Amira K. Brown, Ph.D. Molecular Imaging Branch, NIMH Bldg. 1 Rm. B3-10

Transcription

1 Whole-body biodistribution and radiation dosimetry estimates for the metabotropic glutamate receptor subtype 5 (mglur5) radioligand [ 18 F]SP203 in nonhuman primates Amira K. Brown, Ph.D. Molecular Imaging Branch, NIMH Bldg. 1 Rm. B3-10 November 16, 2006

2 The following report presents measurements of whole-body biodistribution over time of [ 18 F]SP203 and estimation of resulting radiation exposure to organs of the body. Absorbed doses were estimated following administration of [ 18 F]SP203 and calculated from rhesus monkey biodistribution data. Radioactivity distribution Three male rhesus monkeys (5.25, 6.25, and 6.3 kg) underwent whole-body PET scans after intravenous injection via the posterior tibial vein of 9.7, 10.87, and 3.99 mci of [ 18 F]SP203. 2D dynamic scans were acquired on the GE Advance tomography (GE Medical Systems, WI) in 4 segments of the body (head to upper thigh) in frames of increasing duration (75 s to 15 min) for a total scan time of 240 minutes. The tomographic PET images were compressed into a single planar image. Image analysis was done using the PMOD 2.65 computer program on the compressed planar images (Appendix B). Regions of interest (ROIs) were drawn in source organs that could be identified: brain, heart, liver, gallbladder, lungs, spleen, kidneys, vertebra, and urinary bladder. Large ROIs were placed to assure that all accumulated radioactivity in each organ was encompassed. Many of the source organs were not confined to a single bed position. In these cases, new time points were generated for these organs to correspond with the activity data. This was achieved by weighting the time points associated with each bed position the organ appeared in by the percentage of the organ volume present in a given section. These values were then summed to give the final time points. The organ values of IA were corrected for recovery of measured activity. To accomplish this, a large region of interest was placed over the entire body for each of the 22 frames. The IA value for each source organ at every time point was corrected for recovery by multiplying by 100/X, where X is the measured recovery for the individual frame. The remainder of body was calculated for each time point as the decayed value of the original IA minus activity present in the identified source organs. Calculating Residence Times At each time point, decayed activity of the source organs were converted to the fraction of the injected activity (IA). The total injected activity was calculated as the entire activity present in frame 1 in each of the four segments. Time-activity curves (TACs) for the source organs are shown in Figures 1 to 12. The area under the curve of each organ was calculated by the trapezoidal method up to the termination of acquisition (240 min). The area under the curve after the acquisition of the last image, i.e., to infinity, was calculated by assuming that the decline in radioactivity after this time point occurred by only physical decay, without any further biological clearance. The area under the curve of % injected activity from time zero to infinity (after multiplication by 100) is equivalent to residence time for the monkey. The residence times from the monkey were converted into corresponding human values by multiplication with a factor to scale organ and body weights: (b m /o m ) x (b h /o h ), where b m and b h are the body weights of monkey and human, respectively; and o m and o h are the organ weights of monkey and human, respectively(appendix D). Table 1 gives the average residence time for each of the source organs and for the remainder of the body.

3 Uptake in Bone and Marrow. [ 18 F]SP203 showed significant uptake in bone (presumably from defluorination) and in red marrow. To estimate the distribution in bone vs. marrow, skeletal activity was divided into three classifications: 1) trabecular (cancellous or spongy bone), 2) cortical (compact or dense bone), and 3) red marrow. Trabecular bone was sampled as the superior portion of the scapula plus bones in the wrist. Cortical bone was sampled as the majority of the humerus, ulna, and radius, excluding the proximal and distal portions (which encompass the metaphysis and epiphysis). The red marrow was sampled from the thoracic vertebrae. Trabecular and cortical bone was sampled from the planar image compressed in the anterior-posterior direction and had relatively little contamination from regions (e.g., muscle) anterior to posterior to the target organ. However, the thoracic vertebrae showed significant contamination from organs anterior to the vertebral column. To minimize this contamination, the thoracic vertebrae were identified on a planar sagittal image, created by compressing all images right to left. After obtaining these sample measurements of radioactivity, we needed to calculate the total uptake in each of these three compartments (i.e., trabecular bone, cortical bone, and red marrow). For example, we needed to know what percentage of total cortical bone in the body is represented by humerus, ulna, and radius. Since we could not find these data for rhesus monkey, we used the same percentage as that for human subjects in ICRP Publication No., 23, Table 16, page 67. We list below the percentage of the total target represented by the sampled activity. For example, the humerus, ulna, and radius on right and left equal 10.2% of all cortical bone in the MALE human body. Target Sampled Activity % of Target Cortical Bone Humerus, ulna, 10.2 radius Trabecular Bone Superior portion of 9.7 scapula, wrist bones Red Marrow Thoracic vertebrae 16.1 The calculation for red marrow was more complicated, since the thoracic vertebrae contain bone as well as marrow, and the bone would have radioactivity from [ 18 F]fluoride. We estimated the amount of marrow and bone in thoracic samples by analogy to the human. The human thoracic vertebrae contain 210 g bone in ICRP Publication No., 23, Table 16, page 67 and 188 g red marrow (= 16.1% of 1,170 g total marrow in body) as noted in ICRP Publication No., 89, page 183. Thus, the sampled vertebral radioactivity was assumed to be 52% bone (=210 / ( )) and 48% marrow (= 188 / ( )). This calculated thoracic marrow activity was assumed to be 16.1% of total marrow in body (see Table above). Estimation of human absorbed radiation dose The radiation absorbed doses were calculated by entering the residence times for all source organs into OLINDA 1.0 computer program using the model for a 70-kg adult male (Appendix A). Table 2 shows the absorbed dose estimates for humans.

