Human Biodistribution and Dosimetry of the PET Radioligand [11C]Flumazenil (FMZ)

Purpose  

We measure the whole-body distribution of IV injected [¹¹C]Flumazenil (FMZ) as a function of time in adult subjects and determine the absorbed radiation doses.     

Biodistribution and Radiation Dosimetry of the Serotonin 5-HT6 Ligand [11C]GSK215083 Determined from Human Whole-Body PET

Purpose

We measured the whole-body distribution of IV-injected [¹¹C]GSK215083, a new 5-HT₆ antagonist PET tracer, as a function of time in adult subjects, in order to determine the radiation exposure.

Procedures

After injection with a single bolus of [¹¹C]GSK215083 (range 330?C367?MBq; mean 346?MBq), PET emission data were acquired for approximately 120?min in six subjects (three males and three females). Five organs were identified as exhibiting uptake above background. For these, regions of interest were delineated on emission images, and time?Cactivity curves (TAC) generated. Residence times were calculated as the area under the curve of the TAC, normalized to injected activities and standard values of organ volumes. Dosimetry calculations were then performed using the computer program OLINDA/EXM 1.0.

Results

The mean effective dose averaged over both males and females (±standard deviation) was estimated to be 7.7?±?1.0???Sv/MBq (male 7.0?±?0.4; female 8.5?±?0.6). For the effective dose equivalent, the corresponding values are 7.8?±?1.2???Sv/MBq (male 6.8?±?0.5; female 8.9?±?0.1). The organ receiving the highest dose was the lung, with an average equivalent dose of 25.6?±?6.9???Sv/MBq (male 20.8?±?5.6; female 30.4?±?4.4).

Conclusion

The estimated radiation dose for [¹¹C]GSK215083 is consistent with those for other neuroreceptor ligands labeled with carbon-11. The somewhat higher dose estimate for females compared to males may reflect the difference in observed residence times and representative differences in the male and female phantoms used for dosimetry calculations. Based on conventionally accepted dose limits, [¹¹C]GSK215083 may be used for multiple PET scans in the same subject.     

Whole-Body Biodistribution and Radiation Dosimetry of the Cannabinoid Type 2 Receptor Ligand [11C]-NE40 in Healthy Subjects

Purpose

The type 2 cannabinoid receptor (CB2R) is part of the human endocannabinoid system and is involved in central and peripheral inflammatory processes. In vivo imaging of the CB2R would allow study of several (neuro)inflammatory disorders. In this study we have investigated the safety and tolerability of [¹¹C]-NE40, a CB2R positron emission tomography (PET) ligand, in healthy human male subjects and determined its biodistribution and radiation dosimetry.

Procedure

Six healthy male subjects (age 20–65 years) underwent a dynamic series of nine whole-body PET/CT scans for up to 140 min, after injection of an average bolus of 286 MBq of [¹¹C]-NE40. Organ absorbed and total effective doses were calculated through OLINDA.

Results

[¹¹C]-NE40 showed high initial uptake in the spleen and a predominant hepatobiliary excretion. In the brain, rapid uptake and swift washout were seen. Organ absorbed doses were largest for the small intestine and liver, with 15.6 and 11.5 μGy/MBq, respectively. The mean effective dose was 3.64?±?0.81 μSv/MBq. There were no changes with aging observed. No adverse events were encountered.

Conclusions

This first-in-man study of [¹¹C]-NE40 showed an expected biodistribution compatible with lymphoid tissue uptake and appropriate fast brain kinetics in the healthy human brain, underscoring the potential of this tracer for further application in central and peripheral inflammation imaging. The effective dose is within the typical expected range for ¹¹C ligands.     

Biodistribution and Radiation Dosimetry of the Glycine Transporter-1 Ligand 11C-GSK931145 Determined from Primate and Human Whole-Body PET

Purpose

¹¹C-GSK931145 is a novel radioligand suitable for imaging the glycine transporter 1 (GlyT-1) in brain. In the present study, human dosimetry is estimated from baboon and human biodistribution data.

