Whole-body PET/CT evaluation of tumor perfusion using generator-based 62Cu-ethylglyoxal bis(thiosemicarbazonato)copper(II): validation by direct comparison to 15O-water in metastatic renal cell carcinoma.

UNLABELLED: This study was undertaken to demonstrate the feasibility of whole-body (62)Cu-ethylglyoxal bis(thiosemicarbazonato)copper(II) ((62)Cu-ETS) PET/CT tumor perfusion imaging in patients with metastatic renal carcinoma and to validate (62)Cu-ETS as a quantitative marker of tumor perfusion by direct comparison with (15)O-water perfusion imaging. METHODS: PET/CT imaging of 10 subjects with stage IV renal cell cancer was performed after intravenous administration of (15)O-water (10-min dynamic list-mode study) with the heart and at least 1 tumor in the PET field of view, followed 10 min later by intravenous (62)Cu-ETS (6-min list-mode study). Whole-body (62)Cu imaging was then performed from 6 to 20 min at 2-3 min/bed position. Blood flow (K1) was quantified with both agents for normal and malignant tissues in the 21.7-cm dynamic field of view. The required arterial input functions were derived from the left atrium and, in the case of (62)Cu-ETS, corrected for partial decomposition of the agent by blood with data from an in vitro analysis using a sample of each patient's blood. This imaging protocol was repeated at an interval of 3-4 wk after initiation of a standard clinical treatment course of the antiangiogenic agent sunitinib. RESULTS: All subjects received the scheduled (62)Cu-ETS doses for the dynamic and subsequent whole-body PET/CT scans, but technical issues resulted in no baseline (15)O-water data for 2 subjects. Direct comparisons of the perfusion estimates for normal tissues and tumor metastases were made in 18 paired baseline and treatment studies (10 subjects; 8 baseline studies, 10 repeated studies during treatment). There was an excellent correlation between the blood flow estimates made with (62)Cu-ETS and (15)O-water for normal tissues (muscle, thyroid, myocardium) and malignant lesions (pulmonary nodules, bone lesions); the regression line was y = 0.85x + 0.15, R(2) = 0.83, for the 88 regions analyzed. CONCLUSION: (62)Cu-ETS provided high-quality whole-body PET/CT images, and (62)Cu-ETS measures of blood flow were highly and linearly correlated with (15)O-water-derived K1 values (mL(-1) ⋅ min(-1) ⋅ g). This tracer is suitable for use as a PET tracer of tumor perfusion in patients with metastatic renal cell carcinoma.

Performance of a 6²Zn/6²Cu microgenerator in kit-based synthesis and delivery of [6²Cu]Cu-ETS for PET perfusion imaging.

The performance of a commercially produced (62)Zn/(62)Cu microgenerator system, and an associated kit-based radiopharmaceutical synthesis method, was evaluated for clinical site production of [(62)Cu]Cu-ETS (ethylglyoxal bis(thiosemicarbazonato)copper(II)), an investigational agent for PET perfusion imaging. Using 37 generators, containing 1.84±0.23 GBq (62)Zn at 9:00 AM on the day of clinical use, a total of 45 patient doses of [(62)Cu]Cu-ETS (672±172 MBq) were delivered without difficulty. (62)Cu elution yields were high (approximately 90%), accompanied by extremely low (62)Zn breakthrough (<0.001%). Radiopharmaceutical preparation, from the start-of-elution to time-of-injection, consumed less than five minutes. The (62)Zn/(62)Cu microgenerator was a dependable source of short-lived positron-emitting (62)Cu, and the kit-based synthesis proved to be rapid, robust, and highly reliable for "on-demand" delivery of [(62)Cu]Cu-ETS for PET perfusion imaging.

Copper-62 labeled ReCCMSH peptide analogs for melanoma PET imaging.

