Radiolabeling of [(18)F]altanserin - a microfluidic approach

IntroductionOur aim was the optimization of radiochemical parameters for the microfluidic preparation of [¹⁸F]altanserin. The four main parameters evaluated were (1) precursor concentration, (2) reaction temperature, (3) bolus flow rate through the microreactor and (4) bolus volume.MethodsFor the determination of optimal reaction conditions within a flow-through microreactor synthesizer, 5–400 μL of precursor and dried [¹⁸F]fluoride solution were simultaneously pushed through the temperature-controlled reactor (180–220 °C) with defined bolus flow rates of 10–60 μL/min. Radiochemical incorporation yields (RCIYs) were examined using a thin layer chromatography (TLC) set-up and radio- high-performance liquid chromatography (HPLC).ResultsOptimum reaction parameters for the microfluidic set-up were determined as following: 220 °C, 5–10 μL/min pump rate per reactant (10–20 μL/min reaction overall flow rate) and 2 mg/mL precursor concentration in the reaction mixture. Applying these optimized conditions, RCIYs of 53.7 ± 7.9 were observed for scaled-up preparations. A positive “bolus effect” was observed: applying higher reaction volume resulted in increased RCIYs.ConclusionThis study proved that the reaction bolus volume is an essential parameter influencing the RCIY of [¹⁸F]altanserin. A possible explanation is the inhomogeneous distribution within the reaction volume probably caused by diffusion at the bolus interface. This important finding should be considered an important variable for the evaluation of all novel radiotracers labeled using a flow-through reactor device.     

Equilibrium modeling of 5-HT(2A) receptors with [18F]deuteroaltanserin and PET: feasibility of a constant infusion paradigm

ABSTRACT. [¹⁸F]Altanserin has emerged as a promising positron emission tomography (PET) ligand for serotonin-2A (5-HT_2A) receptors. The deuterium substitution of both of the 2′-hydrogens of altanserin ([¹⁸F]deuteroaltanserin) yields a metabolically more stable radiotracer with higher ratios of parent tracer to radiometabolites and increased specific brain uptake than [¹⁸F]altanserin. The slower metabolism of the deuterated analog might preclude the possibility of achieving stable plasma and brain activities with a bolus plus constant infusion within a reasonable time frame for an ¹⁸F-labeled tracer (T_1/2 110 min). Thus, the purpose of this study was to test the feasibility in human subjects of a constant infusion paradigm for equilibrium modeling of [¹⁸F]deuteroaltanserin with PET. Seven healthy male subjects were injected with [¹⁸F]deuteroaltanserin as a bolus plus constant infusion lasting 10 h postinjection. PET acquisitions and venous blood sampling were performed throughout the infusion period. Linear regression analysis revealed that time-activity curves for both specific brain uptake and plasma [¹⁸F]deuteroaltanserin concentration stabilized after about 5 h. This permitted equilibrium modeling and estimation of V^′₃ (ratio of specific uptake to total plasma parent concentration) and the binding potential V₃ (ratio of specific uptake to free plasma parent concentration). Cortical/cerebellar ratios were increased by 26% relative to those we previously observed with [¹⁸F]altanserin using similar methodology in a somewhat older subject sample. These results demonstrate feasibility of equilibrium imaging with [¹⁸F]deuteroaltanserin and suggest that it may be superior to [¹⁸F]altanserin as a PET radioligand.     