Procedures

Three baboons and eight healthy human volunteers underwent whole-body positron emission tomography (PET) scans. Human dosimetry was estimated using three different region-of-interest (ROI) delineation methods that ranged in their complexity and execution time: ROIs drawn on anterior-posterior compressed PET images, on subsamples of the organs, and covering the whole-organ. Residence times for each organ were calculated as the area under the time-activity curves divided by the injected activity. Radiation dose estimates were calculated from organ residence times using the OLINDA/EXM software package.

Results

The overall distribution of activity was similar in baboons and humans. Early scans presented high activity in the liver, and moderate activity in the lungs and kidneys. The principal route of clearance was intestinal and no urinary excretion was observed. The limiting organ with the highest radiation-absorbed dose was the liver. The mean effective dose in humans was 4.02 ??Sv/MBq (male phantom) and 4.95 ??Sv/MBq (female phantom) (ROIs drawn on subsamples of the organs). The human effective dose estimated from baboon data was ~15% larger than the effective dose estimated from human data.

Conclusion

Human PET imaging of the glycine transporter-1 with ¹¹C-GSK931145 results in a moderate effective human radiation dose, which allows for multiple PET examinations in the same individual. Among the three methods compared to delineate ROIs, the organ subsampling method shows the best balance between quantitative accuracy and practical application.     

Biodistribution and Radiation Dosimetry of [<Superscript>18</Superscript>F]Mefway in Humans

Purpose

[¹⁸F]Mefway is a positron emission tomography (PET) radioligand for quantification of the brain serotonin 1A (5-HT_1A) receptor density. The purpose of this study was to evaluate the radiation safety of [¹⁸F]Mefway in humans.

Procedures

Six healthy volunteers (three males and three females) were whole-body PET scanned for 114 min after injection of [¹⁸F]Mefway (226?±?35 MBq). Estimated radiation doses were determined by the OLINDA/EXM software.

Results

[¹⁸F]Mefway was safe and well tolerated by all subjects. Residence time ranges from 0 (gallbladder) to 0.822 h (urinary bladder wall). While the estimated radiation doses in the reproductive and blood-forming organs were below 13.35–22.87 μSv/MBq, radiation dose in the urinary bladder wall was 471 μSv/MBq. The mean effective dose was 40.23?±?6.63 μSv/MBq.

Conclusion

For a typical single injection of 185 MBq (5 mCi), the dose will result in 87.1 mSv for the urinary bladder wall. To reduce radiation burden, the bladder voiding can be used before [¹⁸F]Mefway PET scan.

     

Whole Body PET Imaging with a Norepinephrine Transporter Probe 4-[18F]Fluorobenzylguanidine: Biodistribution and Radiation Dosimetry

Molecular Imaging and Biology - 4-[18F]Fluorobenzylguanidine ([18F]PFBG) is a positron emission tomography (PET) probe for non-invasive targeting of the norepinephrine transporter. The aim of this...     

Radiochemical Synthesis,Rodent Biodistribution and Tumor Uptake,and Dosimetry Calculations of [<Superscript>11</Superscript>C] Methylated LY2181308

Purpose

The aim of the study was to develop a rapid and reproducible method to label LY2181308, an antisense oligonucleotide to Survivin, with carbon-11 in order to study its in vivo biodistribution and tumor uptake in rodents and its human dosimetry based on baboon data.

Methods

Randomly [¹¹C] methylated LY2181308 was produced with [¹¹C] methyl iodide. The biodistribution was performed in female Sprague–Dawley (SD) rats and EMT-6 tumor-bearing mice in the presence of nonradioactive LY2181308. Human dosimetry calculations were based on baboon PET studies.

Results

In SD rats, the kidney and liver were the organs with the most accumulation of radioactivity. Tumor uptake in mice was also relatively high after 5 min and remained constant for up to 1 h. Baboon dosimetry suggested that up to 42 mCi of radioactivity could be administered to human with a dose-limiting organ being the kidneys with a radiation dose of 32 µGy/MBq (0.118 rad/mCi).

Conclusions

[¹¹C] Methylated LY2181308 to rodents and baboons showed its biodistribution, tumor uptake, and human dosimetry evaluation. These results should facilitate the understanding of the pharmacokinetics of LY2181308 prior to use as a potential new therapeutic agent in oncology as well as to warrant more in vivo validations as a potentially useful tumor-imaging agent.