4 Results Intravenous injection of [ 18 F]SP203 caused no significant changes in ECG, heart, or respiration rates from baseline values. Recovery of radioactivity from planar images was 87%, 93%, and 88% of the injected activity in the three animals. The brain, gallbladder, lungs, heart, kidneys, spleen, urinary bladder, thoracic vertebrae (red marrow), cortical and trabecular bone were identified on 2-D planar images (Appendix B). The lungs had the highest uptake of [ 18 F]SP203 with an average peak of 23% IA at about 2 min post-injection. The kidneys and liver also exhibited relatively high uptake of radioactivity with respective peak values of 13%, 13.5%, and 12% IA while the brain, heart, spleen, gallbladder, trabecular bone, cortical bone, and red marrow had peak uptakes of 7%, 7.3%, 0.45%, 0.95%, 1.4%, 2%, and 7.8% respectively. All organs reached peak uptake between 5-25 minutes post injection (Figure 1). We were unable to calculate the radioactivity in the bladder of two monkeys because the animals voided in the last frames of the PET scans. For this reason, we scanned a third animal after a urinary catheter was inserted and clamped. Monoexponential fitting of the accumulated activity in the bladder had an asymptote of 15% (Fig. 12). That is, we estimated that 15% of the IA was excreted in the urine at infinite time. Using the bladder voiding model the effective dose at 2.4h was 15.8 usv/mbq and 16.2 usv/mbq at 4.8h. The residence times for the three animals from 2-D planar images are shown in Table 1. Radiation absorbed dose estimates were calculated from these residence times using OLINDA computer program (Appendix C).

5 Table 1. Human residence times for [ 18 F]SP203 extrapolated from three rhesus monkeys calculated from whole-body planar images. ORGAN Residence Time (h) Monkey 1 Monkey 2 Monkey 3 Mean Brain Heart Lungs Spleen Liver Kidneys Bladder N/A N/A Red Marrow Trabecular Bone Cortical Bone Gallbladder Remainder in Body Total* * If all radioactivity remains in the body, then the sum of the residence times τ i should equal 2.64 for 18 F with T 1/2 = 1.83 h T 1.83 h τ = 1/2 = = 2.64 h ι ln

6 Table 2. Radiation dosimetry estimates for [ 18 F]SP203 extrapolated from the mean of the three monkeys data estimated for human using bladder voiding model at 2.4h. Organ usv/mbq mrem/mci usv/mbq mrem/mci Adrenals Brain Breasts Gallbladder Wall LLI Wall Small Intestine Stomach ULI Wall Heart Wall Kidneys Liver Lungs Muscle Ovaries Pancreas Red Marrow Osteogenic Cells Skin Spleen Testes Thymus Thyroid Urinary Bladder Wall Uterus Total Body Effective Dose Effective Dose Voiding interval 2.4h Voiding interval 4.8h

7 % Injected Activity Time (min) Brain Lungs Heart Gallbladder Liver Kidneys Spleen Trabecular Cortical Red Marrow Red Marrow Figure 1. Mean organ uptake over time without decay correction, expressed as a percentage of injected activity of [ 18 F]SP203 on planar images.

8 % Injected Activity Brain Time (min) Brain Figure 2. Time-activity curve for [ 18 F]SP203 as determined by PET imaging of brain. Data are expressed as the average of three monkeys and without decay correction.