Biodistribution and PET imaging of [(18)F]-fluoroadenosine derivatives

INTRODUCTION: Many fluorinated analogues of adenosine nucleoside have been synthesized and studied as potential antitumor and antiviral agents. Earlier, we reported radiosynthesis of 2'-deoxy-2'-[(18)F]fluoro-1-beta-D-arabinofuranosyl-adenine ([(18)F]-FAA) and 3'-deoxy-3'-[(18)F]fluoro-1-beta-d-xylofuranosyl-adenine ([(18)F]FXA). Now, we report their in vivo studies including blood clearance, biodistribution and micro-PET imaging in tumor-bearing nude mice. METHODS: Tumors were grown in 6-week-old athymic nude mice (Harlan, Indianapolis, IN, USA) by inoculation of HT-29 cells, wild-type cells in the left flank and transduced cells with HSV-tk on the right flank. When the tumor was about 1 cm in size, animals were injected with these radiotracers for in vivo studies, including blood clearance, micro-PET imaging and biodistribution. RESULTS: Uptake of [(18)F]FAA in tumor was 3.3-fold higher than blood, with highest uptake in the spleen. Maximum uptake of [(18)F]FXA was observed in the heart compared to other organs. There was no tumor uptake of [(18)F]FXA. Biodistribution results were supported by micro-PET images, which also showed very high uptake of [(18)F]FAA in spleen and visualization of tumors, and high uptake of [(18)F]FXA in the heart. CONCLUSION: These results suggest that [(18)F]FAA may be useful for tumor imaging, while [(18)F]FXA may have potential as a heart imaging agent with PET.     

PET quantification of 5-HT2A receptors in the human brain: a constant infusion paradigm with [18F]altanserin.

[18F]altanserin has been used to label serotonin 5-HT2A receptors, which are believed to be important in the pathophysiology of schizophrenia and depression. The purpose of this study was to test the feasibility of a constant infusion paradigm for equilibrium modeling of [18F]altanserin with PET. Kinetic modeling with [18F]altanserin may be hampered by the presence of lipophilic radiometabolites observed in plasma after intravenous administration. METHODS: Eight healthy volunteers were injected with [18F]altanserin as a bolus (208+/-9 MBq [5.62+/-0.25 mCi]) plus constant infusion (65+/-3 MBq/h [1.76+/-0.08 mCi/h]) ranging from 555 to 626 min (615+/-24 min) after injection. PET acquisitions (10-20 min) and venous blood sampling were performed every 30-60 min throughout the infusion period. RESULTS: Linear regression analysis revealed that time-activity curves for both brain activity and plasma [18F]altanserin and metabolite concentrations stabilized after about 6 h. This permitted equilibrium modeling and estimation of V3' (ratio of specific uptake [cortical-cerebellar] to total plasma parent concentration after 6 h). Values of V3' ranged from 1.57+/-0.38 for anterior cingulate cortex to 1.02+/-0.39 for frontal cortex. The binding potential V3 (ratio of specific uptake to free plasma parent concentration after 6 h, using group mean f1) was also calculated and ranged from 169+/-41 for anterior cingulate cortex to 110+/-42 for frontal cortex. From 6 h onward, the rate of change for V3' and V3 was only 1.11+/-1.69 %/h. CONCLUSION: These results demonstrate the feasibility of equilibrium imaging with [18F]altanserin over more than 5 radioactive half-lives and suggest a method to overcome difficulties associated with lipophilic radiolabeled metabolites. The stability in V3 and V3' once equilibrium is achieved suggests that a single PET acquisition obtained at 6 h may provide a reasonable measure of 5-HT2A receptor density.     

Comparison of 3'-deoxy-3'-[(18)F]fluorothymidine PET and O-(2-[(18)F]fluoroethyl)-L-tyrosine PET in patients with newly diagnosed glioma

PurposeThe purpose of this prospective study was to clarify the value of FLT PET and FET PET for the noninvasive grading and prognosis of newly diagnosed gliomas.Materials and methodsTwenty patients with newly diagnosed gliomas were investigated with FLT and FET PET before surgery. FLT and FET uptakes were assessed by the maximum standardized uptake (SUVmax) of tumor, and the ratio to uptake in the normal brain parenchyma (TNR). All tumors were graded by WHO system.ResultsFLT PET detected all 17 high-grade gliomas (HGG) and did not detect all 3 low-grade gliomas (LGG). FET PET detected all 20 HGG and LGG regardless of grading. The average FLT SUVmax in HGG and LGG was 1.51 ± 0.72 and 0.30 ± 0.07, and the average FLT TNR in HGG and LGG was 5.52 ± 3.09 and 1.12 ± 0.14, respectively. The differences of FLT SUVmax and TNR between HGG and LGG were statistically significant (p = 0.0069, p = 0.0070). The average FET SUVmax in HGG and LGG was 2.68 ± 0.86 and 1.36 ± 0.15, and the average FET TNR in HGG and LGG was 2.31 ± 0.73 and 1.27 ± 0.12, respectively. The differences of FET SUVmax and TNR between HGG and LGG were statistically significant (p = 0.0129, p = 0.0095).ConclusionsFET PET has higher sensitivity in detection of gliomas rather than FLT PET, but it seems that FLT PET is better than FET PET for noninvasive grading and predicting prognosis of newly diagnosed gliomas, considering high contrast of FLT and overlap of FET uptakes between HGG and LGG.     