     

Acute Rodent Tolerability,Toxicity, and Radiation Dosimetry Estimates of the S1P1-Specific Radioligand [11C]CS1P1

Molecular Imaging and Biology - In preclinical studies with rodent models of inflammatory diseases, [11C]CS1P1 has been identified as a promising imaging agent targeting sphingosine-1-phosphate...     

Preclinical Acute Toxicity Studies and Dosimetry Estimates of the Novel Sigma-1 Receptor Radiotracer, [18F]SFE

[¹⁸F]1-(2-Fluoroethyl)-4-[(4-cyanophenoxy)methyl]piperidine ([¹⁸F]SFE) is a novel, selective, high-affinity sigma-1 receptor radioligand that has been preclinically well characterized in rodents. To support an investigational new drug (IND) application for the first evaluation of [¹⁸F]SFE in humans, single-organ and whole-body radiation adsorbed doses associated with [¹⁸F]SFE injection were estimated from rat distribution data. In addition, single- and multiple-dose toxicity studies were conducted in rabbits and in dogs. Multiple-dose toxicity studies in rabbits and single-dose toxicity studies in beagles suggest at least a 100-fold safety margin for humans studies at a mass dose limit of 4.0 μg per intravenous injection, based on the combined no observable adverse effect levels (NOAEL, mg/m²) measured in these species. Radiation dosimetry estimates obtained from rat biodistribution analyses of [¹⁸F]SFE suggest that most tissues would receive about 0.010–0.020 mGy/MBq, while the adrenal glands, brain, bone, liver, lungs, and spleen would receive slightly higher doses (0.024–0.044 mGy/MBq). The adrenal glands were identified as the critical organ, because they received the highest adsorbed radiation dose. The total exposure resulting from a 5 mCi administration of [¹⁸F]SFE is well below the FDA-defined limits for yearly cumulative and per-study exposures to research participants. These combined results support the expectation that [¹⁸F]SFE will be safe for use in human positron emission tomography (PET) imaging studies with the administration of 5 mCi and a mass dose equal to or less than 4.0 μg SFE per injection.     

Evaluation of [18F]Mefway Biodistribution and Dosimetry Based on Whole-Body PET Imaging of Mice

Purpose

[¹⁸F]Mefway is a novel radiotracer specific to the serotonin 5-HT_1A receptor class. In preparation for using this tracer in humans, we have performed whole-body PET studies in mice to evaluate the biodistribution and dosimetry of [¹⁸F]Mefway.

Methods

Six mice (three females and three males) received IV injections of [¹⁸F]Mefway and were scanned for 2 h in an Inveon-dedicated PET scanner. Each animal also received a high-resolution CT scan using an Inveon CT. The CT images were used to draw volume of interest on the following organs: the brain, large intestine, stomach, heart, kidneys, liver, lungs, pancreas, bone, spleen, testes, thymus, gallbladder, uterus, and urinary bladder. All organ time-activity curves without decay correction were normalized to the injected activity. The area under the normalized curves was then used to compute the residence times in each organ. Data were analyzed using PMOD and Matlab software. The absorbed doses in mouse organs were computed using the RAdiation Dose Assessment Resource animal models for dose assessment. The residence times in mouse organs were converted to human values using scale factors based on differences between organ and body weights. OLINDA/EXM 1.1 software was used to compute the absorbed human doses in multiple organs for both female and male phantoms.

Results

The highest mouse residence times were found in the liver, urinary bladder, and kidneys. The largest doses in mice were found in the urinary bladder (critical organ), kidney, and liver for both females and males, indicating primary elimination via urinary system. The projected human effective doses were 1.21E???02 mSv/MBq for the adult female model and 1.13E???02 mSv/MBq for the adult male model. The estimated human biodistribution of [¹⁸F]Mefway was similar to that of [¹¹C]WAY 100,635, a 5-HT_1A tracer for which dosimetry has been evaluated in humans.

Conclusions

The elimination of radiotracer was primarily via the kidney and urinary bladder with the urinary bladder being the critical organ. Whole-body mouse imaging can be used as a preclinical tool to provide initial estimates of the absorbed doses of [¹⁸F]Mefway in humans.     

