Summation Copper-64 (T1/2=12.7 hours; β+, 0.653MeV [17.8 %]; β−, 0.579MeV [38.4 %]) has decay characteristics that allow for positron emission tomography (PET) imaging and targeted radiotherapy of cancer. The well-established coordination chemistry of copper allows for its reaction with a wide variety of chelator systems that can potentially be linked to peptides and other biologically relevant small molecules, antibodies, proteins, and nanoparticles. The 12.7-hours half-life of 64Cu provides the flexibility to image both smaller molecules and larger, slower clearing proteins and nanoparticles. In a practical sense, the radionuclide or the 64Cu-radiopharmaceuticals can be easily shipped for PET imaging studies at sites remote to the production facility. Due to the versatility of 64Cu, there has been an abundance of novel research in this area over the past 20 years, primarily in the area of PET imaging, but also for the targeted radiotherapy of cancer. The biologic activity of the hypoxia imaging agent, 60/64Cu-ATSM, has been described in great detail in animal models and in clinical PET studies. An investigational new drug application for 64Cu-ATSM was recently approved by the U.S. Food and Drug Administration (FDA) in the United States, paving the way for a multicenter trial to validate the utility of this agent, with the hopeful result being FDA approval for routine clinical use. This article discusses state-of-the-art cancer imaging with 64Cu radiopharmaceuticals, including 64Cu-ATSM for imaging hypoxia, 64Cu-labeled peptides for tumor-receptor targeting, 64Cu-labeled monoclonal antibodies for targeting tumor antigens, and 64Cu-labeled nanoparticles for cancer targeting. The emphasis of this article will be on the new scientific discoveries involving 64Cu radiopharmaceuticals, as well as the translation of these into human studies.

The design, synthesis, and characterization of a synthetic chloride membrane transporter, SCMTR (synthetic chloride membrane transporter, "scimitar"), are presented. The compound [CH3(CH2)17]2NCOCH2OCH2CO-GGGPGGG-OBzl inserts rapidly into liposomes and planar lipid bilayers. SCMTR has a 1.3 +/- 0.01 nS chloride diffusion pathway (>10:1 Cl/K selectivity). Evidence was also obtained for voltage gating behavior.

A new class of cross-bridged cyclam-based macrocycles featuring phosphonate pendant groups has been developed. 1,4,8,11-tetraazacyclotetradecane-1,8-di(methanephosphonic acid) (CB-TE2P, 1) and 1,4,8,11-tetraazacyclotetradecane-1-(methanephosphonic acid)-8-(methanecarboxylic acid) (CB-TE1A1P, 2) have been synthesized and have been shown to readily form neutral copper (II) complexes at room temperature as the corresponding dianions. Both complexes showed high kinetic inertness to demetallation and crystal structures confirmed complete encapsulation of copper (II) ion within each macrocycle’s cleft-like structure. Unprecedented for cross-bridged cyclam derivatives, both CB-TE2P (1) and CB-TE1A1P (2) can be radiolabeled with 64Cu at room temperature in less than 1 hour with specific activities >1mCi/μg. The in vivo behavior of both 64Cu-CB-TE2P and 64Cu-CB-TE1A1P were investigated through biodistribution studies using healthy, male, Lewis rats. Both new compounds showed rapid clearance with similar or lower accumulation in non-target organs/tissues when compared to other copper chelators including CB-TE2A, NOTA and Diamsar.

Cation-pi interactions occur between cations and electron-rich species such as double bonds, triple bonds, and arenes. The pi-electron system may be neutral or anionic, but the latter are less relevant to biology, at least so far as is currently known. Among the 20 essential amino acids, there are four aromatic residues. These are benzene, phenol, indole, and imidazole, on the side chains of phenylalanine, tyrosine, tryptophan, and histidine, respectively. Of these, imidazole is expected to be a sigma-donor, and benzene, phenol, and indole are antipicated to serve as pi-donors. Sodium and potassium are the most abundant cations in living systems. This Account describes an experimental system that has been developed to probe, especially by X-ray crystallography, the interactions that occur between Na(+) or K(+) and the neutral arenes of particular biological significance.

Prostate-specific membrane antigen (PSMA) is a well-recognized target for identification and therapy of a variety of cancers. Here we report five 64Cu-labeled inhibitors of PSMA, [64Cu]3–7, which are based on the lysine–glutamate urea scaffold and utilize a variety of macrocyclic chelators, namely NOTA(3), PCTA(4), Oxo-DO3A(5), CB-TE2A(6), and DOTA(7), in an effort to determine which provides the most suitable pharmacokinetics for in vivo PET imaging. [64Cu]3–7 were prepared in high radiochemical yield (60–90%) and purity (>95%). Positron emission tomography (PET) imaging studies of [64Cu]3–7 revealed specific accumulation in PSMA-expressing xenografts (PSMA+ PC3 PIP) relative to isogenic control tumor (PSMA– PC3 flu) and background tissue. The favorable kinetics and high image contrast provided by CB-TE2A chelated [64Cu]6 suggest it as the most promising among the candidates tested. That could be due to the higher stability of [64Cu]CB-TE2A as compared with [64Cu]NOTA, [64Cu]PCTA, [64Cu]Oxo-DO3A, and [64Cu]DOTA chelates in vivo.

Crown ether-based synthetic cation conducting channels called hydraphiles show clear ionophoretic activity in phospholipid vesicles. These compounds are shown to be active against the bacterium E. coli. Disk diffusion assays were performed to assess the toxicity of different hydraphile derivatives. Liquid culture tests were conducted to quantitate the dependence of bacterical activity on channel length. It is proposed that hydraphiles are toxic to bacteria as a result of channel formation in the membrane. The bactericidal activity is found to depend at least on the presence of a functional central relay and proper channel length. It is speculated that hydraphiles insert into the bilayer and disrupt the cell's osmotic balance, leading to cell death.

A phosphonate pendant-armed cross-bridged cyclam chelator has been synthesized, complexed to Cu(ii), radiolabeled with (64)Cu under mild conditions, and its biodistribution studied.

The synthetic peptide, R 2 N-COCH 2 OCH 2 CO-Gly-Gly-Gly-Pro-Gly-Gly-Gly-OR', was shown to be selective for Cl -over K + when R is n-octadecyl and R' is benzyl. Nineteen heptapeptides have now been prepared in which the N-terminal and C-terminal residues have been varied. All of the Nterminal residues are dialkyl but the C-terminal chains are esters, 2° amides, or 3° amides. The compounds having varied N-terminal anchors and C-terminal benzyl groups are as follows: 1, R = n-propyl; 2, R = n-hexyl; 3, R = n-octyl; 4, R = n-decyl; 5, R = n-dodecyl; 6, R = n-tetradecyl; 7, R = n-hexadecyl; 8, R = n-octadecyl. Compounds 9-19 have R = n-octadecyl and C-terminal residues as follows: 9, OR' = OCH 2 CH 3 ; 10, OR' = OCH(CH 3 ) 2 ; 11, OR' = O(CH 2 ) 6 CH 3 ; 12, OR' = OCH 2 -c-C 6 H 11 ; 13, OR' = O(CH 2 ) 9 CH 3 ; 14, OR' = O (CH 2 ) 17