9 Heart % Injected Activity Time (min) Heart Figure 3. Time-activity curve for [ 18 F]SP203 as determined by PET imaging of heart. Data are expressed as the average of three monkeys and without decay correction.

10 Liver 12.5 % Injected Activity Time (min) Liver Figure 4. Time-activity curve for [ 18 F]SP203 as determined by PET imaging of liver. Data are expressed as the average of three monkeys and without decay correction.

11 % Injected Activity Gallbladder Time(min) Gallbladder Figure 5. Time-activity curve for [ 18 F]SP203 as determined by PET imaging of gallbladder. Data are expressed as the average of three monkeys and without decay correction.

12 % Injected Activity Spleen Time (min) Spleen Figure 6. Time-activity curve for [ 18 F]SP203 as determined by PET imaging of the spleen. Data are expressed as the average of three monkeys and without decay correction.

13 Lungs 25 % Injected Activity Lungs Time (min) Figure 7. Time-activity curve for [ 18 F]SP203 as determined by PET imaging of lungs. Data are expressed as the average of three monkeys and without decay correction.

14 Kidneys 15 % Injected Activity 10 5 Kidneys Time (min) Figure 8. Time-activity curve for [ 18 F]SP203 as determined by PET imaging of kidneys. Data are expressed as the average of three monkeys and without decay correction.

15 Trabecular Bone 2 % Injected Activity 1 Trabecular Bone Time (min) Figure 9. Time-activity curve for [ 18 F]SP203 as determined by PET imaging of the trabecular bones. Data are expressed as the average of three monkeys and without decay correction.

16 Cortical Bone % Injected Activity Time (min) Cortical Bone Figure 10. Time-activity curve for [ 18 F]SP203 as determined by PET imaging of the cortical bones. Data are expressed as the average of three monkeys and without decay correction.

17 % Injected Activity Red Marrow Time (min) Red Marrow Figure 11. Time-activity curve for [ 18 F]SP203 as determined by PET imaging of the red marrow in the thoracic vertebrae. Data are expressed as the average of three monkeys and without decay correction.

18 Fraction %ID Time (h) Figure 12. Time-activity curve for [ 18 F]SP203 as determined by PET imaging of urinary bladder. Data are corrected for radioactive decay. Solid line overlying the measured data points represents a one phase exponential fitting with an asymptote of 15% of urine activity in bladder at infinite time.

19 Appendix A

20 Appendix B Whole-body images demonstrating biodistribution of [ 18 F]SP203 in monkey 1, 25, and 105 min after radioligand injection. 1 min 25 min 105 min

21 Appendix C [ 18 F]SP203 RADIATION DOSIMETRY (USING MONKEY 1 RESIDENCE TIMES) OLINDA - Organ Level Internal Dose Assessment (copyright Vanderbilt University, 2003) NOTE: This code gives doses for stylized models of average individuals - results should be applied with caution to specific human subjects. NOTE: Users should always carefully check input data (shown below) and critically review the reported results. Organ Doses (msv/mbq), Nuclide: F-18 (1.10E02 min), Adult Male Target Organ Alpha Beta Photon Total EDE Cont. ED Cont. Adrenals 0.00E E E E E E-05 Brain 0.00E E E E E E-04 Breasts 0.00E E E E E E-04 Gallbladder Wall 0.00E E E E E E000 LLI Wall 0.00E E E E E E-03 Small Intestine 0.00E E E E E E-05 Stomach Wall 0.00E E E E E E-04 ULI Wall 0.00E E E E E E-05 Heart Wall 0.00E E E E E E000 Kidneys 0.00E E E E E E-04 Liver 0.00E E E E E E-04 Lungs 0.00E E E E E E-03 Muscle 0.00E E E E E E-05 Ovaries 0.00E E E E E E-03 Pancreas 0.00E E E E E E-05 Red Marrow 0.00E E E E E E-03 Osteogenic Cells 0.00E E E E E E-04 Skin 0.00E E E E E E-05 Spleen 0.00E E E E E E-05 Testes 0.00E E E E E E000 Thymus 0.00E E E E E E-05 Thyroid 0.00E E E E E E-04 Urinary Bladder Wall 0.00E E E E E E-03 Uterus 0.00E E E E E E-05 Total Body 0.00E E E E E E000 Effective Dose Equivalent (msv/mbq) Effective Dose (msv/mbq) Organ Doses (rem/mci), Nuclide: F-18 (1.10E02 min), Adult Male 2.69E E-02 Target Organ Alpha Beta Photon Total EDE Cont. ED Cont. Adrenals 0.00E E E E E E-04 Brain 0.00E E E E E E-04 Breasts 0.00E E E E E E-03 Gallbladder Wall 0.00E E E E E E000 LLI Wall 0.00E E E E E E-03 Small Intestine 0.00E E E E E E-04 Stomach Wall 0.00E E E E E E-03 ULI Wall 0.00E E E E E E-04 Heart Wall 0.00E E E E E E000 Kidneys 0.00E E E E E E-04 Liver 0.00E E E E E E-03 Lungs 0.00E E E E E E-02 Muscle 0.00E E E E E E-04 Ovaries 0.00E E E E E E-03 Pancreas 0.00E E E E E E-04 Red Marrow 0.00E E E E E E-03 Osteogenic Cells 0.00E E E E E E-04 Skin 0.00E E E E E E-04 Spleen 0.00E E E E E E-04 Testes 0.00E E E E E E000