Radiation Dosimetry of a Novel Adenosine A<Subscript>2A</Subscript> Receptor Radioligand [<Superscript>11</Superscript>C]Preladenant Based on PET/CT Imaging and Ex Vivo Biodistribution in Rats

Purpose

[¹¹C]Preladenant was developed as a novel adenosine A_2A receptor PET radioligand. The aim of this study was to determine the radiation dosimetry of [¹¹C]preladenant and to investigate whether dosimetry estimation based on organ harvesting can be replaced by positron emission tomography (PET)/x-ray computed tomography (CT) imaging in rats.

Procedures

Male Wistar rats (n?=?35) were i.v. injected with [¹¹C]preladenant. The tracer biodistribution was determined by organ harvesting at 1, 5, 15, 30, 60, and 90 min post injection. Hollow organs including the stomach, intestines, and urinary bladder were harvested with contents. In 10 rats, a 90-min dynamic PET/CT scan of the torso was acquired. Twenty volumes of interest (VOIs) were manually drawn on the PET image using the CT image of the same animal as anatomical reference. The dynamic time-activity curves were used to calculate organ residence times (RTs). Human radiation dosimetry estimates, derived from rat data, were calculated with OLINDA/EXM 1.1.

Results

PET-imaging and organ-harvesting estimated comparable organ RTs, with differences of 6–27 %, except for the lungs, pancreas, and urinary bladder, with differences of 48, 53, and 60, respectively. The critical organ was the small intestine with a dose of 25 μSv/MBq. The effective doses (EDs) calculated from imaging-based and organ-harvesting-derived data were 5.5 and 5.6 μSv/MBq, respectively, using the International Commission on Radiological Protection 60 tissue weighting factors.

Conclusions

The ED of [¹¹C]preladenant (2 mSv for a 370-MBq injected dose) is comparable with other C-11-labeled PET tracers. Estimation of the radiation dosimetry of [¹¹C]preladenant by PET/CT imaging in rats is feasible and gives comparable results to organ harvesting, provided that small VOIs are used and the content of hollow organs is taken into account. Dosimetry by PET imaging can strongly reduce the number of laboratory animals required.

     

A new application of pre-normalized principal component analysis for improvement of image quality and clinical diagnosis in human brain PET studies--clinical brain studies using [11C]-GR205171, [11C]-L-deuterium-deprenyl, [11C]-5-Hydroxy-L-Tryptophan, [11C]-L-DOPA and Pittsburgh Compound-B

Principal component analysis (PCA) is one of the most applied multivariate image analysis tool on dynamic Positron Emission Tomography (PET). Independent of used reconstruction methodologies, PET images contain correlation in-between pixels, correlations in-between frame and errors caused by the reconstruction algorithm including different corrections, which can affect the performance of the PCA. In this study, we have investigated a new approach of application of PCA on pre-normalized, dynamic human PET images. A range of different tracers have been used for this purpose to explore the performance of the new method as a way to improve detection and visualization of significant changes in tracer kinetics and to enhance the discrimination between pathological and healthy regions in the brain. We compare the new results with the results obtained using other methods. Images generated using the new approach contain more detailed anatomical information with higher quality, precision and visualization, compared with images generated using other methods.     

Error analysis for PET measurement of dopamine D2 receptor occupancy by antipsychotics with [11C]raclopride and [11C]FLB 457

Dopamine D₂ receptor occupancy by antipsychotic drugs has been measured with positron emission tomography (PET) by comparing the binding potential (BP) values before and after drug administration. This occupancy has been found to be related to clinical effects and side effects. In this study, we evaluated the uncertainty of the quantitative analysis for estimating the dopamine D₂ receptor occupancy by antipsychotics in simulation and human studies of [¹¹C]raclopride and for the high affinity ligand [¹¹C]FLB 457. Time–activity curves of [¹¹C]raclopride and [¹¹C]FLB 457 were simulated, and the reliability of BP estimated by a simplified reference tissue model and the calculated occupancy were investigated for various noise levels, BP values, and scan durations. Then, in the human PET study with and without antipsychotics, the uncertainty of BP and occupancy estimates and the scan duration required for a reliable estimation were investigated by a bootstrap approach. Reliable and unbiased estimates of [¹¹C]raclopride BP_ND could be obtained with recording as short as 32 min, with the relative standard deviation (SD) of the striatal occupancy remaining less than 10%. Conversely, in [¹¹C]FLB 457 studies, the mean value increased and SD of the temporal cortex and thalamus exceeded 10% when the scan duration was shorter than 60 min. These results demonstrated that dopamine D₂ receptor occupancy by antipsychotics can be estimated precisely with an optimal scan duration with [¹¹C]raclopride and [¹¹C]FLB 457.     