PET measurement of D2 and S2 receptor binding of 3-N-[( 2'-18F]fluoroethyl)spiperone in baboon brain

The regional pharmacokinetic behavior in baboon brain of 18F-fluoroethyl- and 18F-fluoropropylspiperone (18FESP, 18FPSP) at specific activities greater than or equal to 1000 Ci/mmol was studied with PET. Four hours after injection of 5-10 mCi 18FESP, uptake in striatum was 0.048% +/- 0.005% of injected dose per cm3, which is almost the same as with 18F- and 11C-methylspiperone. While 18FPSP was taken up in much smaller amounts than 18FESP, striatum to cerebellum activity ratios were quite similar for both ligands (about 9 to 10 at 4 h p.i.). Because of its higher striatal uptake, 18FESP seems to be better suited for PET. Furthermore, relative binding to S2 receptors was much smaller for FESP: competing cold S2 antagonists (ritanserin, ketanserin) did not alter 18FESP binding to striatum, concurrently reducing uptake in frontal cortex by only 15%-20%. With coinjection of increasing amounts of cold FESP, saturation of 18FESP binding to striatum occurred at doses exceeding 10 micrograms per kg. Quantitative analysis of radiolabelled ligand in arterial plasma (decrease to 8% at 4 h p.i.) demonstrated identical metabolic turnover for both ligands. Direct use of binding fractions from the saturation curve resulted in overestimation of the receptor density in striatum. Using the 18FESP plasma concentration time curve and the dynamic uptake data, k3 of a three compartment model could be determined by non linear regression. However, dramatic changes of the dependence of k3 on the specifically bound ligand concentration were observed even at small loading doses of FESP. Estimation of Bmax yielded a D2 receptor density of only 6 pmol per cm3 in baboon striatum.     

Semi-automated preparation of the dopamine transporter ligand [(18)F]FECNT for human PET imaging studies.

The fluorine-18 labeled dopamine transport (DAT) ligand 2 beta-carbomethoxy-3beta-(4-chlorophenyl)-8-(2-fluoroethyl)nortropane (FECNT) has shown promising properties as an in vivo DAT imaging agent in human and monkey PET studies. A semi-automated synthesis has been developed to reliably produce [(18)F]FECNT in a 16% decay corrected yield. This method utilizes a new [(18)F]fluoralkylating agent and provides high purity [(18)F]FECNT in a formulation suitable for human use.     

(18)F]FMISO and [(18)F]FDG PET imaging in soft tissue sarcomas: correlation of hypoxia,metabolism and VEGF expression

Hypoxia imparts resistance to radiotherapy and chemotherapy and also promotes a variety of changes in tumor biology through inducible promoters. The purpose of this study was to evaluate the use of positron emission tomography (PET) imaging with fluorine-18 fluoromisonidazole (FMISO) in soft tissue sarcomas (STS) as a measure of hypoxia and to compare the results with those obtained using [(18)F]fluorodeoxyglucose (FDG) and other known biologic correlates. FDG evaluates energy metabolism in tumors while FMISO uptake is proportional to tissue hypoxia. FMISO uptake was compared with FDG uptake. Vascular endothelial growth factor (VEGF) expression was also compared with FMISO uptake. Nineteen patients with STS underwent PET scanning with quantitative determination of FMISO and FDG uptake prior to therapy (neo-adjuvant chemotherapy or surgery alone). Ten patients receiving neo-adjuvant chemotherapy were also imaged after chemotherapy but prior to surgical resection. Standardized uptake value (SUV) was used to describe FDG uptake; regional tissue to blood ratio (>or=1.2 was considered significant) was used for FMISO uptake. Significant hypoxia was found in 76% of tumors imaged prior to therapy. No correlation was identified between pretherapy hypoxic volume (HV) and tumor grade ( r=0.15) or tumor volume ( r=0.03). The correlation of HV with VEGF expression was 0.39. Individual tumors showed marked heterogeneity in regional VEGF expression. The mean pixel-by-pixel correlation between FMISO and FDG uptake was 0.49 (range 0.09-0.79) pretreatment and 0.32 (range -0.46-0.72) after treatment. Most tumors showed evidence of reduced uptake of both FMISO and FDG following chemotherapy. FMISO PET demonstrates areas of significant and heterogeneous hypoxia in soft tissue sarcomas. The significant discrepancy between FDG and FMISO uptake seen in this study indicates that regional hypoxia and glucose metabolism do not always correlate. Similarly, we did not find any relationship between the hypoxic volume and the tumor volume or VEGF expression. Identification of hypoxia and development of a more complete biologic profile of STS will serve to guide more rational, individualized cancer treatment approaches.     