22 Thymus 0.00E E E E E E-04 Thyroid 0.00E E E E E E-03 Urinary Bladder Wall 0.00E E E E E E-02 Uterus 0.00E E E E E E-04 Total Body 0.00E E E E E E000 Effective Dose Equivalent (rem/mci) Effective Dose (rem/mci) Number of Disintegrations in Source Organs: Adrenals Brain 2.00E-01 MBq-h/MBq or uci-h/uci Breasts Gallbladder Contents 2.00E-03 MBq-h/MBq or uci-h/uci LLI Small Intestine Stomach ULI Heart Contents 4.30E-02 MBq-h/MBq or uci-h/uci Heart Wall Kidneys 5.00E-02 MBq-h/MBq or uci-h/uci Liver 1.01E-01 MBq-h/MBq or uci-h/uci Lungs 3.70E-01 MBq-h/MBq or uci-h/uci Muscle Ovaries Pancreas Red Marrow 4.90E-02 MBq-h/MBq or uci-h/uci Cortical Bone 4.50E-02 MBq-h/MBq or uci-h/uci Trabecular Bone 5.60E-02 MBq-h/MBq or uci-h/uci Spleen 7.00E-03 MBq-h/MBq or uci-h/uci Testes Thymus Thyroid Urinary Bladder Contents 2.50E-01 MBq-h/MBq or uci-h/uci Uterus/Uterine Wall Remainder 8.00E-01 MBq-h/MBq or uci-h/uci 9.94E E-02 Target Organ Masses: Adrenals Brain Breasts Gallbladder Wall LLI Wall Small Intestine Stomach Wall ULI Wall Heart Wall Kidneys Liver Lungs Muscle Ovaries Pancreas Red Marrow Osteogenic Cells Skin Spleen Testes Thymus Thyroid Urinary Bladder Wall Uterus Total Body 1.63E001 g 1.42E003 g 3.51E002 g 1.05E001 g 1.67E002 g 6.77E002 g 1.58E002 g 2.20E002 g 3.16E002 g 2.99E002 g 1.91E003 g 1.00E003 g 2.80E004 g 8.71E000 g 9.43E001 g 1.12E003 g 1.20E002 g 3.01E003 g 1.83E002 g 3.91E001 g 2.09E001 g 2.07E001 g 4.76E001 g 7.90E001 g 7.37E004 g * Mass modified by user Radiation Weighting Factors: Alpha: 5.00E00 Beta: 1.00E00 Photon: 1.00E00 ** Weighting factor modified by user

23 Appendix D Weights of rhesus monkey and human organs are from references 1 and 2, respectively, except for bone and marrow. Weight (kg) Organ Monkey Human Brain Heart Liver Lung Kidney Gallbladder 1 1 Spleen Trabecular: wrist & scapula: Cortical Bone: humerus, ulna, and radius Red Marrow: thoracic vertebrae Total body Remainder Monkey bone and red marrow were assumed to represent the same percentage of total body weight as for the human. For example, trabecular bone was sampled as the two wrists and scapulae and had mass of 0.4 kg in a 69.9 kg human subject. Thus, this sample of trabecular bone in a monkey was calculated as 6 kg * (0.4/ 69.9) = 0.03 References 1. Bourne GH (1975) The Rhesus Monkey. Academic Press, Academic Press 2. Venes D, Taber CW (2005) Taber's cyclopedic medical dictionary, Ed. 20, illustrated in full color / edn. F.A. Davis Co., F.A. Davis Co. 3. Snyder, WS, Cook, MJ, Nasset, ES, Karhausen, LR, Howells, GP, & Tipton, IH. (1975) Report of the task Group on Reference Man. Pergamon Press 4. Valentin, J (2001) Basic Anatomical and Physiological Data for Use in Radiological Protection: reference Values. Annals of the ICRP, Publication 89. Pergamon Press