Whole-body biodistribution and radiation dosimetry estimates for the β-amyloid radioligand [ 11 C]MeS-IMPY in non-human primates

Transcription

1 Whole-body biodistribution and radiation dosimetry estimates for the β-amyloid radioligand [ 11 C]MeS-IMPY in non-human primates Molecular Imaging Branch, NIMH Bldg. 1 Rm. B3-10 September 6 th, 2006

2 The following report presents measurements of whole-body biodistribution over time of [ 11 C]MeS- IMPY and estimation of resulting radiation exposure to organs of the body. Absorbed doses were estimated following administration of [ 11 C]MeS-IMPY and calculated from rhesus monkey biodistribution data. Radioactivity distribution Two male rhesus monkeys (5.25 and 5.95 kg) underwent whole-body PET scans after intravenous injection via the posterior tibial vein of 6.77 and 9.95 mci of [ 11 C]MeS-IMPY. 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 120 minutes. The tomographic PET images were compressed into a single planar image. Image analysis was done using the PMOD 2.6 computer program on the compressed planar images. Regions of interest (ROIs) were drawn in source organs that could be identified: brain, heart, liver, gallbladder, lungs, kidneys, 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, non-decay-corrected data of those organs were converted to the fraction of the injected dose by dividing the organ activities by the total 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 8. The area under the curve of each organ was calculated by the trapezoidal method up to the termination of acquisition (120 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. Table 1 gives the average residence time for each of the source organs and for the remainder of the body. 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. Table 2 shows the absorbed dose estimates for humans.

3 Table 1. Human residence times for [ 11 C]MeS-IMPY extrapolated from two rhesus monkeys calculated from whole-body planar images. Residence time (h) Monkey Organ 1 2 Brain Heart Liver Gallbladder Lung Bladder Kidney Remainder

4 Table 2. Radiation dosimetry estimates for [ 11 C]MeS-IMPY extrapolated from the mean of the two monkey data estimated for human (Dynamic urinary bladder model was used, based on 2.4 h voiding interval). Organ μsv/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 Equivalent Effective Dose

5 %Injected Activity Brain Heart Liver GB Lungs Kidneys Bladder Time (min) Figure 1. Mean organ uptake over time without decay correction, expressed as a percentage of injected activity of [ 11 C]MeS-IMPY on planar images.

6 Brain %Injected Activity Brain Time (min) Figure 2. Time-activity curve for [ 11 C]MeS-IMPY as determined by PET imaging of brain. Data are expressed as the average of two monkeys and without decay correction.

7 Heart %Injected Activity Heart Time (min) Figure 3. Time-activity curve for [ 11 C]MeS-IMPY as determined by PET imaging of heart. Data are expressed as the average of two monkeys and without decay correction.

8 Liver %Injected Activity Liver Time (min) Figure 4. Time-activity curve for [ 11 C]MeS-IMPY as determined by PET imaging of liver. Data are expressed as the average of two monkeys and without decay correction.

9 Gallbladder 1.5 Gallbladder %Injected Activity Time (min) Figure 5. Time-activity curve for [ 11 C]MeS-IMPY as determined by PET imaging of gallbladder. Data are expressed as the average of two monkeys and without decay correction.

10 Lungs %Injected Activity Lungs Time (min) Figure 6. Time-activity curve for [ 11 C]MeS-IMPY as determined by PET imaging of lungs. Data are expressed as the average of two monkeys and without decay correction.

11 Kidneys 5 Kidneys %Injected Activity Time (min) Figure 7. Time-activity curve for [ 11 C]MeS-IMPY as determined by PET imaging of kidneys. Data are expressed as the average of two monkeys and without decay correction.

12 Bladder 2.5 Bladder %Injected Activity Time (min) Figure 8. Time-activity curve for [ 11 C]MeS-IMPY as determined by PET imaging of bladder. Data are expressed as the average of two monkeys and are non-corrected for radioactive decay.

13 Fraction injected activity Time (h) Figure 9. Time-activity curve for [ 11 C]MeS-IMPY as determined by PET imaging of urinary bladder. Data are expressed as the average of two monkeys and are corrected for radioactive decay. Solid line overlying the measured data points represents a biexponential fitting with an asymptote of 15% of urine activity in bladder at infinite time.

14 Appendix A

15 Appendix B Whole-body images demonstrating biodistribution of [ 11 C]MeS-IMPY in monkey 1 at 1, 25, and 105 min after radioligand injection. 1 min 25 min 105 min

16 Appendix C [ 11 C]MeS-IMPY RADIATION DOSIMETRY (USING MONKEY 1 RESIDENCE TIMES) OLINDA - Organ Level Internal Dose Assessment Code (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: C-11 (1.22E03 sec), 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-05 Breasts 0.00E E E E E E-05 GB Wall 0.00E E E E E E000 LLI Wall 0.00E E E E E E-04 Small Int. 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-05 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-04 Pancreas 0.00E E E E E E-05 Red Marrow 0.00E E E E E E-04 Osteogenic Ce 0.00E E E E E E-05 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-06 Thyroid 0.00E E E E E E-05 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): 1.01E-02 Effective Dose (msv/mbq): 6.97E-03 Organ Doses (rem/mci), Nuclide: C-11 (1.22E03 sec), 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-05 Breasts 0.00E E E E E E-04 GB Wall 0.00E E E E E E000 LLI Wall 0.00E E E E E E-03 Small Int. 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

17 Liver 0.00E E E E E E-03 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-04 Osteogenic Ce 0.00E E E E E E-05 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 Bladder Wall 0.00E E E E E E-02 Uterus 0.00E E E E E E-05 Total Body 0.00E E E E E E000 Effective Dose Equivalent (rem/mci): 3.74E-02 Effective Dose (rem/mci): 2.58E-02 Number of Disintegrations in Source Organs: Adrenals Brain 1.70E-02 MBq-h/MBq or uci-h/uci Breasts Gallbladder Contents 1.40E-02 MBq-h/MBq or uci-h/uci LLI Small Intestine Stomach ULI Heart Contents Heart Wall 3.00E-03 MBq-h/MBq or uci-h/uci Kidneys 7.00E-03 MBq-h/MBq or uci-h/uci Liver 7.40E-02 MBq-h/MBq or uci-h/uci Lungs 4.00E-02 MBq-h/MBq or uci-h/uci Muscle Ovaries Pancreas Red Marrow Cortical Bone Trabecular Bone Spleen Testes Thymus Thyroid Urinary Bladder Contents 9.00E-02 MBq-h/MBq or uci-h/uci Uterus/Uterine Wall Remainder 2.40E-01 MBq-h/MBq or uci-h/uci Target Organ Masses: Adrenals Brain Breasts Gallbladder Wall LLI Wall Small Intestine Stomach Wall ULI Wall Heart Wall Kidneys 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

18 Liver Lungs Muscle Ovaries Pancreas Red Marrow Osteogenic Cells Skin Spleen Testes Thymus Thyroid Urinary Bladder Wall Uterus Total Body 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

19 Appendix D Weights of rhesus monkey 1 and human organs 2 (kg). Weight(kg ) Organ Monkey Human Brain Heart Liver Lung Kidney Total body Remainder 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.