Evaluation of 6-([18F]fluoroacetamido)-1-hexanoicanilide for PET imaging of histone deacetylase in the baboon brain

IntroductionHistone deacetylases (HDACs) are enzymes involved in epigenetic modifications that shift the balance toward chromatin condensation and silencing of gene expression. Here, we evaluate the utility of 6-([¹⁸F]fluoroacetamido)-1-hexanoicanilide ([¹⁸F]FAHA) for positron emission tomography imaging of HDAC activity in the baboon brain. For this purpose, we assessed its in vivo biodistribution, sensitivity to HDAC inhibition, metabolic stability and the distribution of the putative metabolite [¹⁸F]fluoroacetate ([¹⁸F]FAC).Methods[¹⁸F]FAHA and its metabolite [¹⁸F]FAC were prepared, and their in vivo biodistribution and pharmacokinetics were determined in baboons. [¹⁸F]FAHA metabolism and its sensitivity to HDAC inhibition using suberanilohydroxamic acid (SAHA) were assessed in arterial plasma and by in vitro incubation studies. The chemical form of F-18 in rodent brain was assessed by ex vivo studies. Distribution volumes for [¹⁸F]FAHA in the brain were derived.Results[¹⁸F]FAHA was rapidly metabolized to [¹⁸F]FAC, and both labeled compounds entered the brain. [¹⁸F]FAHA exhibited regional differences in brain uptake and kinetics. In contrast, [¹⁸F]FAC showed little variation in regional brain uptake and kinetics. A kinetic analysis that takes into account the uptake of peripherally produced [¹⁸F]FAC indicated that SAHA inhibited binding of [¹⁸F]FAHA in the baboon brain dose-dependently. In vitro studies demonstrated SAHA-sensitive metabolism of [¹⁸F]FAHA to [¹⁸F]FAC within the cell and diffusion of [¹⁸F]FAC out of the cell. All radioactivity in brain homogenate from rodents was [¹⁸F]FAC at 7 min postinjection of [¹⁸F]FAHA.ConclusionThe rapid metabolism of [¹⁸F]FAHA to [¹⁸F]FAC in the periphery complicates the quantitative analysis of HDAC in the brain. However, dose-dependent blocking studies with SAHA and kinetic modeling indicated that a specific interaction of [¹⁸F]FAHA in the brain was observed. Validating the nature of this interaction as HDAC specific will require additional studies.     

Time-efficient and convenient synthesis of [18F]altanserin for human PET imaging by a new work-up procedure

[¹⁸F]Altanserin, an important PET radioligand for the in vivo imaging of the 5-HT_2A receptor, was synthesized from its precursor nitro-altanserin in DMF or DMSO at high temperatures of 150 °C in an overall radiochemical yield (EOB) of 23–25% after 75 min. A new solid phase work-up procedure involving the acidification of the crude reaction mixture and a C18-SepPak-solid phase separation preceded the final HPLC purification. This led to a significantly reduced synthesis time as a result of a stable and early elution from the HPLC column using improved HPLC conditions (MeOH/THF/NaOAc 0.05 N pH 5: 27/18/55, flow: 5 mL/min, Symetry Prep 7 μm C18 (Waters)). The synthesis was performed semi-automatically in a modified GE TracerLab synthesis module using an in-house-developed program. The synthesized [¹⁸F]altanserin was used in our ongoing human and animal PET imaging studies.     

