Production of therapeutic quantities of (64)Cu using a 12 MeV cyclotron.

(64)Cu is a useful radiotracer for positron emission tomography (PET) and a promising radiotherapy agent for the treatment of cancer. Recently, (64)Cu-labeled radiopharmaceuticals were reported to be useful for internal radiation therapy as well as PET monitoring of tumors.(64)Cu was produced at the Fukui Medical University's cyclotron using twelve MeV proton irradiation and the (64)Ni(p,n) (64)Cu nuclear reaction. A (64)Ni target was electroplated on a gold disk at a thickness of 50 to > 100 microm. Electroplating was performed at 2.5 V, at currents between 5-15 mA, and was completed in 12-24 hr. The (64)Ni target was bombarded with a 50 +/- 3 microA proton current. After bombardment, (64)Cu was separated from the (64)Ni target and other contaminants using an anion exchange column. Target (64)Ni was recovered and re-used. The yield of (64)Cu was 0.6 to > 3.0 mCi/microA*h, and averaged 1.983 mCi/microA*h. The radionuclidic purity of (64)Cu was over 99%. In this study, we obtained sufficient qualities and quantities of (64)Cu for therapeutic application and dose monitoring using PET using an ultra-small cyclotron.

MicroPET imaging of a gastrin-releasing peptide receptor-positive tumor in a mouse model of human prostate cancer using a 64Cu-labeled bombesin analogue.

The gastrin-releasing peptide receptor (GRPR) is overexpressed on a variety of carcinomas and has been the target for detection and treatment of these neoplasms in animals. In particular, analogues of the tetradecapeptide bombesin (BN) have been radiolabeled with (99m)Tc and (111)In for detection of GRPR-positive tumors by gamma ray scintigraphy. The goal of this study was to evaluate the potential of the bombesin analogue, DOTA-Aoc-BN(7-14), for positron-emission tomographic (PET) imaging after radiolabeling with the positron-emitter (64)Cu. A saturation binding assay on PC-3 human prostate cancer cells showed that (64)Cu-DOTA-Aoc-BN(7-14) had an equilibrium binding constant (K(d)) of 6.1 +/- 2.5 nM and a receptor concentration (B(max)) of 2.7 +/- 0.6 x 10(5) receptors/cell. The radiolabeled analogue also showed rapid internalization with 18.2% internalized into 10(5) PC-3 cells by 2 h. The tumor localization of (64)Cu-DOTA-Aoc-BN(7-14) was 5.5% injected dose per gram in athymic nude mice bearing PC-3 xenografts at 2 h postinjection. The tumor retention with respect to the 2 h value was 76% and 45% at 4 and 24 h, respectively, and was GRPR-mediated as shown by inhibition with a coinjection of excess peptide. MicroPET imaging of (64)Cu-DOTA-Aoc-BN(7-14) in athymic nude mice bearing subcutaneous PC-3 tumors showed good tumor localization. Further studies with (64)Cu-pyruvaldehyde-bis(N(4)-methylthiosemicarbazone) ((64)Cu-PTSM) suggested that low blood flow to the PC-3 tumors may have limited the localization of (64)Cu-DOTA-Aoc-BN(7-14). This study demonstrates that (64)Cu-DOTA-Aoc-BN(7-14) can be used to detect GRPR-positive tumors by PET imaging.

Ex vivo cell labeling with 64Cu-pyruvaldehyde-bis(N4-methylthiosemicarbazone) for imaging cell trafficking in mice with positron-emission tomography.

We have used copper-64-pyruvaldehyde-bis(N4-methylthiosemicarbazone) (64Cu-PTSM) to radiolabel cells ex vivo for in vivo positron-emission tomography (PET) imaging studies of cell trafficking in mice and for eventual application in patients. 2-[18F]-Fluoro-2-deoxy-d-glucose (FDG) cell labeling also was evaluated for comparison. 64Cu-PTSM uptake by C6 rat glioma (C6) cells increased for 180 min and then stabilized. The labeling efficiency was directly proportional to 64Cu-PTSM concentration and influenced negatively by serum. Label uptake per cell was greater with 64Cu-PTSM than with FDG. However, both 64Cu-PTSM- and FDG-labeled cells showed efflux of cell activity into supernatant. The 64Cu-PTSM labeling procedure did not interfere significantly with C6 cell viability and proliferation rate. MicroPET images of living mice indicate that tail-vein-injected labeled C6 cells traffic to the lungs and liver. In addition, transient splenic accumulation of radioactivity was clearly detectable in a mouse scanned at 3.33 h postinfusion of 64Cu-PTSM-labeled lymphocytes. In contrast, the liver was the principal organ of tracer localization after tail-vein administration of 64Cu-PTSM alone. These results indicate that in vivo imaging of cell trafficking is possible with 64Cu-PTSM-labeled cells. Given the longer t(1/2) of 64Cu (12.7 h) relative to 18F (110 min), longer cell-tracking periods (up to 24-36 h) should be possible now with PET.