Radiation dosimetry of [18F](N-methyl)benperidol as determined by whole-body PET imaging of primates

Nuclear Medicine & Biology, Vol. 24, pp. 311-318, Copynght 0 1997 Elsevier Science Inc.

ISSN 0969-805 l/97/$1 7.00 + 0.00 PII SO969-8051(97)00042-5

1997

ELSEVIER

Radiation Dosimetry of [18F](N-Methyl)Benperidol as Determined by Whole-Body PET Imaging of Primates S. M. Moerlein,“2 ‘THE

EDWARD AND

MALLINCKRODT ‘DEPARTMENT

J. S. Perlmutter,‘~3 P. D. Cutler’ and M. J. Welch’

INSTITUTE OF NEUROLOGY

OF RADIOLOGY, AND

‘DEPARTMENT

NEUROSURGERY, ST. LOUIS,

OF BIOCHEMISTRY

WASHINGTON

MISSOURI,

AND

UNIVERSITY

MOLECULAR

SCHOOL

BIOPHYSICS.

OF MEDICINE,

USA

ABSTRACT. Radiation absorbed doses due to IV administration of [“F](N-methyl)benperidol ([ 18F]NMB) were estimated by whole-body PET imaging of nonhuman primates. Time-activity curves were obtained for nine compartments (striatum, eyes, heart, lungs, liver, gallbladder, intestines, kidneys, bladder) by using dynamic PET scans of three different baboons given the radiotracer. These time-activity curves were used to calculate the residence times of radioactivity in these tissues. Human absorbed dose estimates were calculated using the updated MIRDOSE 3 S values and assuming the same biodistribution. Based on an average of three studies, the critical organs were the lower large intestine, gallbladd er, and liver, receiving doses of 585, 281, and 210 mrad/mCi, respectively. The brain received a dose of 13 mrad/mCi; other organs received doses between 32-77 mrad/mCi. These results indicate that up to 8.5 mCi of [“F]NMB can be safely administered NUCL MED BIOL 24;4:311-318, 1997. @ 1997 to human subjects for PET studies of D2 receptor binding. Elsevier Science Inc. KEY WORDS. Dosimetry, tomography, PET

[‘sF](N-methyl)benperidol,

[‘“FINMB,

INTRODUCTION It has been shown that [‘8F](N-methyl)benperidol ([‘“FINMB) has characteristics as a dopaminergic D2 receptor-binding radioligand not found with any other tracer used for PET study of D2 receptor activity in humans (23). There is greater D2 receptor selectivity for [18F]NMB than radiolabeled spiperone and its analogs (4, 11, 26), and, unlike [“Clraclopride (7, 27), [18F]NMB is inert to displacement from receptor sites by endogenous dopamine. Moreover, [18F]NMB binds to D2 receptors in a reversible manner and is not internalized (23), characteristics that may be useful for in viva evaluation of centrally acting drugs. Thus, institution of [‘*F]NMB as a PET radiopharmaceutical for routine human studies represents a potentially important advancement in this area of research. To promote the clinical application of this novel radioligand in humans, we report here the estimated organ dosimetry associated with use of [‘“FINMB. Primates were used in these preclinical investigations, as the interspecies differences with man are minor and hence extrapolation to humans is anticipated to be close.

MATERIALS AND METHODS Radiopharmaceutical Preparation Radionuclide production was done using the Washington University JSW BC- 16/8 or CS-15 medical cyclotrons. The [ ‘sF]NMB was synthesized from [‘*F]fluoride using a three-step procedure (22). The radioligand had a radiochemical purity exceeding 99% and an end-of-synthesis specific activity greater than 2000 Ci/mmol (74 GBq/mmol), and was dissolved in 6 mL of lactate-buffered physiological saline for injection. [“O]Water for PET measurement of Address reprint requests to: Dr. Stephen Moerlein, Mallinckrodt Radiology, 510 S. Kingshighway Blvd., St. Louis, MO 63110, Received 10 August 1996. Accepted 8 December 1996.