PET imaging of the brain serotonin transporters (SERT) with N,N-dimethyl-2-(2-amino-4-[18F]fluorophenylthio)benzylamine (4-[18F]-ADAM) in humans: a preliminary study

Purpose

The aim of this study was to assess the feasibility of using 4-[¹⁸F]-ADAM as a brain SERT imaging agent in humans.

Methods

Enrolled in the study were 19 healthy Taiwanese subjects (11 men, 8 women; age 33?±?9?years). The PET data were semiquantitatively analyzed and expressed as specific uptake ratios (SUR) and distribution volume ratios (DVR) using the software package PMOD. The SUR and DVR of 4-[¹⁸F]-ADAM in the raphe nucleus (RN), midbrain (MB), thalamus (TH), striatum (STR) and prefrontal cortex (PFC) were determined using the cerebellum (CB) as the reference region.

Results

4-[¹⁸F]-ADAM bound to known SERT-rich regions in human brain. The order of the regional brain uptake was MB (RN) > TH > STR > PFC > CB. The DVR (n?=?4, t*?=?60?min) in the RN, TH, STR and PFC were 3.00?±?0.50, 2.25?±?0.45, 2.05?±?0.31 and 1.40?±?0.13, respectively. The optimal time for imaging brain SERT with 4-[¹⁸F]-ADAM was 120?C140?min after injection. At the optimal imaging time, the SURs (n?=?15) in the MB, TH, STR, and PFC were 2.25?±?0.20, 2.28?±?0.20, 2.12?±?0.18 and 1.47?±?0.14, respectively. There were no significant differences in SERT availability between men and women (p?<?0.05).

Conclusion

The results of this study showed that 4-[¹⁸F]-ADAM was safe for human studies and its distribution in human brain appeared to correlate well with the known distribution of SERT in the human brain. In addition, it had high specific binding and a reasonable optimal time for imaging brain SERT in humans. Thus, 4-[¹⁸F]-ADAM may be feasible for assessing the status of brain SERT in humans.     

Radiosynthesis of 3'-deoxy-3'-[(18)F]fluorothymidine: [(18)F]FLT for imaging of cellular proliferation in vivo

A reliable radiosynthesis of 3'-deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT) has been developed based on [(18)10 mCi (370 MBq) of radiochemically pure [(18)1 Ci/micromol (37 GBq/micromol) at EOS within 100 min and in 13% radiochemical yield (end of bombardment (EOB); 7% end of synthesis (EOS)). [(18)F]FLT has been designed as a new positron emission tomography imaging agent for visualizing cellular proliferation in vivo based on the metabolism of thymidine.     

N(3)-Substituted thymidine analogues V: synthesis and preliminary PET imaging of N(3)-[(18)F]fluoroethyl thymidine and N(3)-[(18)F]fluoropropyl thymidine

INTRODUCTION: [(18)F]-Labeled analogues of thymidine have demonstrated efficacy for PET imaging of cellular proliferation. We have synthesized two [(18)F]-labeled N(3)-substituted thymidine analogues, N(3)-[(18)F]fluoroethyl thymidine (N(3)-[(18)F]-FET) and N(3)-[(18)F]fluoropropyl thymidine (N(3)-[(18)F]-FPrT), and performed preliminary PET imaging studies in tumor-bearing mice. METHODS: Thymidine was converted to its 3',5'-O-bis-tetrahydropyranyl ether, which was then converted to the N(3)-ethyl and propyl-substituted mesylate precursors. Reactions of these mesylate precursors with n-Bu(4)N[(18)F] or K[(18)F]/kryptofix followed by acid hydrolysis and HPLC purification yielded N(3)-[(18)F]-FET and N(3)-[(18)F]-FPrT, respectively. Subcutaneous (sc) xenografts of H441 human non-small cell lung cancer were established in two groups of mice (each n=6). Micro-PET images of the tumor-bearing animals were acquired after intravenous injection of N(3)-[(18)F]-FET or N(3)-[(18)F]-FPrT (3700 KBq/animal). RESULTS: The radiochemical yields were 2-12% (d.c.) for N(3)-[(18)F]-FET and 30-38% (d.c.) for N(3)-[(18)F]-FPrT. Radiochemical purity was >99% and calculated specific activity was >74 GBq/mumol at the end of synthesis. The accumulation of N(3)-[(18)F]-FET and N(3)-[(18)F]-FPrT in the tumor tissue at 2 h postinjection was 1.81+/-0.78 and 2.95+/-1.14 percent injected dose per gram (%ID/g), respectively; tumor/muscle ratios were 5.57+/-0.82 and 7.69+/-2.18, respectively; the unidirectional influx rates (K(i)) were 0.013 and 0.018 ml/g per minute, respectively. CONCLUSION: Two novel [(18)F]- N(3)-substituted thymidine analogues have been synthesized in good yields, high purity and high specific activity. Preliminary in vivo studies demonstrated the efficacy of these [(18)F]- N(3)-substituted thymidine analogues for PET imaging of tumors.     