Simplified parametric methods for [11C]PIB studies

The purpose of the present study was to evaluate the performance of various parametric reference tissue models for quantification of [11C]PIB studies. Several models with and without fixing the reference tissue efflux rate constant (k'(2)) were investigated using both simulations and clinical data. The following parametric methods were evaluated: receptor parametric mapping (basis function implementation of the simplified reference tissue model with and without fixed k'(2)), reference Logan, and several multi-linear reference tissue methods (again with and without fixed k'(2)). In addition, standardised uptake value ratios with cerebellum (SUV(r)) were evaluated. Simulations were used to assess the effects of variation in flow (R(1)), fractional blood volume (V(b)) and binding potential (BP(ND)) itself on precision and accuracy of parametric BP(ND). For clinical studies, most parametric methods showed comparable performance, with poorest results for SUV(r). Best performance was obtained for receptor parametric mapping (RPM2) and one of the multi-linear reference tissue models (MRTM2), both with fixed k'(2): BP(ND) outcome was less affected by noise and the images showed better contrast than other tested methods. RPM2 and MRTM2 also provided best accuracy and precision in the simulation studies and are therefore the methods of choice for parametric analysis of clinical [11C]PIB studies.     

A comparison of recent parametric neuroreceptor mapping approaches based on measurements with the high affinity PET radioligands [11C]FLB 457 and [11C]WAY 100635

In positron emission tomography (PET) studies, the detailed mapping of neuroreceptor binding is a trade-off between parametric accuracy and spatial precision. Logan's graphical approach is a straightforward way to quickly obtain binding potential values at the voxel level but it has been shown to have a noise-dependent negative bias. More recently suggested approaches claim to improve parametric accuracy with retained spatial resolution. In the present study, we used PET measurements on regional D2 dopamine and 5-HT1A serotonin receptor binding in man to compare binding potential (BP) estimates of six different parametric imaging approaches to the traditional Logan ROI-based approach which was used as a "gold standard". The parametric imaging approaches included Logan's reference tissue graphical analysis (PILogan), its version recently modified by Varga and Szabo (PIVarga), two versions of the wavelet-based approach, Gunn's basis function method (BFM) and Gunn et al.'s recent compartmental theory-based approach employing basis pursuit strategy for kinetic modeling (called DEPICT). Applicability for practical purposes in basic and clinical research was also considered. The results indicate that the PILogan and PIVarga approaches fail to recover the correct values, the wavelet-based approaches overcome the noise susceptibility of the Logan fit with generally good recovery of BP values, and BFM and DEPICT seem to produce values with a bias dependent on receptor density. Further investigations on this bias and other phenomena revealed fundamental issues regarding the use of BFM and DEPICT on noisy voxel-wise data. In conclusion, the wavelet-based approaches seem to provide the most valid and reliable estimates across regions with a wide range of receptor densities. Furthermore, the results support the use of receptor parametric imaging in applied studies in basic or clinical research.     