Institute USA.

of

D2 receptor

regional blood system (38).

flow

ligands,

was produced

Positron

emission

using

a remotely

controlled

Instrumentation PET Images were acquired with use of an ECAT 953B scanner (Siemens/CTI, Knoxville, TN) in the 2-D mode (19, 33). This instrument scans 31 simultaneous slices with a center-to-center separation of 3.37 mm, yielding an axial field of view of about 10.5 cm. Attenuation factors were measured for each subject using three 68Ge/68Ga rotating rod sources. Random and dead-time corrections were done with the manufacturer’s algorithms. Scatter correction was done with a deconvolution method (1). Images were reconstructed using a Butterworth low-pass filter giving a reconstructed transverse resolution of about 5-6 mm. The axial resolution is about 4.2 mm at the center of the slice. The PET scanner was calibrated daily using a 20-cm-diameter cylindrical solid source of 68Ge/68Ga. The scanner was also cross-calibrated with a NaI(T1) well-type dose calibrator using a fluid-filled cylindrical phantom containing [“Flfluoride solution. In this manner, measured PET counts could be converted to microcuries of 18F.

Subjects Three male Pupio am&s baboons weighing 10.5-18.5 kg were used for these studies. All experimental procedures were approved by the Animal Studies Committee of Washington University. PET studies were performed with the animal fully sedated; there were no signs of distress in the animals throughout the PET procedures. The baboons were fasted overnight, but allowed free access to water up to 2 h before each study. Just prior to the study, the animal was initially anesthetized with lo-15 mg/kg ketamine i.m. and given glycopyrrolate 2-3 kg/kg i.m. to decrease secretions. A 20-gauge plastic catheter was inserted into a limb vein to permit

312

S. M. Moerlein

A B C D

et al.

Study 1 f

.-s z ’ .-0 c % b E r-0

A B

1-1

c D

A B C D

Study 2

Study 3

0

50

150

100

200

250

300

Time (min) FIG. 1. Outline of the scanning sequences for the three studies. H, transmission scan; W, blood-flow measurement only); 0, [ “F]NMB emission scan. Approximately 1.4-2.2 min were required for repositioning the animal between

radiotracer and drug administration. The animal was paralyzed with gallamine 2-4 mg/kg IV, intubated with a soft-cuffed endotracheal tube, and ventilated with 70% nitrous oxide and 30% oxygen to maintain heavy sedation. Lacrilube was placed into the eyes to protect the corneas. Pulse, end-tidal PCO, and rectal temperature were monitored, and periodic arterial-blood gases confirmed that carbon dioxide and oxygen tensions were constant throughout the procedures.

(study 3 each scan.

sample was counted before and after injection into the animal with use of a NaI(T1) well-type scintillation counter that was crosscalibrated with the PET scanner (21). Sequential scans were obtained for each baboon over a total scanning time of 3.6-4.0 h. As shown in Fig. 1, the sequence of the acquisition frames differed slightly for the three test subjects. Generally, 5-6 successive PET scans were done for the four tomographic sections, with acquisition times of 120 set, 2 X 300 set, 2 X 600 set, and 900 sec. The set of 120.set scans was not performed on one of the three animals (Study 1).

Data Acquisition Imaging of each animal consisted of four pre-injection transmission scans and 24 static emission scans. Corresponding transmission and emission scans were identical and comprised four sections of each animal’s body. The animal was firmly secured to the scanning table, which was moved to a set position for each of the four assigned body sections. The assigned sections (and tissues included therein) were: A (eyes and brain, including striatum, frontal cortex), B (heart, lungs), C (liver, gallbladder, kidneys), and D (bladder, lower large intestines). Transmission images were acquired immediately before injection of radiotracer and at least 3 h after induction of anesthesia. For one of the three test subjects, blood-flow images were acquired for each section immediately prior to injection of [“FINMB. This was achieved by four separate IV bolus injections of 7-33 mCi (0.261.22 GBq) [150]water into an antecubital vein, followed by 40-set emission scans of sections A-D (36), separated approximately 15 min apart. Immediately after acquisition of the transmission and the bloodflow data, 2.7-4.4 mCi (98-161 MBq) of [‘*F]NMB was injected IV over 30 set into an antecubital vein. The syringe containing the