The synthesis and in vivo evaluation of [(18)F]PF-9811: a novel PET ligand for imaging brain fatty acid amide hydrolase (FAAH)

IntroductionFatty acid amide hydrolase (FAAH) is responsible for the enzymatic degradation of the fatty acid amide family of signaling lipids, including the endogenous cannabinoid (endocannabinoid) anandamide. The involvement of the endocannabinoid system in pain and other nervous system disorders has made FAAH an attractive target for drug development. Companion molecular imaging probes are needed, however, to assess FAAH inhibition in the nervous system in vivo. We report here the synthesis and in vivo evaluation of [¹⁸F]PF-9811, a novel PET ligand for non-invasive imaging of FAAH in the brain.MethodsThe potency and selectivity of unlabeled PF-9811 were determined by activity-based protein profiling (ABPP) both in vitro and in vivo. [¹⁸F]PF-9811 was synthesized in a 3-step, one-pot reaction sequence, followed by HPLC purification. Biological evaluation was performed by biodistribution and dynamic PET imaging studies in male rats. The specificity of [¹⁸F]PF-9811 uptake was evaluated by pre-administration of PF-04457845, a potent and selective FAAH inhibitor, 1 h prior to radiotracer injection.ResultsBiodistribution studies show good uptake (SUV ~ 0.8 at 90 min) of [¹⁸F]PF-9811 in rat brain, with significant reduction of the radiotracer in all brain regions (37%–73% at 90 min) in blocking experiments. Dynamic PET imaging experiments in rat confirmed the heterogeneous uptake of [¹⁸F]PF-9811 in brain regions with high FAAH enzymatic activity, as well as statistically significant reductions in signal following pre-administration of the blocking compound PF-04457845.Conclusions[¹⁸F]PF-9811 is a promising PET imaging agent for FAAH. Biodistribution and PET imaging experiments show that the tracer has good uptake in brain, regional heterogeneity, and specific binding as determined by blocking experiments with the highly potent and selective FAAH inhibitor, PF-04457845.     

Determination of optimal acquisition time of [18F]FCWAY PET for imaging serotonin 1A receptors in the healthy male subjects

The purpose of this research is to find optimal acquisition time point of [¹⁸F]FCWAY PET for the assessment of serotonin 1A receptor (5-HT_1A) density. To achieve this goal, we examined the specific-to-nonspecific ratios in various brain regions. The cerebellum has very few 5-HT_1A receptors in the brain, so we set this region as the reference tissue. As a result, specific-to-nonspecific binding ratios in the frontal, temporal cortex and the hippocampus were steadily increased at 90 min after injection and remained stable at 120 min. In addition, the binding ratio of the late time was significantly higher than that of the previous time points. From these results, we recommend that 90 min p.i. is a better single time point for the analysis rather than previous time points for assessing [¹⁸F]FCWAY binding to 5-HT_1A receptors.     

