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

https://doi.org/10.1016/j.nucmedbio.2007.01.002Get rights and content

Abstract

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-μm microspheres was confirmed in four immature farm pigs using co-injected 46Sc- and 57Co-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 [64Cu]Cu-ETS administration was compared to microsphere measurements of renal perfusion. The distribution and kinetics of [64Cu]Cu-ETS were further studied by PET imaging of the kidneys. The rate of [64Cu]Cu-ETS decomposition by blood was evaluated in vitro, employing octanol extraction to recover intact [64Cu]Cu-ETS.

Results

The co-injected 11- and 15-μm microspheres provided similar estimates of renal flow. A linear relationship was observed between the renal uptake of intravenous [64Cu]Cu-ETS and regional renal perfusion measured using microspheres. [64Cu]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°C, the [64Cu]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 [60,61,62,64Cu]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 [60/61/62/64Cu]Cu-ETS.

Introduction

The copper complex of ethylglyoxal bis(thiosemicarbazone), Cu-ETS (Fig. 1), has potential utility as a generator-based PET radiopharmaceutical for evaluation of renal perfusion using the positron-emitting isotopes of copper (specifically, generator-produced 62Cu, or cyclotron-produced 60Cu, 61Cu or 64Cu). Of these nuclides, copper-62 may be the most suitable for widespread clinical use, since the 62Zn/62Cu parent/daughter generator system can serve as a source of short-lived PET radiopharmaceuticals even in locations remote from cyclotron-based radionuclide production facilities [1]. The cyclotron-produced 62Zn parent is sufficiently long-lived (9.26-h half-life) to allow generator distribution from centralized production sites [2], [3], while the 62Cu-daughter (9.67-min half-life) is sufficiently long-lived for radiopharmaceutical synthesis, but still decays rapidly enough to allow back-to-back imaging studies in a single imaging session.

The best-studied 62Cu-radiopharmaceutical, Cu-PTSM (Fig. 1), has shown promise for use in PET evaluation of cerebral, myocardial, renal and tumor perfusion [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16]. This bis(thiosemicarbazone) chelate affords high first-pass tissue extraction of radiocopper, followed by prolonged “microsphere-like” tissue retention of the 62Cu-radiolabel upon intracellular reductive decomposition of CuII-PTSM [4], [5], [6], [7], [8], [9], [14], [15], [17], [18], [19], [20].

[62Cu]Cu-PTSM is suitable for flow quantification in animal models [6], [8], [12] and provides high-quality images of the resting human heart that qualitatively and quantitatively map the pattern of myocardial perfusion [2], [3], [10], [13], [14], [15]. However, in humans there is marked attenuation of the tissue uptake of Cu-PTSM at high rates of flow [13], [14], [15], due to the tracer's noncovalent association with serum albumin, a species-dependent interaction that is anomalously strong with human serum albumin [13], [21]. The “second-generation” copper(II) bis(thiosemicarbazone) radiopharmaceutical, [62Cu]Cu-ETS, does not exhibit the inter-species variations in albumin binding seen with Cu-PTSM [21]; thus, it is expected that the performance of [62Cu]Cu-ETS as a perfusion tracer in humans can be more faithfully predicted from experiments in animal models.

The present study was undertaken to evaluate the suitability of [62Cu]Cu-ETS for PET measurements of regional renal perfusion.

Section snippets

General

All animal experiments were performed in accordance with protocols reviewed and approved by the appropriate institutional review committee. Immature pigs were obtained from a local farm, while Göttingen mini-swine were obtained from a commercial breeder (Marshall Farms, North Rose, NY, USA). The pigs were anesthetized throughout all studies with ketamine (15–20 mg kg−1 im) and xylazine (1–2 mg kg−1 im) for induction, followed by inhaled isoflurane (0.8–2.5%) with 100% oxygen. Respiration was

Effects of microsphere size on measurements of regional renal perfusion

The literature defines size-related skimming as a limitation in the use of radiolabeled microspheres as markers of regional renal perfusion [23], [24], [25], [26]. So, prior to initiating studies to validate Cu-ETS as a marker of regional renal perfusion, we examined the behavior of 11- and 15-μm microspheres in the pig kidney when sampling at tissue volumes approximating those which might be resolved in [62Cu]Cu-ETS PET images.

There was generally good agreement between renal perfusion

Discussion

There is no consensus on the best radionuclide technique for measurement of renal perfusion, although attenuation-corrected PET imaging has intrinsic advantages over gamma scintigraphy for quantitative studies of absolute blood flow. PET has been employed for assessment of regional renal perfusion using both cyclotron-produced radiopharmaceuticals (15O-water, 13N-ammonia) [29], [30], [31], [32], [33], [34] and generator-produced radiopharmaceuticals (82RbCl; 62Cu-PTSM) [8], [35], [36]. An

Conclusions

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 values of regional perfusion. The radiocopper label exhibits prolonged retention in the kidneys, consistent with the Cu(II)-ETS's expected susceptibility to loss of the copper radiolabel into the cellular pool of ionic copper following intracellular reductive decomposition of the chelate. This trapping mechanism will

Acknowledgments

This work was supported by NIH Grant #R44DK58466. 64Cu production at Washington University was supported by NCI grant R24CA86307. The Indiana Center of Excellence in Biomedical Imaging is supported in part by the Indiana Genomics Initiative and the Lilly Endowment, Inc.

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