Image Quantification Based on the emission scan data, radioactivity from the blood compartment localized primarily within nine organs or compartments. All organs and tissues containing a visible accumulation of activity were included for image quantification. Image analysis involved two approaches, which depended upon the size of the organ under consideration. For small organs (striata, eyes, heart, and gallbladder), regions of interest (ROIs) much larger than the target organ were drawn to assure that all of the accumulated radioactivity was encompassed. For example, the striatum (caudate and putamen) of a baboon weighs about 1 g wet weight on each side of the brain, or 2 g total. This typical weight is based upon our experience in dissecting more than 40 baboon striata over the past 15 years. The volume of each ROI was determined from the PET scans by multiplying the number of pixels encompassed by the ROI times the pixel dimensions. Each pixel was about 2 X 2 mm in the transverse dimensions and about 4.5 mm in the axial dimension. The PET regions chosen for the two striata enclosed 12.8-15.6 cc for both sides of the brain, or about six times the true size of the striata. Our data analysis method thus ensures

Radiation

Dosimetry

313

of [‘sF](N-methyl)Benperidol

TABLE 1. Regions Quantification

of

Interest

Organ ROIs that encompass the organ Striata Heart Gallbladder Eyes

(ROI)

Number of PET slices

Used

Number of ROIs sampled

8 14 9 5-7

for

Image

Organ ROI volume (cc)= 12.8-15.6 82.9-l 13.9 12.8-15.5 19.5-23.4 Total sampled volume (cc)”

ROIs that sample the organ Lungs Liver Kidneys Lower large intestines Bladder

2 3 2 6 4

4-5 3 4 3-6

2-4

4.6-21.6 3.5-7.4 3.5-5.8 2.7-10.4 3.8-10.1

d Range for three animals. that we have included most of the radioactivity from the striata in the corresponding ROIs that were selected. For the heart and eyes, ROIs were identified on the attenuation images and were generously outlined to reach beyond the target organ. The total volume of the eye ROIs amounted to 19.5-23.4 cc, which is almost twice the volume of a pair of typical baboon eyes (18). Similarly, the total volume of the heart ROIs was about 50% greater than the typical size of age-matched baboon hearts (18). The gallbladder was identified on the attenuation image, and an ROI was drawn much larger than the corresponding region of concentrated uptake of ‘sF activity on the emission image. For all sequential scans made on an animal, the position of each ROI was held constant for regional radioactivity measurements. As organs were sampled on multiple PET slices, radioactivity levels from all of the relevant ROIs for a given organ were added to give the entire radioactivity accumulation in that organ. The volumes of the ROIs that correspond to the four organs in which ROIs encompassed the entire organ are listed in Table 1. The PET-based regional radioactivity measurements for each of these total organ volumes were used to determine the percent injected dose per organ (%ID/organ). For larger organs (lungs, liver, kidneys, and bladder), several small ROIs were chosen to include all areas of selective radioactivity accumulation within the target organ. The concentration levels of radioactivity that accumulated within these sampled parts of the organ were calculated, and the resulting radioactivity concentrations were averaged and multiplied by the entire organ weight to give a generous estimate of the radioactivity accumulation within the total organ. Standard organ and tissue volumes (29, 30) were used for these calculations. The representative sample ROIs spanned several slices and had different volumes, as listed in Table 1. Our approach of multiplying the average radioactivity concentration in representative sample ROIs times total organ volume overestimates the organ dose, as it assumes that regions of nonselective accumulation within an organ have the same uptake of radioactivity as those regions with selective accumulation.

Standard organ volumes were used in these calculations because organ volumes could not be accurately obtained from the PET images. Although it is feasible to measure accurately the volumes of small organs or compartments in which the ROI included the entire organ (striatum, heart, eyes, gallbladder), volume measurement was not necessary for these compartments since the radioactivity accumulation in the entire organ was measured directly by PET. For larger organs in which selection of a single comprehensive ROI around the entire organ was not possible (lungs, liver, kidneys, intestines, and bladder), it was necessary to use multiple representative ROIs for each organ. In these organs, we could not visualize the entire organ on the emission or transmission images, making it difficult to encompass with confidence the entire organ. For this reason, we used standard volumes to calculate the O/ID/organ for large organs, rather than attempt to measure the individual compartmental volumes by PET. There was no loss of urine or fecal matter from the animals during these studies. Thus, correction to the absorbed dose calculations for loss of radiation from the animals through these routes was unnecessary.

