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