High-specific activity radiolabeled melanocortin peptide preparations are necessary for optimal melanoma imaging due to the relatively low number of melanocortin-1 receptors (MC1-Rs) per tumor cell. In this study, a one-step synthesis of 62Cu-labeled MC1-R targeting peptide Re(Arg11)CCMSH was developed, which yielded high specific activity radiolabeled peptide preparations that required no post-labeling purification. DOTA and NOTA conjugated Re(Arg11)CCMSH peptides were synthesized and examined for 62Cu radiolabeling and cell binding properties. Biodistribution and PET imaging studies were performed to assess the in vivo tumor targeting and imaging characteristics of the optimal radiolabeled peptide. Melanoma cell binding affinities for NOTA-, NOTA-GGG-, and NOTA-GSG- conjugated Re(Arg11)CCMSH were determined to be 1.3×10-9 M, 1.9×10-9 M and 6.0×10-9 M. The 62Cu radiolabeling efficiencies of DOTA- and NOTA- conjugated Re(Arg11)CCMSH analogs were 30% and > 98% after 2 min at 24° C, while 0.5 µg of NOTA-GGG-peptide could be labeled to > 95% with a maximum specific activity of 138 Ci/µmol. Tumor uptake of 62Cu- NOTA-GGG-Re(Arg11)CCMSH in B16/F1 melanoma bearing mice was 4.65±0.48% ID/g and 9.43±2.69% ID/g at 20 and 40 min post injection and was visualized by PET imaging. High specific activity 62Cu-NOTA-GGG-Re(Arg11)CCMSH was prepared in a one-step procedure at 24°C in 6 min. 62Cu-NOTA-GGG-Re(Arg11)CCMSH exhibited MC1-R selective binding and rapid tumor uptake in B16/F1 melanoma bearing mice that was confirmed by PET imaging studies. High specific activity 62Cu from a 62Zn/62Cu generator coupled with simple one step radiolabeling procedures makes 62Cu an attractive radionuclide for PET imaging of low-density receptor targets.

PET of hypoxia and perfusion with 62Cu-ATSM and 62Cu-PTSM using a 62Zn/62Cu generator.

OBJECTIVE: Copper-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) and copper-pyruvaldehyde-bis(N4-methylthiosemicarbazone) (Cu-PTSM) are being studied as potential markers of hypoxia and perfusion, respectively. The use of short-lived radionuclides (e.g., 62Cu) has advantages for clinical PET, including a lower radiation dose than long-lived radionuclides and serial imaging capability. A 62Zn/62Cu microgenerator and rapid synthesis kits now provide a practical means of producing 62Cu-PTSM and 62Cu-ATSM on-site. Tumors can be characterized with 62Cu-PTSM, 62Cu-ATSM, and 18F-FDG PET scans during one session. We present the initial clinical data in two patients with lung neoplasms. CONCLUSION: Hypoxia and perfusion are important parameters in tumor physiology and can have major implications in diagnosis, prognosis, treatment planning, and response to therapy. We have shown the feasibility of performing 62Cu-ATSM and 62Cu-PTSM PET together with FDG PET/CT during a single imaging session to provide information on both perfusion and hypoxia and tumor anatomy and metabolism.

Assessment of Cu-ETS as a PET radiopharmaceutical for evaluation of regional renal perfusion.

UNLABELLED: The copper(II) complex of ethylglyoxal bis(thiosemicarbazone) (Cu-ETS) was evaluated as a positron emission tomography (PET) radiopharmaceutical for assessment of regional renal perfusion. METHODS: The concordance of renal flow estimates obtained with 11- and 15-microm microspheres was confirmed in four immature farm pigs using co-injected (46)Sc- and (57)Co-microspheres administered into the left ventricle. With the use of both immature farm pigs (n=3) and mature Göttingen minipigs (n=6), regional renal radiocopper uptake following intravenous [(64)Cu]Cu-ETS administration was compared to microsphere measurements of renal perfusion. The distribution and kinetics of [(64)Cu]Cu-ETS were further studied by PET imaging of the kidneys. The rate of [(64)Cu]Cu-ETS decomposition by blood was evaluated in vitro, employing octanol extraction to recover intact [(64)Cu]Cu-ETS. RESULTS: The co-injected 11- and 15-microm microspheres provided similar estimates of renal flow. A linear relationship was observed between the renal uptake of intravenous [(64)Cu]Cu-ETS and regional renal perfusion measured using microspheres. [(64)Cu]Cu-ETS provided high-quality PET kidney images demonstrating the expected count gradient from high-flow outer cortex to low-flow medulla. When incubated with pig blood in vitro at 37 degrees C, the [(64)Cu]Cu-ETS radiopharmaceutical was observed to decompose with a half-time of 2.8 min. CONCLUSION: Cu-ETS appears suitable for use as a PET radiopharmaceutical for evaluation of regional renal perfusion, affording renal uptake of radiocopper that varies linearly with microsphere perfusion measurements. Quantification of renal perfusion (in ml min(-1) g(-1)) with [(60,61,62,64)Cu]Cu-ETS will require correcting the arterial input function for the fraction of blood radiocopper remaining present as the intact Cu-ETS radiopharmaceutical, since the Cu-ETS chelate has limited chemical stability in blood. Rapid octanol extraction of blood samples appears suitable as an approach to capturing the actual blood concentration of [(60/61/62/64)Cu]Cu-ETS.