Time-Actiwity

Curves

Time-activity curves were constructed for the various compartments after correcting the emission data for radionuclide half-life, scanner dead time, and tissue attenuation. The average counts per cc in each organ ROI (or collection of representative ROIs) were converted to activity (pCi) per cc with use of a cross-calibration factor between the PET system, the well counter, and the dose calibrator. The blood content was included in each organ with the organ, which produces a more accurate assessment of the dose delivered to the organ by nonpenetrating radiation. The average activity per cc for each organ or tissue was multiplied by the respective standard organ and tissue volumes (29, 30) to yield the total accumulated activity for each scan frame. The standard organ or tissue volumes were normalized for each animal’s weight. In generating time-activity curves, the midpoint (weighted for radioactive decay of ‘sF) of each scan was recorded as the time elapsed since the start of radioligand injection. Decay-corrected data for the different compartments were fitted by a least-squares regression to achieve a maximum correlation. For compartments not showing a decrease in tracer concentration with time, it was assumed that tracer remained constant at the level attained at the end of the imaging session.

Residence-Time

Calculations

Residence times for each organ or tissue were obtained by analytical integration of the time-activity curves. Each least-squares fit was integrated from 0 to ~0 after first multiplying by the physical decay of “F. Although the fit excluded physical decay of the radionuclide so that biological trends would be more clearly evident, physical decay must be included in determining residence time. Residence times for 14 source organs were derived from the time-activity data of the nine image regions. The value for blood was extrapolated from the residence time of the heart, using standard heart and total body blood volumes (29, 30). Hematopoietic organs (spleen, red marrow), though they showed no obvious tracer accumulation, were assigned a residence time based on their blood volume. This was also done for other selected blood-rich organs (brain, stomach) whose tracer concentration was not measured directly. The residence time assigned to the remainder-of-

314

S. M. Moerlein

body consisted of blood activity not specifically assigned to an organ (heart, brain, kidneys, liver, lungs, spleen, marrow, stomach) and any “missing” activity not accounted for elsewhere.

TABLE Following

2. Approximate Biodistribution IV Injection of [“F]NMB

of

% Injected

Organ-Absorbed

Organ The mean dose-to-target organs per unit administered calculated with use of the equation

activity

2 0.06 h)b

Scan time 2 (3.14 + 0.19 h)b

was

D/A, =c (7,5) where D is the mean absorbed dose to the target organ, A, is the administered activity, 7, is the residence time for the source organ i, and S, is the cumulated mean absorbed dose in the target per unit cumulated activity in the source i (17). The total absorbed dose for each target organ was calculated by summing the absorbed dose per unit of injected activity for all organs and tissues containing activity. The S values were taken from the updated MIRDOSE 3 software package (34). Organ dose estimates are conservative in that they include irradiation from activity in the blood volume of each organ. This approach is similar to the way in which the contents of excretory organs (gallbladder, intestines, kidneys) are included in the calculation of the absorbed dose to these organs. The only brain region demonstrating selective accumulation of radioactivity is the D2 receptor-rich striatum (23). In this work, we have assigned uptake in the striatum to the whole brain and assumed uniform distribution. This approach will underestimate the dose to the striatum, which is nevertheless low. The dose to the lens of the eye was conservatively set equal to the total eye dose, and was calculated using the following guidelines. It was assumed that each eye is a uniform sphere of 15 g, and that the lens contains no water so its dose is due to photons originating from other tissues. The dose to the eyes consists of three components. The first of these is self-irradiation by activity measured in the eyes, which has a residence r = 0.005 h and specific absorbed fractions of 0.028 for annihilation radiation and 1.0 for beta irradiation. The second contribution to the eye dose is from penetrating radiation from activity assumed to be uniformly distributed in the brain, which has a r = 0.01 h and a brain-to-eye S factor determined using a specific absorbed fraction of 2.5 X 1O-5 (9). The third and most substantial contribution to the eye dose is irradiation by activity in the trunk, which was estimated as one-half the calculated dose to the thyroid (which is not itself a source organ).

