Introduction: Our previous work demonstrated that the 99m Tc renal tracer, 99m Tc(CO) 3 (FEDA) ( 99m Tc-1), has a rapid clearance comparable in rats to that of 131 I-OIH, the radioactive gold standard for the measurement of effective renal plasma flow. The uncharged fluoroethyl pendant group of 99m Tc-1 provides a route to the synthesis of a structurally analogous rhenium-tricarbonyl 18 F renal imaging agent, Re(CO) 3 ([ 18 F]FEDA) ( 18 F-1). Our goal was to develop an efficient one-step method for the preparation of 18 F-1 and to compare its pharmacokinetic properties with those of 131 I-OIH in rats. Methods: 18 F-1 was prepared by the nucleophilic 18 F-fluorination of its tosyl precursor. The labeled compound was isolated by HPLC and subsequently evaluated in Sprague-Dawley rats using 131 I-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: 18 F-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 131 I-OIH, with minimal hepatic/gastrointestinal elimination. The activity in the urine, as a percentage of 131 I-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 18 F-1 through the kidneys and into the bladder; there was no demonstrable activity in bone verifying the absence of free [ 18 F]fluoride. Conclusions: 18 F-1 exhibited a high specificity for the kidney, rapid renal excretion comparable to that of 131 I-OIH and high in vivo radiochemical stability. Not only is 18 F-1 a promising PET renal tracer, but it provides a route to the development of a pair of analogous 18 F/ 99m Tc renal imaging agents with almost identical structures and comparable pharmacokinetic properties. These promising in vivo results warrant subsequent evaluation in humans.
Purpose
Anti-1-amino-2-[18F]fluorocyclopentane-1-carboxylic acid (anti-2-[18F]FACPC) is an unnatural alicyclic amino acid radiotracer with high uptake in the DU-145 prostate cancer cell line in vitro. Our goal was to determine if anti-2-[18F]FACPC is useful in the detection of prostate carcinoma.
Procedures
Five patients with elevated PSA (1.1–20.5 ng/mL) after curative therapy for prostate carcinoma underwent 60 min dynamic positron emission tomography (PET) of the pelvis after IV injection of 193–340 MBq of anti-2-[18F]FACPC. Uptake was compared against PET scans in the same patients with the leucine analog, anti-1-amino-3-[18F]fluorocyclobutane-1-carboxylic acid (anti-[18F]FACBC), at similar time points and validated via pathology, clinical, and imaging follow-up.
Results
At 5 min, average (±SD) SUVmax of malignant lesions is 4.1(±1.3) for anti-2-[18F] FACPC and 4.3(±1.1) for anti-[18F]FACBC. Yet, blood pool activity at 5 min is significantly higher for anti-2-[18F]FACPC with average (±SD) lesion/blood pool SUVmax/SUVmean ratio of 1.4 (±0.5) vs. 3.0 (±0.9) for anti-[18F]FACBC. At 20 min, average (±SD) SUVmax of malignant lesions is 2.6 (±1.0) for anti-2-[18F]FACPC and 3.4 (±0.8) for anti-[18F]FACBC. Yet, bladder activity at 20 min is significantly more intense for anti-2-[18F] FACPC with average (±SD) lesion/bladder SUVmax/SUVmean ratio of 0.3 (±0.8) vs. 2.3 (±1.4) for anti-[18F]FACBC.
Conclusions
While prostate bed lesions are visible on early imaging with anti-2-[18F]FACPC, there is high blood pool activity obscuring nodes. As blood pool fades, nodal uptake decreases and high bladder activity then obscures pelvic structures. Compared with anti-[18F]FACBC, imaging characteristics for anti-2-[18F]FACPC are unfavorable for pelvic recurrent prostate carcinoma detection.
The novel PET radioligand 11C-N,N-dimethyl-2-(2′-amino-4′-hydroxymethylphenylthio)benzylamine (11C-HOMADAM) binds with high affinity and selectively to the serotonin transporter (SERT). The purpose of this study was to develop a reliable kinetic model to describe the uptake of 11C-HOMADAM in the healthy human brain.Methods
Eight volunteers participated in the study; 5 of them were fitted with arterial catheters for blood sampling and all were scanned on a high-resolution research tomograph after the injection of 11C-HOMADAM. Regional distribution volumes and binding potentials were calculated with 2- and 4-parameter arterial-input compartment models, a 3-parameter reference tissue compartment model, and the Logan graphic approach.
Results
The 2-parameter arterial-input compartment model was statistically superior to the 4-parameter model and described all brain regions. Calculated binding potentials agreed well between the arterial-input model and the reference tissue model when the cerebellum was used as the reference tissue. The Logan graphic approach was not able to estimate the higher concentration of SERT in the dorsal raphe than in the midbrain.