Imaging sensitive and drug-resistant bacterial infection with [11C]-trimethoprim

BACKGROUNDSeveral molecular imaging strategies can identify bacterial infections in humans. PET affords the potential for sensitive infection detection deep within the body. Among PET-based approaches, antibiotic-based radiotracers, which often target key bacterial-specific enzymes, have considerable promise. One question for antibiotic radiotracers is whether antimicrobial resistance (AMR) reduces specific accumulation within bacteria, diminishing the predictive value of the diagnostic test.METHODSUsing a PET radiotracer based on the antibiotic trimethoprim (TMP), [¹¹C]-TMP, we performed in vitro uptake studies in susceptible and drug-resistant bacterial strains and whole-genome sequencing (WGS) in selected strains to identify TMP resistance mechanisms. Next, we queried the NCBI database of annotated bacterial genomes for WT and resistant dihydrofolate reductase (DHFR) genes. Finally, we initiated a first-in-human protocol of [¹¹C]-TMP in patients infected with both TMP-sensitive and TMP-resistant organisms to demonstrate the clinical feasibility of the tool.RESULTSWe observed robust [¹¹C]-TMP uptake in our panel of TMP-sensitive and -resistant bacteria, noting relatively variable and decreased uptake in a few strains of P. aeruginosa and E. coli. WGS showed that the vast majority of clinically relevant bacteria harbor a WT copy of DHFR, targetable by [¹¹C]-TMP, and that despite the AMR, these strains should be “imageable.” Clinical imaging of patients with [¹¹C]-TMP demonstrated focal radiotracer uptake in areas of infectious lesions.CONCLUSIONThis work highlights an approach to imaging bacterial infection in patients, which could affect our understanding of bacterial pathogenesis as well as our ability to better diagnose infections and monitor response to therapy.TRIAL REGISTRATIONClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT03424525","term_id":"NCT03424525"}}NCT03424525.FUNDINGInstitute for Translational Medicine and Therapeutics, Burroughs Wellcome Fund, NIH Office of the Director Early Independence Award (DP5-OD26386), and University of Pennsylvania NIH T32 Radiology Research Training Grant (5T32EB004311-12).     

Human Radiation Dosimetry of [<Superscript>18</Superscript>F]AV-1451(T807) to Detect Tau Pathology

Purpose

[¹⁸F]AV-1451 is a positron emission tomography (PET) radioligand for detecting paired helical filament tau. Our aim was to estimate the radiation dose of [¹⁸F]AV-1451 in humans.

Procedures

Whole-body PET scans were acquired for six healthy volunteers (three male, three female) for 128 min after injection of [¹⁸F]AV-1451 (268?±?31 MBq). Radiation doses were estimated using the OLINDA/EXM software.

Results

The estimated organ doses ranged from 7.81 to 81.2 μSv/MBq. The critical organ for radiation burden was the liver. Radiation doses to the reproductive and blood-forming organs were 14.15, 8.43, and 18.35 μSv/MBq for the ovaries, testes, and red marrow, respectively. The mean effective dose was 22.47?±?3.59 μSv/MBq.

Conclusions

A standard single injection of 185 MBq (5 mCi) results in an effective dose of 4.7 mSv in a healthy subject. Therefore, [¹⁸F]AV-1451 could be used in multiple PET scans of the same subject per year.

     

[<Superscript>11</Superscript>C] Acetoacetate Utilization by Breast and Prostate Tumors: a PET and Biodistribution Study in Mice

PURPOSE: A significant positive correlation has been observed between ketone body availability and their uptake by tumor cells. Our objective was to evaluate [11C]acetoacetate as a potential tracer of ketone body utilization by breast and prostate tumors and to compare it with [11C]acetate. METHODS: Biodistribution studies were performed with [11C]acetoacetate and [11C]acetate in mice bearing breast or prostate tumors. The percentage of the injected dose accumulated per gram of tissue was determined. These results were complemented by dynamic positron emission tomography (PET) imaging of the radiotracer uptake and dosimetry calculations. RESULTS: [11C]Acetoacetate uptake was optimal between 5 and 30 min, with maximal uptake of 2.72, 2.42, 2.54, and 2.19% injected dose (%ID)/g for MC7-L1, MC4-L2, PC3, and LN-CaP tumors respectively. Tumor retention for [11C]acetoacetate tended to be higher than [11C]acetate, but this did not reach statistical significance. [11C]Acetate uptake was reached within 15 min with optimal uptake of 1.25, 2.30, and 0.96%ID/g for MC7-L1, MC4-L2, and PC-3 tumors, respectively. CONCLUSIONS: We observed a moderate uptake of [11C]acetoacetate in breast and prostate tumors with low background activity due to rapid elimination of this tracer. Further studies are warranted to determine if this tracer can detect slow-growing breast and prostate cancers in the clinical setting.     

