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

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.

Test-Retest Reliability of the SERT Imaging Agent 11C-HOMADAM in Healthy Humans.

The aim of this study was to measure the test-retest reliability of 11C-N,N-dimethyl-2-(2'-amino-4'-hydroxymethylphenylthio)benzylamine (11C-HOMADAM) imaging of serotonin transporter (SERT) density in healthy control subjects. Methods: Two female and 2 male volunteers participated in the study, with each undergoing three 90-min 11C-HOMADAM PET scans. Time-activity curves were derived from SERT-rich structures and fit to 2 models: a simplified reference tissue model and a multilinear graphical model. Binding potential, the ratio of specifically bound uptake to nondisplaceable uptake at equilibrium, was calculated from the model parameter estimates. Ninety-five percent confidence intervals and the intraclass correlation coefficient (ICC) were calculated and adjusted for repeated measures. Results: The ICC values ranged from -0.13 in the dorsal raphe to 0.88 in the caudate nucleus. The highest average ICC values were in the striatum, but other regions were sensitive to measurement outliers. Conclusion: Good-to-excellent test-retest reliability was observed for SERT binding in the striatum. The dorsal raphe ICC value was sensitive to a measurement outlier. 11C-HOMADAM binding potential calculated from the simplified reference tissue model and the multilinear graphical model were robust and in good agreement.

Synthesis and biological properties of radiohalogenated α,α-disubstituted amino acids for PET and SPECT imaging of amino acid transporters (AATs).

Fluorine-18 and iodine-123 labeled nonnatural alicyclic and methyl branched disubstituted α,α-amino acids are a diverse and useful class of tumor imaging agents suitable for positron emission tomography and single photon emission computed tomography. These tracers target the increased expression of the cell membrane amino acid transporter systems L, ASC, and A exhibited by many human tumor cells. The most established clinical use for these radiolabeled amino acids is imaging primary and recurrent gliomas and primary, recurrent, and metastatic prostate cancer. This review focuses on the synthesis, radiolabeling, and amino acid transport mechanism of a series of nonnatural fluorine-18 and iodine-123 labeled analogs of 1-aminocyclobutane-1-carboxylic acid, 1-aminocyclopentane-1-carboxylic acid, α-aminoisobutyric acid, and α-methylaminoisobutyric acid.

Monoanionic 99mTc-tricarbonyl-aminopolycarboxylate complexes with uncharged pendant groups: Radiosynthesis and evaluation as potential renal tubular tracers.

INTRODUCTION: 99mTc(CO)3-nitrilotriacetic acid, 99mTc(CO)3(NTA), is a new renal tubular agent with pharmacokinetic properties comparable to those of 131I-OIH but the clearance of 99mTc(CO)3(NTA) and 131I-OIH is still less than the clearance of PAH, the gold standard for the measurement of effective renal plasma flow. At physiological pH, dianionic 99mTc(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 99mTc(CO)3(NTA) metal-coordination sphere but with uncharged pendant groups. METHODS: 99mTc(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 131I-OIH as an internal control; urine was analyzed for metabolites. Plasma protein binding and erythrocyte uptake were determined from the 10min blood samples. Re(CO)3(FEDA), the analog of 99mTc(CO)3(FEDA), was prepared and characterized. RESULTS: 99mTc(CO)3(ADA), 99mTc(CO)3(HDA) and 99mTc(CO)3(FEDA) were efficiently prepared as a single species with high radiochemical purities (>99%). These new monoanionic 99mTc(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 131I-OIH at 10 and 60min, 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 99mTc(CO)3(NTA) analogs have metal-coordination spheres identical to that of 99mTc(CO)3(NTA). CONCLUSIONS: New tracers lacking the negatively charged pendant carboxyl group previously thought to be essential for rapid renal extraction, 99mTc(CO)3(ADA), 99mTc(CO)3(HDA) and 99mTc(CO)3(FEDA), exhibit pharmacokinetics in rats comparable to those of 99mTc(CO)3(NTA) and 131I-OIH. Furthermore, these encouraging results in rats warrant evaluation of this new tracer type in humans.

Synthesis of a phenolic precursor and its efficient O-[18F]fluoroethylation with purified no-carrier-added [18F]2-fluoroethyl brosylate as the labeling agent.

[(18)F]2-Fluoroethyl-p-toluenesulfonate also called [(18)F]2-fluoroethyl tosylate has been widely used for labeling radioligands for positron emission tomography (PET). [(18)F]2-Fluoroethyl-4-bromobenzenesulfonate, also called [(18)F]2-fluoroethyl brosylate ([(18)F]F(CH2)2OBs), was used as an alternative radiolabeling agent to prepare [(18)F]FEOHOMADAM, a fluoroethoxy derivative of HOMADAM, by O-fluoroethylating the phenolic precursor. Purified by reverse-phase HPLC, the no-carrier-added [(18)F]F(CH2)2OBs was obtained in an average radiochemical yield (RCY) of 35%. The reaction of the purified and dried [(18)F]F(CH2)2OBs with the phenolic precursor was performed by heating in DMF and successfully produced [(18)F]FEOHOMADAM, after HPLC purification, in RCY of 21%.

