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. 2018 Mar:58:42-50.
doi: 10.1016/j.nucmedbio.2017.12.001. Epub 2017 Dec 27.

Re(CO)3([18F]FEDA), a novel 18F PET renal tracer: Radiosynthesis and preclinical evaluation

Malgorzata Lipowska  1 , Nashwa Jarkas  2 , Ronald J Voll  3 , Jonathon A Nye  3 , Jeffrey Klenc  2 , Mark M Goodman  3 , Andrew T Taylor  2
Affiliations

Re(CO)3([18F]FEDA), a novel 18F PET renal tracer: Radiosynthesis and preclinical evaluation

Malgorzata Lipowska et al. Nucl Med Biol. 2018 Mar.

Abstract

Introduction: Our previous work demonstrated that the 99mTc renal tracer, 99mTc(CO)3(FEDA) (99mTc-1), has a rapid clearance comparable in rats to that of 131I-OIH, the radioactive gold standard for the measurement of effective renal plasma flow. The uncharged fluoroethyl pendant group of 99mTc-1 provides a route to the synthesis of a structurally analogous rhenium-tricarbonyl 18F renal imaging agent, Re(CO)3([18F]FEDA) (18F-1). Our goal was to develop an efficient one-step method for the preparation of 18F-1 and to compare its pharmacokinetic properties with those of 131I-OIH in rats.

Methods: 18F-1 was prepared by the nucleophilic 18F-fluorination of its tosyl precursor. The labeled compound was isolated by HPLC and subsequently evaluated in Sprague-Dawley rats using 131I-OIH as an internal control and by dynamic PET/CT imaging. Plasma protein binding (PPB) and erythrocyte uptake (RCB) were determined and the urine was analyzed for metabolites.

Results: 18F-1 was efficiently prepared as a single species with high radiochemical purity (>99%) and it displayed high radiochemical stability in vitro and in vivo. PPB was 87% and RCB was 21%. Biodistribution studies confirmed rapid renal extraction and high specificity for renal excretion, comparable to that of 131I-OIH, with minimal hepatic/gastrointestinal elimination. The activity in the urine, as a percentage of 131I-OIH, was 92% and 95% at 10 and 60 min, respectively. All other organs (heart, spleen, lungs) showed a negligible tracer uptake (<0.4% ID). Dynamic microPET/CT imaging demonstrated rapid transit of 18F-1 through the kidneys and into the bladder; there was no demonstrable activity in bone verifying the absence of free [18F]fluoride.

Conclusions: 18F-1 exhibited a high specificity for the kidney, rapid renal excretion comparable to that of 131I-OIH and high in vivo radiochemical stability. Not only is 18F-1 a promising PET renal tracer, but it provides a route to the development of a pair of analogous 18F/99mTc renal imaging agents with almost identical structures and comparable pharmacokinetic properties. These promising in vivo results warrant subsequent evaluation in humans.

Keywords: Biodistribution; PET imaging; Radiolabeling; Re(CO)(3)([(18)F]FEDA); Renal radiotracer.

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Figures

Figure 1
Figure 1
Structures of known 99mTc-tricarbonyl renal tracers based on the iminodiacetate chelate with different pendant groups; tracers’ overall charges at physiological pH are included.
Figure 2
Figure 2
HPLC chromatograms of Re(CO)3([18F]FEDA) (18F-1; top, red) co-injected with Re(CO)3(FEDA) (1; bottom, green) to confirm the radiotracer identity (HPLC: 0.05 M TEAP pH 7/MeOH, 80:20 v/v, isocratic method, flow 1 mL/min).
Figure 3
Figure 3
In vitro stability of Re(CO)3([18F]FEDA) (18F-1) at physiological pH was confirmed by HPLC at 2 hours (A) and 23 hours (B) after radiolabeling. The upper trace shows the radio-profile (red) and the lower trace shows the UV profile at 254 nm (green).(HPLC: 0.05 M TEAP pH 7/MeOH, 80:20 v/v, isocratic method, flow 1 mL/min).
Figure 4
Figure 4
Fused volume rendering of PET and CT (summed 5–30 min) of a normal rat injected with Re(CO)3([18F]FEDA) (18F-1) (injected radioactivity: 0.3 mCi, anesthesia: 2% isoflurane).
Figure 5
Figure 5
Representative sequence of microPET maximum intensity projection coronal images (2 min/frame, total 30 min) of Re(CO)3([18F]FEDA) (18F-1) showing rapid accumulation in the kidneys and clearance into the bladder.
Figure 6
Figure 6
Representative time activity curves (TAC) in kidney, bladder, heart and liver for PET imaging studies with Re(CO)3([18F]FEDA) (18F-1) in rats.
Figure 7
Figure 7
Radio-HPLC chromatograms of purified Re(CO)3([18F]FEDA) (18F-1) before injection (A) and of rat urine 10 min after i.v. injection of (18F-1) (B) (HPLC: 0.05 M TEAP pH 2.5/MeOH, gradient method [25] flow 1 mL/min).
Scheme 1
Scheme 1
Synthesis of labeling precursor Re(CO)3(TsDA) (Re-OTs) and reference complex Re(CO)3(FEDA) (1) starting from the FEDA ligand (Eg.1) [22] and the labeling precursor Re-OTs (Eg.2).
Scheme 2
Scheme 2
Radiosynthesis of Re(CO)3([18F]FEDA) (18F-1).
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