RESULTS

Radioactivity

(0.58

Radioactivity

dose per organ”

Scan time 1

Dose Calculations

et al.

Distribution

Table 2 gives the distribution of radioactivity in selected organs at approximately 30 min and 3 h after IV injection of [‘sF]NMB. Our validation studies of [‘“FINMB as a receptor-binding PET tracer indicate that the D2 receptor-specific localization of the radioligand is high within this time interval (23). Data are reported in terms of percent injected dose per organ; the standard error is also given. The error in the time points derives from the different intervals used to scan the respective organs (see Fig. 1). Note that at the earlier time point, radioactivity accumulates substantially within the liver. After 3 h, liver accumulation has decreased slightly, whereas activity in the bowel has increased, apparently due to excretion of radiometabolites via the gallbladder. This behavior of [‘sF]NMB in viva is anticipated from the predominant hepatic pathway for metabolism of the neuroleptic (32).

Brain Heart Lungs Liver Gallbladder Lower large intestines Kidneys Bladder Eyes

0.43 1.07 2.27 17.8 0.87 2.13 1.07 0.0 0.17

t ? ? ? + + ” ? ?

0.05 0.30 0.83 4.2 0.32 0.85 0.68 0.0 0.05

0.40 0.23 0.40 12.1 1.97

-t + 2 -c It

11.5 -c

1.73 -+ 0.13 ? 0.17 ?

0.05 0.07 0.25 7.5 0.20 7.3 1.33 0.11 0.05

‘Includes radioactivity in blood compartment. Results are the mean i- standard error for three experiments. The two columns of data refer t0 tw0 separate scanning intervals. h Mean

2 standard

error for the measurement

times for three experiments.

Accumulation of activity within the kidneys and bladder is insignificant, and clearance from the lungs and liver reflects clearance of the radioligand from the blood compartment. Uptake and retention of [“F]NMB within the brain is relatively constant at approximately 0.4%.

Residence

Times

Representative time-activity curves from a PET study are shown in Fig. 2. Curves are illustrated for the striatum, blood, liver, gallbladder, and kidneys. The total blood-activity curve was extrapolated from the known heart-blood volume and the activity measured in the heart ROI. The time course of radioactivity in the remainder of the body is also shown. This curve consisted of activity in blood not specifically assigned to an organ (72% of the total blood) plus any “missing” activity. “Missing” activity is thought to represent nonselective distribution of activity throughout the body. It grew from 0 to 40% at 1 h, and extrapolated to roughly 80% at 5 h. For each set of curves, the scatter plots were fitted with mono- or bi-exponential functions to yield the best possible correlation coefficient (R). For simplicity, the fits were performed on decaycorrected data. These curves were constrained so that they passed through an appropriate value of %ID at t = 0. The best fit for the nonlinear regression was then adjusted to include physical decay; these curves (lacking data points) are also shown within each set of axes. The residence time T was obtained by analytical integration of the least-squares fit of the time-activity curves from 0 to 33 after including physical decay of the radioisotope. The resulting value for r is shown in Fig. 2 for the respective compartments. Table 3 gives the mean value of the residence times for all three experiments, together with the standard error.

Absorbed

Dose

Results of the MIRDOSE 3 dose calculations for the three PET studies of [“F]NMB are given in Table 4. The data are presented as the mean -C standard error for the three experiments, and is tabulated in units of mrad/mCi as well as mGy/kBq. The organs of the hepatic excretory pathway (liver, gallbladder, intestines) receive the highest doses. The critical organ is the lower large

Radiation

(a)

Dosimetry

I

I

,

315

of [‘8F](N-methyl)Benperidol

(b) 101,

1

1

Striatum

HO

0 H-

x 6 Ml et; .= 40 5 8

hr

K = 0.013

20

0 0

4

2

Time

(cl

6

after injection

8

10

0

I

I

IO

thrsJ

I

I

Gallbladder

Liver

35

s

6

4

Time after injection

I

40

2

(hrs)

.30 w 8 25 0 -0 01 20 F ‘S

15

Y-----l r=0-0’8hr

8 10

K = 0.314

hr

5

I

0 0

4

2

Time

te)

10

I

6

after injection

I

8

10

0

2

4

(hrs)

I

6

Time after injection

s

10

(hrs)

I

Kidneys

4 Time

after

6 injection

x (hrs)

Ill

?