Fluorinated diaryl sulfides.

Diaryl sulfides also known as diphenyl sulfides, phenylthiobenzylamines, and biphenylthiols are a class of compounds with phenylthiophenyl scaffold that have been validated as biomarkers to label the brain serotonin transporter (SERT), in vivo. The development of those synthetic and non-natural compounds started more than a decade ago when the observation that 5-chloro-((2-((dimethylamino)methyl)phenyl)thio)benzene-methanol hydrochloride also called 403U76 inhibited the serotonin and norepinephrine uptake into rat brain synaptosomes, led to the preparation of few derivatives based on 403U76 chemical structure. The new class of compounds, called the diaryl sulfide family, was investigated as biomarkers for the brain SERT. The promising data demonstrated by the carbon-11 labeled diaryl sulfides led to the translation of few of them into humans and the further evaluation of the phenylthiophenyl core structure by developing some fluorinated derivatives. This review will mainly focus on the fluorinated diaryl sulfides as fluorine-containing tracers validated to image the human brain SERT using positron emission tomography.

Biodistribution and human dosimetry of enantiomer-1 of the synthetic leucine analog anti-1-amino-2-fluorocyclopentyl-1-carboxylic acid.

INTRODUCTION: The enantiomerically enriched (ee=90%, enantiomer 1) synthetic amino acid (R,S)-anti-1-amino-2-fluorocyclopentyl-1-carboxylic acid (anti-2-[(18)F]FACPC-1) accumulates in malignant cells by elevated transport through the sodium-independent system-L (leucine preferring) amino acid transporter. The purpose of this study was to evaluate in vivo uptake and single-dose toxicity of anti-2-[(18)F]FACPC-1 in animals as well as the individual organ and whole-body dose in humans. METHODS: A DU145 xenograft rodent model was used to measure anti-2-[(18)F]FACPC-1 uptake at 15, 30 and 60 min post-injection. Animals were sacrificed and organs harvested to measure the percent injected activity per organ and to calculate residence time. Anti-2-[(18)F]FACPC-1 toxicity was assessed using a single microdose (37-74 MBq/kg) in nonhuman primates. Their vital signs were monitored for 2 h post-injection for drug-related effects. Human biodistribution studies were collected by sequential whole-body PET/CT scans on six healthy volunteers (three male and three female) for 120 min following a single 247±61 MBq bolus injection of anti-2-[(18)F]FACPC-1. Estimates of radiation dose from anti-2-[(18)F]FACPC-1 to the human body were calculated using recommendations of the MIRD committee and MIRDOSE 3.0 software. RESULTS: High anti-2-[(18)F]FACPC-1 residence time was observed in the pancreas of the rodent model compared to the human data. No abnormal treatment-related observations were made in the nonhuman primate toxicity studies. Human venous blood showed no metabolites of anti-2-[(18)F]FACPC-1 in the first 60 min post-injection. All volunteers showed initially high uptake in the kidneys followed by a rapid washout phase. The estimated effective dose equivalent was 0.0196 mSv/MBq. CONCLUSION: Anti-2-[(18)F]FACPC-1 showed low background uptake in the brain, thoracic and abdominal cavities of humans, suggesting a possible use for detecting malignant tissues in these regions.

Pilot evaluation of anti-1-amino-2-[18F] fluorocyclopentane-1-carboxylic acid (anti-2-[18F] FACPC) PET-CT in recurrent prostate carcinoma.

PURPOSE: Anti-1-amino-2-[(18)F]fluorocyclopentane-1-carboxylic acid (anti-2-[(18)F]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-[(18)F]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-[(18)F]FACPC. Uptake was compared against PET scans in the same patients with the leucine analog, anti-1-amino-3-[(18)F]fluorocyclobutane-1-carboxylic acid (anti-[(18)F]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-[(18)F] FACPC and 4.3(±1.1) for anti-[(18)F]FACBC. Yet, blood pool activity at 5 min is significantly higher for anti-2-[(18)F]FACPC with average (±SD) lesion/blood pool SUVmax/SUVmean ratio of 1.4 (±0.5) vs. 3.0 (±0.9) for anti-[(18)F]FACBC. At 20 min, average (±SD) SUVmax of malignant lesions is 2.6 (±1.0) for anti-2-[(18)F]FACPC and 3.4 (±0.8) for anti-[(18)F]FACBC. Yet, bladder activity at 20 min is significantly more intense for anti-2-[(18)F] FACPC with average (±SD) lesion/bladder SUVmax/SUVmean ratio of 0.3 (±0.8) vs. 2.3 (±1.4) for anti-[(18)F]FACBC. CONCLUSIONS: While prostate bed lesions are visible on early imaging with anti-2-[(18)F]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-[(18)F]FACBC, imaging characteristics for anti-2-[(18)F]FACPC are unfavorable for pelvic recurrent prostate carcinoma detection.