N-[(18)F]Fluoroethylpiperidinyl,N-[(18)F]fluoroethylpiperidinemethyl and N-[(18)F]fluoroethylpyrrolidinyl esters as radiotracers for acetylcholinesterase

A series of N-fluoroethylpiperidinyl (1), N-fluoroethylpiperidinemethyl (2) and N-fluoroethylpyrrolidinyl (3) esters were synthesized and examined as new (18)F-labeled radiotracers for measuring brain cholinesterase activity. The fluoroethyl group, instead of methyl group, results in slower in vitro enzymatic cleavage rates and higher selectivity for AChE. Based on metabolism in mouse blood and PET time-activity curves in rats, two radiotracers were identified as potential candidates for further in vivo evaluation in higher species.     

Comparison of [(18)F]FDG PET and (201)Tl SPECT in evaluation of pulmonary nodules.

Recent reports have indicated the value of [(18)F]FDG PET and (201)Tl SPECT in diagnosing lung cancer. In this study, we compared the diagnostic value of FDG PET and (201)Tl SPECT in the evaluation of pulmonary nodules. METHODS: Sixty-three patients with 66 pulmonary nodules suspected to be lung cancer on the basis of chest CT were examined by FDG PET and (201)Tl SPECT (early and delayed scans) within a week of each study. For semiquantitative analysis, the standardized uptake value (SUV) or the tumor-to-nontumor activity ratio (T/N) (or both) was calculated. All of these lesions were completely removed thoracoscopically or by thoracotomy and were examined histologically. RESULTS: Fifty-four nodules were histologically confirmed to be malignant tumors, and 12 were benign. Both techniques delineated focal lesions with an increase in tracer accumulation in 41 of 54 lung cancers. (201)Tl SPECT on early or delayed scans (or both) identified 4 additional lung cancers that FDG PET images did not reveal: 3 bronchioloalveolar carcinomas and a well-differentiated adenocarcinoma. FDG PET identified 3 additional lung cancers that (201)Tl SPECT images did not reveal; 2 of these lung cancers were <2 cm in diameter. The mean FDG SUV and T/N of bronchioloalveolar carcinomas (2.06 +/- 0.76 and 3.49 +/- 1.03, respectively) were significantly lower than those of poorly differentiated adenocarcinomas (5.55 +/- 2.01 [P = 0.026] and 8.23 +/- 2.16 [P = 0.01], respectively). However, no significant difference was found in (201)Tl T/N on early and delayed scans between bronchioloalveolar carcinomas (1.64 +/- 0.29 and 1.87 +/- 0.42, respectively) and poorly differentiated adenocarcinomas (1.58 +/- 0.32 and 2.76 +/- 1.36, respectively). Of the 12 benign nodules, FDG PET and (201)Tl SPECT showed false-positive results for the same 7 benign nodules (58.3%) (4 granulomas, 1 sarcoidosis, 1 inflammatory pseudotumor, and 1 aspergilloma). Negative FDG PET findings and positive (201)Tl SPECT findings were obtained only for bronchioloalveolar carcinomas or a well-differentiated adenocarcinoma but not for other histologic types of lung cancers or benign pulmonary nodules. CONCLUSION: No significant difference was found between FDG PET and (201)Tl SPECT in specificity for the differentiation of malignant and benign pulmonary nodules. The degree of differentiation of lung adenocarcinoma correlated with FDG uptake but not with (201)Tl uptake. Bronchioloalveolar carcinoma (a well-differentiated, slow-growing tumor) findings typically were positive with (201)Tl but were negative with FDG. The combination of FDG PET and (201)Tl SPECT may provide additional information regarding the tissue characterization of pulmonary nodules.     

18F]Fluoroethylflumazenil: a novel tracer for PET imaging of human benzodiazepine receptors.