Biodistribution and Radiation Dosimetry of the <Emphasis Type="Italic">Enterobacteriaceae</Emphasis>-Specific Imaging Probe [<Superscript>18</Superscript>F]Fluorodeoxysorbitol Determined by PET/CT in Healthy Human Volunteers

Purpose

[¹⁸F]fluorodeoxysorbitol ([¹⁸F]FDS) is the first radiopharmaceutical specific for a category of bacteria and has the potential to specifically detect Enterobacteriaceae infections. The purpose of this study was to testify the safety and investigate the biodistribution and radiation dosimetry of [¹⁸F]FDS in healthy human bodies.

Procedures

Six healthy subjects were intravenously injected with 320–520 MBq [¹⁸F]FDS. On each subject, 21 whole-body emission scans and a brain scan were conducted at settled time points within the next 4 h. Residence time for each source organ was determined by multi-exponential regression. Absorbed doses for target organs and effective dose were calculated via OLINDA/EXM.

Results

No adverse events due to [¹⁸F]FDS injection were observed in the study. The tracer was cleared rapidly from the blood pool through the urinary system. A small portion was cleared into the gut through the hepatobiliary system. The effective dose (ED) was estimated to be 0.021?±?0.001 mSv/MBq. The organ receiving the highest absorbed dose was the urinary bladder wall (0.25?±?0.03 mSv/MBq).

Conclusions

[¹⁸F]FDS is safe and well tolerated. The effective dose was comparable to that of other F-18 labeled radiotracers. [¹⁸F]FDS is suitable for human use from a radiation dosimetry perspective.

     

Pharmacokinetics, Metabolism, Biodistribution, Radiation Dosimetry, and Toxicology of 18F-Fluoroacetate (18F-FACE) in Non-human Primates

Introduction

To facilitate the clinical translation of ¹⁸F-fluoroacetate (¹⁸F-FACE), the pharmacokinetics, biodistribution, radiolabeled metabolites, radiation dosimetry, and pharmacological safety of diagnostic doses of ¹⁸F-FACE were determined in non-human primates.

Methods

¹⁸F-FACE was synthesized using a custom-built automated synthesis module. Six rhesus monkeys (three of each sex) were injected intravenously with ¹⁸F-FACE (165.4?±?28.5?MBq), followed by dynamic positron emission tomography (PET) imaging of the thoracoabdominal area during 0?C30?min post-injection and static whole-body PET imaging at 40, 100, and 170?min. Serial blood samples and a urine sample were obtained from each animal to determine the time course of ¹⁸F-FACE and its radiolabeled metabolites. Electrocardiograms and hematology analyses were obtained to evaluate the acute and delayed toxicity of diagnostic dosages of ¹⁸F-FACE. The time-integrated activity coefficients for individual source organs and the whole body after administration of ¹⁸F-FACE were obtained using quantitative analyses of dynamic and static PET images and were extrapolated to humans.

Results

The blood clearance of ¹⁸F-FACE exhibited bi-exponential kinetics with half-times of 4 and 250?min for the fast and slow phases, respectively. A rapid accumulation of ¹⁸F-FACE-derived radioactivity was observed in the liver and kidneys, followed by clearance of the radioactivity into the intestine and the urinary bladder. Radio-HPLC analyses of blood and urine samples demonstrated that ¹⁸F-fluoride was the only detectable radiolabeled metabolite at the level of less than 9% of total radioactivity in blood at 180?min after the ¹⁸F-FACE injection. The uptake of free ¹⁸F-fluoride in the bones was insignificant during the course of the imaging studies. No significant changes in ECG, CBC, liver enzymes, or renal function were observed. The estimated effective dose for an adult human is 3.90?C7.81?mSv from the administration of 185?C370?MBq of ¹⁸F-FACE.

Conclusions

The effective dose and individual organ radiation absorbed doses from administration of a diagnostic dosage of ¹⁸F-FACE are acceptable. From a pharmacologic perspective, diagnostic dosages of ¹⁸F-FACE are non-toxic in primates and, therefore, could be safely administered to human patients for PET imaging.