Conclusion
11C-HOMADAM is a highly promising radioligand with high ratios of specific binding to nonspecific binding in known SERT-rich structures, such as the raphe nuclei. The 3-parameter reference tissue model approach permits a simplified quantitatively accurate method for estimating SERT binding potentials.
The meta-vinylhalide fluoroalkyl ester nortropanes 1-4 were synthesized as ligands of the serotonin transporter (SERT) for use as positron emission tomography (PET) imaging agents. In vitro competition binding assays demonstrated that 1-4 have a high affinity for the SERT (Ki's = 0.3 - 0.4 nM) and are selective for the SERT over the dopamine and norepinephrine transporters (DAT and NET). MicroPET imaging in anesthetized cynomolgus monkeys with [18F]1-[18F]4 demonstrated that all four tracers behave similarly with peak uptake in the SERT-rich brain regions achieved after 45-55 min followed by a steady washout. An awake monkey study was performed with [18F]1 which demonstrated that the uptake of [18F]1 was not influenced by anesthesia. Chase studies with the SERT ligand 15 displaced [18F]1-[18F]4 but chase studies with the DAT ligand 16 did not displace [18F]1-[18F]4 thus indicating that the tracers were binding specifically to the SERT.
Introduction 99m Tc(CO) 3 -nitrilotriacetic acid, 99m Tc(CO) 3 (NTA), is a new renal tubular agent with pharmacokinetic properties comparable to those of 131 I-OIH but the clearance of 99m Tc(CO) 3 (NTA) and 131 I-OIH is still less than the clearance of PAH, the gold standard for the measurement of effective renal plasma flow. At physiological pH, dianionic 99m Tc(CO) 3 (NTA) has a mononegative inner metal-coordination sphere and a mononegative uncoordinated carboxyl group. To evaluate alternate synthetic approaches, we assessed the importance of an uncoordinated carboxyl group, long considered essential for tubular transport, by evaluating the pharmacokinetics of three analogs with the 99m Tc(CO) 3 (NTA) metal-coordination sphere but with uncharged pendant groups. Methods 99m Tc(CO) 3 complexes with N-(2-acetamido)iminodiacetic acid (ADA), N-(2-hydroxyethyl)iminodiacetic acid (HDA) and N-(fluoroethyl)iminodiacetic acid (FEDA) were prepared using a tricarbonyl kit and isolated by HPLC. The pharmacokinetics were evaluated in Sprague–Dawley rats, with 131 I-OIH as an internal control; urine was analyzed for metabolites. Plasma protein binding and erythrocyte uptake were determined from the 10 min blood samples. Re(CO) 3 (FEDA), the analog of 99m Tc(CO) 3 (FEDA), was prepared and characterized. Results 99m Tc(CO) 3 (ADA), 99m Tc(CO) 3 (HDA) and 99m Tc(CO) 3 (FEDA) were efficiently prepared as a single species with high radiochemical purities ( > 99%). These new monoanionic 99m Tc(CO) 3 tracers with uncharged dangling groups all showed rapid blood clearance and high specificity for renal excretion. Activity in the urine, as a percent of 131 I-OIH at 10 and 60 min, was 96% and 99% for ADA, 96% and 100% for HDA, and 100% and 99% for FEDA, respectively. Each new tracer was excreted unchanged in the urine. The Re(CO) 3 (FEDA) structure adds compelling evidence that such 99m Tc(CO) 3 (NTA) analogs have metal-coordination spheres identical to that of 99m Tc(CO) 3 (NTA). Conclusions New tracers lacking the negatively charged pendant carboxyl group previously thought to be essential for rapid renal extraction, 99m Tc(CO) 3 (ADA), 99m Tc(CO) 3 (HDA) and 99m Tc(CO) 3 (FEDA), exhibit pharmacokinetics in rats comparable to those of 99m Tc(CO) 3 (NTA) and 131 I-OIH. Furthermore, these encouraging results in rats warrant evaluation of this new tracer type in humans.
Reboxetine analogs with methyl and fluoroalkyl substituents at position 2 of the phenoxy ring 1–4 were synthesized. In vitro competition binding demonstrated that 1–4 have a high affinity for the norepinephrine transporter (NET) with Ki’s = 1.02, 3.14, 3.68, and 0.30 nM (vs [3H]nisoxetine), respectively. MicroPET imaging in rhesus monkeys showed that the relative regional distribution of [11C]1 and [11C]4 is consistent with distribution of the NET in the brain, while [18F]2 and [18F]3 showed only slight regional differentiation in brain uptake. Especially, the highest ratios of uptake of [11C]1 in NET-rich regions to that in caudate were obtained at 1.30–1.45 at 45 min, and remained relatively constant over 85 min. Pretreatment of the monkey with the selective NET inhibitor, desipramine, decreased the specific binding for both [11C]1 and [11C]4. PET imaging in awake monkeys suggested that anesthesia influenced the binding potential of [11C]1 and [11C]4 at the NET.