compound, 3, or (2) direct complexation of fac-M(OH2)3(CO)3+ with the prepared ligand acachistimine, 4, to yield the monomer product fac-M(CO)3(acachistimine), 5. The results observed with rhenium complexes characterized by standard chemical analysis and X-ray analysis correlated with the radioactive experiments conducted with 99mTc(CO)3+.The fac-M(CO)3+ (M = Re, 99mTc) moiety was investigated with a known bidentate ligand, acetylacetone (acac) to generate fac-Re(CO)3(acac)(OH2) followed by the introduction of imidazole based ligands in a 2 + 1 and tridentate approach. Depending on the ligand and reaction conditions, monomer and dimer complexes were isolated.

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

Development of new ligands for fac-M(OH2)3(CO)3+ (M = Re, 99mTc) 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,NPy, N,S,NPy). From the reaction with 1, two species were observed in the 1H NMR, where the primary product was the linear fac-Re(N,S,NPy-1)(CO)3+, 2a, complex. To identify the coordination mode of the minor product, functionalized analogues of 1 were prepared from S-(pyridin-2-ylmethyl)-Boc-l-cysteine-methyl ester, 3, with orthogonal protecting groups on the C terminus (methyl ester) in S-(pyridin-2-ylmethyl)-l-cysteine methyl ester, 4, or N terminus (Boc) in S-(pyridin-2-ylmethyl)-Boc-l-cysteine, 6, that specifically directed the coordination mode of fac-M(H2O)3(CO)3+ to either N,S,NPy or O,S,NPy, respectively. Two diastereomers [fac-Re(CO)3(N,S,NPy-4)]+, 5a and 5b, were observed and independently characterized by X-ray structure analysis and NMR in high yield with 4. Surprisingly, the O,S,NPy Re complex with ligand 6 was not observed and simplified versions, 3-(pyridin-2-ylmethylthio) propanoic acid, 7, and 2-(pyridin-2-ylmethylthio)acetic acid, 8, were investigated. Ligand 7 did not yield the desired linear tridentate O,S,NPy product. However, the shorter ligand 8 formed fac-Re(CO)3(O,S,NPy-8), 9, in high yield. 99mTc labeling studies were conducted and yielded similar results to the rhenium complex and effective (>99%) at 10−5 M ligand concentration.

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(OH2)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. From compound 1, several ligands (i.e., cysteine 2, histidine 5, imidazole 3) were conjugated to the flutamide derivative to yield targeting ligands capable of either tridentate or monodentate coordination in a “2 + 1” complex. fac-Re(CO)3+ complexes were prepared and characterized with the functionalized conjugates to yield fac-Re(CO)3(2-amino-3-(1-(2-(4-nitro-3-(trifluoromethyl)phenylamino)-2-oxoethyl)-1H-imidazol-4-yl) propanoate), 4, fac-Re (CO)3(2-(S-cysteinyl)-N-[4-nitro-3-(trifluoromethyl) phenyl]-acetamide), 6, and fac-Re(CO)3(picolinate)(2-(1H-imidazol-1-yl)-N-[4-nitro-3-(trifluoromethyl)phenyl]-acetamide), 7. The corresponding radioactive 99mTc analogues were prepared and stability studies of the radioactive compounds were also conducted.

Reactions of 2,5-bis(benzylthio)-1,3,4-thiadiazole (1) with a common organometallic rhenium starting material [NEt4]2[fac-[Re(I)Br3(CO)3] yielded two distinct types of complexes. Both complexes coordinate only through the nitrogen of the thiadiazole ring. Reaction of 1 with the rhenium starting material alone yielded a bimetallic complex fac-(di-μ-bromo)(μ-2,5-bis(benzylthio)-1,3,4-thiadiazole-κN:κ′N)bis(tricarbonyl rhenium (I)) (2). The nitrogens of the thiadiazole ring of 1 each coordinate to a different rhenium center combined with two bridging bromide ligands in 2. A “2+1” complex was prepared in a two step process by reacting the rhenium starting material with picolinic acid followed by 1 to yield fac-Re(I)(2,5-bis(benzylthio)-1,3,4-thiadiazole)(CO)3(picolinate) (3). Compounds 2 and 3 were characterized by NMR, IR, UV, elemental analysis, and single crystal X-ray diffraction.Reactions of 2,5-bis(benzylthio)-1,3,4-thiadiazole (1) with [NEt4]2[fac-[Re(I)Br3(CO)3] yielded two distinct types of complexes: a bimetallic complex fac-(di-μ-bromo) (μ-2,5-bis(benzylthio)-1,3,4-thiadiazole-κN:κ′N) bis (tricarbonyl rhenium (I)) (2) and a “2+1” complex fac-Re(I)(2,5-bis(benzylthio)-1,3,4-thiadiazole)(CO)3(picolinate) (3).

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. When a mixed-nitrogen donor bidentate ligand, 2-(2-aminoethyl)pyridine, that has different coordination affinities for fac-Re(acac)(OH2)(CO)3 was utilized, a unique tridentate ligand was formed in situ utilizing a metal-assisted Schiff base formation to yield a complex fac-Re(CO)3(3[(2-phenylethyl)imino]-2-pentanone) (3). Tridentate ligand formation was found to occur only with the Re-coordinated acac ligand. Reactions of acac with fac-Re(CO)3Br(2-(2-aminoethyl)pyridine) (4) or a mixture of [NEt4]2[ReBr3(CO)3], acac, and 2-(2-aminoethyl)pyridine did not yield the formation of complex 3 in water.

Facile reactivity of hydrazides and aldehydes was explored as potential coupling partners for incorporation into M(CO)3 (M = Re, 99mTc) 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.

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

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

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.

In the last two decades, a number of chelate strategies have been proposed for the fac-[MI(CO)3]+ (M = Re, 99mTc) 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. anionic) containing an aromatic amine in combination with monodentate pyridine analogs or imidazole were explored to determine the influence of the bidentate and monodentate ligands on the formation and stability of the respective complexes. The 2 + 1 complexes with Re and 99mTc were synthesized in two steps and characterized by standard radio/chemical methods. X-ray characterization and density functional theory analysis of the Re 2 + 1 complexes with the complete bidentate series with 4-dimethylaminopyridine were conducted, indicating enhanced ligand binding energies of the neutral over anionic ligands. In the 99mTc studies, anionic bidentate ligands had significantly higher formation yields of the 2 + 1 product, but neutral ligands appear to have increased stability in an amino acid challenge assay. Both bidentate series exhibited improved stability by increasing the basicity of the pyridine ligands.