Evaluation of Cu-PTSM as a tracer of tumor perfusion: Comparison with labeled microspheres in spontaneous canine neoplasms

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Abstract

Copper-62-labeled Cu-PTSM is a promising generator-produced PET tracer for myocardial, cerebral and renal perfusion. To evaluate whether [62Cu]Cu-PTSM could also serve as a blood flow tracer in PET studies of tumor tissue, the tumor uptake of [67Cu]Cu-PTSM was examined in dogs with spontaneously-occurring soft-tissue neoplasms. Copper-67-labeled Cu-PTSM was administered intravenously to four anesthetized dogs, followed c. 5 min later by a left ventricular injection of 85Sr-labeled microspheres (15 μm) to provide an independent measure of tumor perfusion. Forty-seven tumors (average weight = 2.5 ± 3.7 g) were obtained and sectioned into 80 samples. The correlation of 67Cu-PTSM uptake with regional renal perfusion was also examined in data from 395 tissue samples ranging in flow from 0.02 to 9.39 mL min−1 g−1. Rates of tumor perfusion assessed with 85Sr-labeled microspheres ranged from 0.011 to 3.0 mL min−1 g−1. No correlation was found between tumor size and the rate of tumor perfusion. However, an excellent linear correlation exists between tumor perfusion calculated from [67Cu]Cu-PTSM data and tumor perfusion measured with 85Sr-microspheres (r = 0.94 for 80 samples), suggesting that [62Cu]Cu-PTSM may be useful as a radiopharmaceutical for PET studies of tumor perfusion.

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      Radiocopper-labeled Cu-PTSM shows high first-pass cerebral extraction and radionuclide retention (Green et al., 1988; Mathias et al., 1990), as well as high extraction and retention in myocardium over a broad flow range (Shelton et al., 1989; Barnhart et al., 1989; Shelton et al., 1990; Herrero et al., 1993), without sensitivity to underlying myocardial hypoxia. Cu-PTSM has similarly been shown to be suitable for PET assessment of renal perfusion (Barnhart et al., 1989; Shelton et al., 1990) and tumor perfusion (Mathias et al., 1991; Mathias et al., 1994) in animal models. Unfortunately, in contrast to its behavior in animal models, the Cu-PTSM chelate strongly associates with Warfarin binding site of human serum albumin (HSA) (Mathias et al., 1995; Basken et al., 2008; Basken et al., 2009; Basken and Green, 2009).

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      Prior to use for hypoxia, most the initial investigations into thiosemicarbazones and their metal complexes focused on their role in the treatment of a variety of diseases including bacterial and viral infections, malaria and cancer [349,350]. The bisthiosemicarbazone 62Cu-PTSM (copper pyruvaldehyde-bis(N4-methylthiosemicarbazone)) has been investigated extensively as a blood perfusion tracer, particularly for myocardial and neurological purposes [351–368]. Work by Fujibayashi and co-workers in 1997 showed that CuATSM (copper diacetyl-bis(N4-methylthiosemicarbazone)), which differs by only a methyl group on the backbone, had statistically significant hypoxic selectivity in ex vivo ischaemic rat heart models [369,370].

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      Compounds such as Cu-PTSM and Cu-ETS (Fig. 3) show the desired high first-pass extraction of tracer, along with prolonged “microsphere-like” tissue retention of the radiolabel12,33,36-39 as these chelates undergo rapid intracellular reductive decomposition (liberating the 62Cu radiolabel to the endogenous cellular copper pool40-43). The lead Cu-PTSM radiopharmaceutical showed significant potential as a multi-organ tracer for flow quantification (mL · min−1 · g−1) in a variety of animal models28,34,44,45 and also has been studied in human beings.28,35,39,46-49 Unfortunately, in contrast to its behavior in animal models, Cu-PTSM strongly associates with the warfarin binding site of human serum albumin,50-53 making its tissue extraction fraction strongly perfusion-rate–dependent in human beings and undermining clinical use for robust flow quantification.

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