I’ll

1’5

Time after injection

FIG. 2. Time-activity curves for [ “F]NMB as determined by PET imaging of six compartments. liver; (d) gallbladder; (e) kidneys; (f) remainder of body. The decay-corrected data (which include each compartment are fitted with mono- or bi-exponential functions using leastasquares analysis. curves multiplied by the physical decay factor. Functional forms are integrated to determine compartment.

(hrs)

(a) striatum; (b) blood; (c) the blood contribution) for Also shown are the best-fit residence times for each

316

TABLE Organs Organ

S. M. Moerlein

3. Residence

Times

of

[“F]NMB

in

or tissue

Selected

7 W

Brain Gallbladder Lower large intestines Stomach Heart Kidneys Liver Lungs Red marrow Spleen Blood Remainder of body Eyes Bladder

0.010 0.036 0.243 0.003 0.020 0.033 0.407 0.032 0.017 0.003 0.241 1.817 0.004 0.001

+ ? ? ? ? t ? ? k ? It ? ? ?

0.001 0.008 0.159 0.001 0.002 0.027 0.160 0.012 0.003 0.001 0.059 0.078 0.001 0.001

intestine, which receives a radiation burden of 585 mrad/mCi mGy/kBq). Tissues and organs other than the liver, gallbladder, intestines receive a relatively moderate radiation dose, ranging 30-77 mrad/mCi (9-21 mGy/kBq). Because of the modest tioning of the compound into the brain, this organ receives absorbed dose of only 13 mrad/mCi (3 mGy/kBq).

(158 and from partia low

,’ Data are the mean + standard ermr for three experiments.

DISCUSSION An important radiochemical TABLE [ “F]NMB Organ

aspect in the transition of a positron-emitting into a clinically useful PET radiopharmaceutical

4. Human Absorbed Based on Whole-Body or tissue

Large intestinal Gallbladder Liver Kidneys Ovaries Spleen Large intestinal Small intestinal Pancreas Uterus Red marrow Lungs Heart wall Whole body Adrenals Urinary bladder Bone surfaces Muscle Thymus Stomach Testes Thyroid Breasts Skin Brain Lens of eye

Dose Imaging

Estimates of Primates

mrad/mCi” wall (lower)

wall (upper) wall

wall

585 ? 355 281 ? 50 210 k 74 77 ? 20 77 2 19 66-c 10 66 -c 9 66 -c 9 61 53 58 -+ 8 52 ? 3 52 ? 9 53 ? 3 48 ? 1 48 ? 5 46 t 7 43 z 2 43 -+ 2 41 ? 2 40 ? 1 40 + 3 38 2 2 34 ? 2 32 2 1 13 -+ 1 19 * 1

” LIara are the mean t standard error for three experitnents.

is

from

mGy/kBq” 158 -+ 76 ? 57 ? 21 IT 21 5 18 2 18 k 18 + 165 16 ? 14 ? 14 ? 14 -f 13 ? 13 ? 12 2 12 2 12? 11 -+ 11 -t 11 + 10 ? 9?1 9*1 3Zl 5-tl

96 13 20 5 5 3 2 2 1 2 1 2 1 1 1 2 1 1 1 1 1 1

et al.

