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]

Bombesin is a tetradecapeptide neurohormone that binds to gastrin-releasing peptide receptors (GRPR). GRPRs have been found in a variety of cancers including invasive breast and prostate tumors. The peptide MP2346 (DOTA-(Pro(1),Tyr(4))-bombesin(1-14)) was designed to bind to these GRP receptors. This study was undertaken to evaluate radiolabeled MP2346 as a positron emission tomography (PET) imaging agent. MP2346 was radiolabeled, in high radiochemical purity, with the positron-emitting nuclides (64)Cu (t(1/2) = 12.7 h, beta+ = 19.3%, E(avg) = 278 keV) and (86)Y (t(1/2) = 14.7 h, beta+ = 33%, E(avg) = 664 keV). (64)Cu-MP2346 and (86)Y-MP2346 were studied in vitro for cellular internalization by GRPR-expressing PC-3 (human prostate adenocarcinoma) cells. Both (64)Cu- and (86)Y-MP2346 were studied in vivo for tissue distribution in nude mice with PC-3 tumors. Biodistribution in PC3 tumor-bearing mice demonstrated higher tumor uptake, but lower liver retention, in animals injected with (86)Y-MP2346 compared to (64)Cu-MP2346. Receptor-mediated uptake was confirmed by a significant reduction in uptake in the PC-3 tumor and other receptor-rich tissues by coinjection of a blockade. Small animal PET/CT imaging was carried out in mice bearing PC-3 tumors and rats bearing AR42J tumors. It was possible to delineate PC-3 tumors in vivo with (64)Cu-MP2346, but superior (86)Y-MP2346-PET images were obtained due to lower uptake in clearance organs and lower background activity. The (86)Y analogue demonstrated excellent PET image quality in models of prostate cancer for the delineation of the GRPR-rich tumors and warrants further investigation.

The aim of this work was to prepare a novel class of 64Cu(II) labeled complexes with the new macrocyclic ligands 1,10-dithia-4,7-diazacyclododecane-3,8-dicarboxylic acid (NEC-SE, 1), 1,10-dithia-4,7-diazacyclotridecane-3,8-dicarboxylic acid (NEC-SP, 2) and 1,10-dithia-4,7-diazacyclotetradecane-3,8-dicarboxylic acid, (NEC-SB, 3) to evaluate the usefulness of these macrocycles for potential utility as 64Cu(II) chelators. The corresponding non-radioactive complexes [Cu(NEC-SE)]·3H2O (4), [Cu(NEC-SP)]·3H2O (5) and [Cu(NEC-SB)] (6) were prepared and their 64Cu-analogs, [64Cu(NEC-SE)] (7) and [64Cu(NEC-SP)] (8) and [64Cu(NEC-SB)] (9) were produced in >98% radiochemical purity. Rats were injected with complex 7, 8 or 9 and were euthanized at 1, 4 and 24 h. All three complexes are cleared from the blood over the first hour following injection but there is poor clearance of this activity over 24 h. A similar pattern of retention was noted in the liver where the levels of activity in this tissue at 1 h are not statistically different from those at 24 h. Molecular mechanics and DFT studies were performed on the complexes in order to gain insight into the lower stability.

Hydrolysis of the new metallorganic precursor Fe(OBu t ) 2 -(THF) 2 followed by ultrasound and thermal treatment yielded either nanoparticles of c-Fe 2 O 3 or Fe 3 O 4 , depending on the process conditions. The samples have been characterised by X-ray powder diffraction, TEM, SEM, Mo ¨ssbauer spectroscopy and magnetization measurements. The maghemite nanoparticles (9¡2 nm) are superparamagnetic and form unique needle-like assemblies of nanoparticle arrays. The nanoparticles of Fe 3 O 4 (19¡ 2 nm) form plate-like aggregates about 10 mm thick.