Monkey Dosimetry Estimates for the Phosphodiesterase 4 (PDE4) Enzyme Radioligand (R)- 11C

Radiationdosimetry estimates for the [11C](-)-RWAY determined from whole body imaging in non-human primates

Molecular Imaging Branch, NIMH

Bldg. 1 Rm. B3-10

September 30, 2005

The following report provides human dosimetry estimates for the[11C](-)-RWAY radioligand based on whole-body PET imaging of monkeys.

Radioactivity distribution

Two male rhesus monkeys (10 and 13 kg) underwent whole-body PET scans after intravenous injection via the posterior tibial vein of 3.43 and 8.79 mCi [11C](-)-RWAY. 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. A urinary catheter was inserted and clamped so that the radioactivity overlaying the bladder represented the total urinary excretion during the scanning interval.

The tomographic PET images were compressed into a single planar image. Image analysis was done using the PMOD 2.5 computer program on the compressed planar images. Regions of interest (ROIs) were drawn in source organs that could be identified: brain, heart, lungs, liver, small intestine, spleen, 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 measured recovery was only 40.7% for the first frame, but an average of 88.0% for the remaining frames (for both monkeys). The low recovery of the first frame was presumably due to the injection site being below the field of view. 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 9. 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: (bm/om) x (bh/oh), where bm and bh are the body weights of monkey and human, respectively; and om and oh are the organ weights of monkey and human, respectively, except for gall bladder and small intestine where the specific organ weights of the monkey were not available.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

Urinary bladder residence time was calculated with the dynamic bladder model. For each subject, decay-corrected cumulative urine activity was fitted with a bi-exponential curve by limiting the urine activity not exceeding 100% of the injected activity, and the total excretion in urine in terms of fraction of the injected dose and biological half-life were determined. The fraction excreted via urine was on average 10.9%, and average biological half-lives with the bi-exponential fitting were 7.9655 and 0.5653 h. The dynamic bladder model was applied to calculate residence time of the urinary bladder wall with urine voiding interval of 2.4 h. [An example of the bi-exponential fitting with PRISM software is attached on Figure 10.]After determining the residence times for the urinary bladder, the final radiation absorbed doses were calculated by entering the residence times for all source organs into OLINDA 1.0/EXM computer program using the model for a 70-kg adult male. Table 2 shows the absorbed dose estimates for humans.

Table 1: Average residence times of source organs and remainder of body

OrganResidence time (h)

Brain0.1252

Heart0.0089

Lung0.1199

Liver0.0626

Kidney0.0787

Spleen0.0032

Gall Bladder0.0030

Small Intestine0.0248

Remainder of the Body0.2409

Table 2: Radiation dose estimates for [11C](-)-RWAY

Organ μSv/MBq mrem/mCi

Adrenals / 3.19 / 11.80
Brain / 28.40 / 105.00
Breasts / 1.08 / 3.98
Gallbladder Wall / 9.60 / 35.50
LLI Wall / 0.80 / 2.95
Small Intestine / 8.17 / 30.20
Stomach / 1.43 / 5.28
ULI Wall / 1.84 / 6.81
Heart Wall / 9.25 / 34.20
Kidneys / 70.60 / 261.00
Liver / 11.90 / 44.00
Lungs / 30.90 / 114.00
Muscle / 0.91 / 3.38
Ovaries / 1.07 / 3.94
Pancreas / 2.55 / 9.43
Red Marrow / 1.48 / 5.46
Bone Surfaces / 1.24 / 4.60
Skin / 0.57 / 2.13
Spleen / 6.89 / 25.50
Testes / 0.21 / 0.76
Thymus / 1.30 / 4.81
Thyroid / 0.86 / 3.20
Urinary Bladder Wall / 11.10 / 41.00
Uterus / 1.24 / 4.60
Total Body / 2.57 / 9.51
Effective Dose Equivalent / 12.30 / 45.40
Effective Dose / 7.53 / 27.90

Figure 2. Time-activities curve for[11C](-)-RWAY as determined by PET imaging of brain.