the accurate assessment of the absorbed radiation dosimetry associated with its use. Calculation of the absorbed radiation dose of radiopharmaceuticals requires the determination of the time course of radioactivity in the various organs of the body. This is sometimes performed with use of ex vioo experiments in small animals, in which the organ concentration of radioactivity is assayed following tissue dissection (15, 35). This invasive approach, though quantitative, is unsuitable for application with large animals, and interspecies metabolic variation potentially leads to large errors when results are extrapolated to humans. Alternative noninvasive in viva techniques using gamma scintigraphy have been developed for dosimetry assessment (3, 3 1 ), and such methodology has been used for dosimetry estimation of several SPECT brain agents (2, 8, 24, 25, 28, 37). However, difficulty in the quantification of tissue radioactivity concentrations is an inherent limitation with planar imaging methods, and gamma scintillation cameras are suboptimal for detection of positrons. These limitations are avoided by whole-body PET imaging of the in viva biodistribution of radioactivity following administration of positron-emitting radiopharmaceuticals. PET measures tissue radioactivity concentrations in a quantitative manner (lo), so that dosimetry determinations are more precise. The noninvasive nature of PET permits measurements on human subjects or large animals whose physiology differs little from humans. PET has been applied to dosimetry estimation for various radiopharmaceuticals (5, 12, 13, 14, 16, 20). In the present work we have extended this whole-body PET imaging methodology to dosimetry estimation for [“FINMB. In reviewing the results of these studies, it is observed that the number of organs and compartments listed in each table differ. This apparent discrepancy derives from the specific parameters that are tabulated. Table 2 gives the accumulation of radioactivity in the nine primary organs for tracer localization, as determined from inspection of PET images. Table 3 gives the residence times of the tracer in 14 organs; the nine primary organs listed in Table 2 plus estimates for an additional five organs/compartments (blood, stomach, spleen, red marrow, and remainder of body). Residence times for the stomach, spleen, and red marrow were estimated by multiplying the blood concentration times the appropriate organ/ compartmental blood volumes (29, 30). The residence time for the remainder of the body was determined by subtracting the cumulated activity specifically assigned to organs/compartments from the cumulated activity in the total body. Table 4 lists the absorbed dose estimates for 26 organs and tissues. The number of entries here exceeds that of Tables 2 and 3 because the latter tables list only the predominant organs of radioactivity accumulation, i.e., the source organs. In contrast, Table 4 compiles estimates for all tissues receiving absorbed radiation dose. These individual dose estimates include not only the component attributable to organ self-irradiation, but also that fraction attributable to external irradiation from source organs in close proximity. The relative contribution of source organs to the absorbed dose for a given tissue is determined by the respective S, values. The number of organs tabulated in Table 4 is clearly larger than that of Tables 2 and 3, for an organ does not have to contain appreciable radioactivity itself to endure a radiation burden arising from radiation localized in nearby tissues. The tissue biodistribution of [‘sF]NMB is characterized by relatively rapid blood clearance of the tracer and predominantly hepatic metabolism with excretion via the gallbladder into the intestinal tract. This metabolic pathway is common to D2 antagonists of the butyrophenone type (32), and the organ distribution of radioactivity (Table 2) and the associated residence times for the various

