Solid tumors often develop an acidic environment due to the Warburg effect. The effectiveness of diagnosis and therapy may therefore be enhanced by the design and use of pHsensitive agents that target acidic tumors. Recently, a novel technology was introduced to target acidic tumors using pH low insertion peptide (pHLIP), a peptide that inserts across cell membranes as an A-helix when the extracellular pH (pH e ) is acidic. In this study, we expanded the application of the pHLIP technology to include positron emission tomography imaging of the acidic environment in prostate tumors using 64 Cu conjugated to the pHLIP ( 64 Cu-DOTA-pHLIP). Studies showed that this construct avidly accumulated in LNCaP and PC-3 tumors, with higher uptake and retention in the LNCaP tumors. Uptake correlated with differences in the bulk pH e of PC-3 and LNCaP tumors measured in magnetic resonance spectroscopy experiments by the 31 P chemical shift of the pH e marker 3-aminopropylphosphonate. This article introduces a novel class of noninvasive pH-selective positron emission tomography imaging agents and opens new research directions in the diagnosis of acidic solid tumors. [Cancer Res 2009;69(10):4510-6]

Copper(II)-diacetyl-bis(N(4)-methylthiosemicarbazone), Cu-ATSM, labeled with a positron emitting isotope of copper ((60)Cu, (61)Cu, (62)Cu or (64)Cu) has been shown, in vitro and in vivo, to be selective for hypoxic tissue. In silico studies have explored the mechanism of its hypoxia selectivity, and clinical studies with this agent have shown non-invasive imaging data that is predictive of a cancer patients' response to conventional therapy. This Perspective discusses the evolution of Cu-ATSM, how its selectivity can be improved upon, and where this metal-ligand platform could be taken in the future.

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The copper(II) bisthiosemicarbazonato complex, copper-diacetyl-bis(N 4 -methylthiosemicarbazonate) (Cu-ATSM), has been used clinically as a positron emission tomography (PET) tracer for the delineation of hypoxia. Six novel, asymmetric bis(thiosemicarbazones) derived from diacetyl-2-(4-N-methyl-3-thiosemicarbazone)-3-(4-Namino-3-thiosemicarbazone) (H 2 ATSM/A), one of which contained a nitroimidazole functionality, were radiolabeled with 64 Cu (t ½ = 12.7 h, β+ = 19.3%). In vitro studies were performed on three of the compounds using EMT6 mammary carcinoma cells under hypoxic and normoxic conditions. All compounds displayed rapid cellular association and appreciable hypoxic selectivity with increased uptake under normoxic and hypoxic conditions when compared to 64 Cu-ATSM. Biodistribution and small animal PET imaging studies were then carried out in vivo using two compounds in EMT6 tumor-bearing mice. The compounds showed high tumor uptake, but also substantial accumulation in the liver. These complexes demonstrate that H 2 ATSM/A represents a novel and versatile synthetic platform that can be utilized to provide hypoxic cell selectivity through functionalization of the bisthiosemicarbazonate group.

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Introduction-Diagnosis of malignant melanoma is critical, since a patient's prognosis is poor. Previous studies have shown that 64 Cu-and 86 Y-DOTA-ReCCMSH(Arg 11 ) have the potential for early detection of malignant melanoma by exploiting the sensitivity and high resolution of PET. This encouraged us to investigate DOTA-ReCCMSH(Arg 11 ) labeled with another β + -emitting radionuclide, 68 Ga.Methods-DOTA-ReCCMSH(Arg 11 ) was successfully labeled with 68 Ga at pH 3.8-4 at 85 ºC. Acute biodistribution and small animal PET imaging studies were performed in B16/F1 melanoma tumor bearing mice.Results-Biodistribution studies showed moderate receptor-mediated tumor uptake, fast non-target organ clearance, and high tumor to non-target tissue ratios. Pre-administration of D-lysine significantly reduced kidney uptake without affecting the uptake of the agent in the tumor. Small animal PET images showed that the tumor could be clearly visualized at all time points examined (0.5 -2 h) with the standardized uptake value (SUV) analysis following a similar trend as the biodistribution data.Conclusions-The preliminary data obtained suggests that 68 Ga-DOTA-ReCCMSH(Arg 11 ) is a promising PET imaging agent for early detection of malignant melanoma.

Several titanium complexes are currently being investigated for their ability to exhibit antitumor activity both in vitro and in vivo (1). Sun et al. recently showed the first specific Ti(IV)‐protein complex through binding experiments with transferrin (2). This suggests that transferrin could be the mode of transport for titanium anticancer drugs since tumor cells show high levels of transferrin receptors on the cell surface (3). Transferrin has a molecular weight of 80 kDa and is only 30% saturated with iron, leaving available binding sites for other metal ions (4). Titanium‐45 has a half‐life of 3.09 hours and a positron branching ratio of 85% with an Eβ+max of 1.04 MeV. The work of Ishiwata et al. investigated 45Ti as a potential metal for labeling pharmaceuticals for PET imaging (5). In the current study, the biodistribution of 45Ti‐transferrin was examined to investigate the mode of transport of titanium compounds to tumors.

Introduction-PET imaging with Cu-ATSM for delineating hypoxia has provided valuable clinical information, but investigations in animal models of prostate cancer have shown some inconsistencies. As a defense mechanism in prostate cancer cells, the fatty acid synthesis pathway harnesses its oxidizing power for improving the redox balance despite conditions of extreme hypoxia, potentially altering Cu-ATSM hypoxia-selectivity.