5-(2'-[18F]Fluoroethyl)flumazenil ([18F]FEF) is a fluorine-18 labelled positron emission tomography (PET) tracer for central benzodiazepine receptors. Compared with the established [11C]flumazenil, it has the advantage of the longer half-life of the fluorine-18 label. After optimisation of its synthesis and determination of its in vitro receptor affinities, we performed first PET studies in humans. PET studies in seven healthy human volunteers were performed on a Siemens ECAT EXACT whole-body scanner after injection of 100-280 MBq [L8F]FEF. In two subjects, a second PET scan was conducted after pretreatment with unlabelled flumazenil (1 mg or 2.5 mg i.v., 3 min before tracer injection). A third subject was studied both with [18F]FEF and with [11C]flumazenil. Brain radioactivity was measured for 60-90 min p.i. and analysed with a region of interest-oriented approach and on a voxelwise basis with spectral analysis. Plasma radioactivity was determined from arterial blood samples and metabolites were determined by high-performance liquid chromatography. In human brain, maximum radioactivity accumulation was observed 4 +/- 2 min p.i., with a fast clearance kinetics resulting in 50% and 20% of maximal activities at about 10 and 30 min, respectively. [18F]FEF uptake followed the known central benzodiazepine receptor distribution in the human brain (occipital cortex >temporal cortex >cerebellum >thalamus >pons). Pretreatment with unlabelled flumazenil resulted in reduced tracer uptake in all brain areas except for receptor-free reference regions like the pons. Parametric images of distribution volume and binding potential generated on a voxelwise basis revealed two- to three-fold lower in vivo receptor binding of [18F]FEF compared with [11C]flumazenil, while relative uptake of [18F]FEF was higher in the cerebellum, most likely owing to its relatively higher affinity for benzodiazepine receptors containing the alpha6 subunit. Metabolism of [18F]FEF was very rapid. Polar metabolites represented about 50%-60% of total plasma radioactivity at 5 min and 80%-90% at 20 min p.i. Although [11C]flumazenil has some advantages over [18F]FEF (higher affinity, slower metabolism, slower kinetics), our results indicate that [18F]FEF is a suitable PET ligand for quantitative assessment of central benzodiazepine receptors, which can be used independently of an on-site cyclotron.     

[18F]Fluoroethylflumazenil: a novel tracer for PET imaging of human benzodiazepine receptors

5-(2'-[¹⁸F]Fluoroethyl)flumazenil ([¹⁸F]FEF) is a fluorine-18 labelled positron emission tomography (PET) tracer for central benzodiazepine receptors. Compared with the established [¹¹C]flumazenil, it has the advantage of the longer half-life of the fluorine-18 label. After optimisation of its synthesis and determination of its in vitro receptor affinities, we performed first PET studies in humans. PET studies in seven healthy human volunteers were performed on a Siemens ECAT EXACT whole-body scanner after injection of 100-280 MBq [¹⁸F]FEF. In two subjects, a second PET scan was conducted after pretreatment with unlabelled flumazenil (1 mg or 2.5 mg i.v., 3 min before tracer injection). A third subject was studied both with [¹⁸F]FEF and with [¹¹C]flumazenil. Brain radioactivity was measured for 60-90 min p.i. and analysed with a region of interest-oriented approach and on a voxelwise basis with spectral analysis. Plasma radioactivity was determined from arterial blood samples and metabolites were determined by high-performance liquid chromatography. In human brain, maximum radioactivity accumulation was observed 4DŽ min p.i., with a fast clearance kinetics resulting in 50% and 20% of maximal activities at about 10 and 30 min, respectively. [¹⁸F]FEF uptake followed the known central benzodiazepine receptor distribution in the human brain (occipital cortex >temporal cortex >cerebellum >thalamus >pons). Pretreatment with unlabelled flumazenil resulted in reduced tracer uptake in all brain areas except for receptor-free reference regions like the pons. Parametric images of distribution volume and binding potential generated on a voxelwise basis revealed two- to three-fold lower in vivo receptor binding of [¹⁸F]FEF compared with [¹¹C]flumazenil, while relative uptake of [¹⁸F]FEF was higher in the cerebellum, most likely owing to its relatively higher affinity for benzodiazepine receptors containing the Ő subunit. Metabolism of [¹⁸F]FEF was very rapid. Polar metabolites represented about 50%-60% of total plasma radioactivity at 5 min and 80%-90% at 20 min p.i. Although [¹¹C]flumazenil has some advantages over [¹⁸F]FEF (higher affinity, slower metabolism, slower kinetics), our results indicate that [¹⁸F]FEF is a suitable PET ligand for quantitative assessment of central benzodiazepine receptors, which can be used independently of an on-site cyclotron.