Re(CO)₃([¹⁸F]FEDA), a new PET renal tracer: pharmacokinetics and metabolism in rats

Objectives: Positron emission tomography (PET) is increasingly used in early detection and treatment of many diseases because of its high spatial resolution, sensitivity, and quantitative accuracy. At present, however, there are no PET radiopharmaceuticals to evaluate the kidney comparable to ^99mTc-MAG3, the most commonly used ^99mTc renal radiopharmaceutical. We recently reported an efficient one-step method for the preparation of rhenium-tricarbonyl-N-[¹⁸F]fluoroethyl-iminodiacetic acid, Re(CO)₃([¹⁸F]FEDA) (J.Nucl.Med. 2016, 57 (Suppl. 2): 1066). This new ¹⁸F tracer is a structural analog of ^99mTc(CO)₃(FEDA), which is actively transported by the renal tubules and rapidly excreted in the urine (J.Nucl.Med. 2015, 56 (Suppl 3): 654). This present study was conducted in rats to compare the in vivo pharmacokinetic properties and metabolism of this new ¹⁸F renal tracer with those of ¹³¹I-OIH, the radioactive standard for the measurement of effective renal plasma flow.

Methods: Re(CO)₃([¹⁸F]FEDA) was prepared by the nucleophilic ¹⁸F-fluorination of its tosyl precursor. The labeled compound was isolated by high-performance liquid chromatography (HPLC), formulated in a 0.05 M TEAP solution containing 10% ethanol, and subsequently evaluated in Sprague-Dawley rats at 10 and 60 min using ¹³¹I-OIH as an internal control. In vivo stability and metabolites were determined by HPLC analysis of urine collected from a normal rat at 15 min after injection of ¹⁸F tracer. Plasma protein binding (PPB) and erythrocyte uptake (RCB) were determined from the 10 min blood samples. The Re(CO)₃(FEDA) analog was prepared for structural characterization.

Results: Re(CO)₃([¹⁸F]FEDA) was efficiently prepared as a single species with high radiochemical purity (>99%), and was stable in vitro through 24 hours at physiological pH. PPB was 87% and RCB was 21%. The renal uptake and renal excretion at 10 and 60 min were comparable to that of ¹³¹I-OIH. The activity in the urine, as a percentage of ¹³¹I-OIH, was 92% and 95% at 10 and 60 min, respectively. At 60 min, the percent injected dose in the bowel was 3.9% compared to 1.1% for ¹³¹I-OIH and there was minimal liver uptake (0.4% for ¹⁸F tracer vs. 0.6% for ¹³¹I-OIH). All other organs (heart, spleen, lungs) showed a negligible tracer uptake (less than 0.5%) indicating a high specificity for renal elimination. HPLC analysis of urine showed that the ¹⁸F compound was excreted intact with no metabolic products. Moreover, no detectable bone uptake was observed at 10 and 60 minutes post-injection demonstrating high in vivo stability.

Conclusion: Re(CO)₃([¹⁸F]FEDA) exhibited a high specificity for the kidney, rapid renal excretion comparable to that of ¹³¹I-OIH and high in vivo metabolic stability. These results suggest that Re(CO)₃([¹⁸F]FEDA) is a promising PET renal tracer that could result in a pair of analogous ¹⁸F/^99mTc renal imaging agents with almost identical structures and pharmacokinetic properties. These promising pre-clinical in vivo results warrant evaluation in humans. Research Support: This work was supported by the NIH/NIDDK grant R37 DK038842.