Radiation

Dosimetry

317

of [‘8F](N-methyl)Benperidol

organs (Table 3) reflect the in viwo degradation of [“F]NMB to radiometabolites by the liver, followed by concentration in the gallbladder, which empties into the intestinal tract. The rapid clearance and hepatic metabolism of the radioligand induce the greatest radiation burden in the intestines, gallbladder, and liver, with relatively modest absorbed radiation dose to remaining organs and tissues. As shown in Table 4, the critical organs for [‘“FINMB dosimetry are the lower large intestines, gallbladder, and liver. The associated doses are 585 mrad/mCi (158 mGy/kBq), 281 mrad/mCi (76 mGy/kBq), and 210 mrad/mCi (57 mGy/kBq), respectively. The organ doses were conservatively estimated in our calculations. For radioactivity concentrations, the foci of highest radioactivity concentration in an organ were used as representative of the entire organ mass; the actual concentration (and associated radiation burden) is likely to be substantially lower. Nevertheless, for a maximum absorbed dose of 5 rad to the critical organ (as required by the U.S. Food and Drug Administration for institutional Radioactive Drug Research Committee approval), our estimates indicate that 5000 mrad/(585 mrad/mCi) = 8.5 mCi of [18F]NMB can be administered to human subjects. The high dose to the lower large intestines relative to other compartments of the hepatic excretion pathway is likely due to the fecal concentration of radioactivity in this region. The lower absorbed dose to the small intestines and upper large intestines can be attributed to the more diffuse distribution (and lower concentration) of radiometabolites within the luminal contents, as well as a decreased residence time of radioactivity in these compartments due to transit of bowel contents to the lower large intestines. Note that the absorbed doses to the liver, gallbladder, and lower large intestine have relatively large standard errors. These results reflect variable emptying times of the gall bladder. A similar effect has been noted in PET studies of the chemically related PET tracer 3-N-( [‘HF]fluoroethyl)spiperone ([‘*F]FESP) (16). The initial baboon studies show substantial gallbladder accumulation. We have found similar accumulation with another lipophilic compound ([18F]FDHT) in fasted, anesthetized baboons (6). Furthermore, when the same compound was administered to an awake human subject, the hepatobiliary kinetics were considerably faster, suggesting that either the fasted state of the animal and/or the anesthesia hindered the normal clearance from the gallbladder. This experience would lead us to conclude that [“F]NMB, which is a highly lipophilic tracer, will clear through the liver of humans more rapidly than in these baboon studies. The absorbed dose to the human gallbladder wall may be roughly a factor of two less than what we have measured here. It is appropriate that the results from this work be compared to the absorbed dosimetry of [ lRF]FESP, which has also been measured via whole-body PET scanning (16). Both [18F]NMB and [18F]FESP are D2 receptor-binding radioligands of the butyrophenone type, and they share the same basic molecular skeleton for this class of D2 antagonists. Butyrophenones are metabolized via hepatic pathways (32), and the critical organs for both [‘“FIFESP and [‘“F]NMB are included in this pathway. The critical organ for [“F]FESP is the gallbladder (767 mrad/mCi; 207 mGy/kBq) (16), whereas that of [‘#F]NMB is the lower large intestine, with the secondary critical organ being the gallbladder. The two PET radioligands differ in the location of the radiolabel, however. Whereas [‘“FINMB is labeled at an aromatic site within the pharmacophore of butyrophenone ligands, [18F]FESP is labeled via N-[‘“Flfluoroalkylation. The radiolabeled functionality of [‘“FIFESP undergoes metabolic N-defluoroalkylation to generate

hydrophilic species and fluoride (39). Thus, [lRF]FESP shows kidney uptake of radioactivity and excretion into the urinary bladder, as well as bone localization. Such in viva accumulation of radioactivity is insignificant with [18F]NMB. CONCLUSIONS We have determined the absorbed radiation dosimetry associated with IV injection of [18F]NMB by whole-body PET imaging of primates and MIRDOSE 3 calculation methods. The critical organs were the lower large intestines (585 mrad/mCi; 158 mGy/kBq), gallbladder (281 mrad/mCi; 76 mGy/kBq), and liver (210 mrad/ mCi; 57 mGy/kBq). Other organs were associated with absorbed doses in the range of 32-77 mrad/mCi (9 -2 1 mGy/kBq). The results show the utility of whole-body PET imaging in preclinical evaluation of radiopharmaceutical dosimetry, and they suggest that up to 8.5 mCi of [18F]NMB can be safely administered to human subjects for PET study of D2 receptor binding. The authors thank Dr. J. Eichling and Dr. F. Dehdashti for helpful discussions. We also thank L. Lich and J. Carl for expert technical assistance with the animal studies, J. Hood and J. Giovanni for data processing, and D. Ficke and W. Murgewu for radioisotope production. This work was supported by NIH FIRST Award lR29N526788 (S.M.M.), NIH Grants R01NS31001, ROlNS32318, and 2POlHL 1385132, as well as rhe generous support of the Dana Clinical Hypothesis Resenrch Program of the Charles A. Dana Foundation, rhe McDonnell Center for the Study of Higher Brain Function, the Greater St. Louis Chapter of the American Parkinson’s Disease Association, and the Barbara B Sam Murphy Fund. References 1. Bergstrom M., Eriksson L., Bohm C., Blomqvist G. and Litton J. (1983) Correctmn for scattered radlation in a ring detector positron camera by integral transformanon of the projections. J. Comput. Assist. Tomogr. 7, 42-50. 2. Boundy K. L., Barnden L. R., Rowe C. C., Reid M., Kassiou M., Katsifis A. G. and Lambrecht R. M. (1995) Human dosimetry and biodistribution of iodine-123-iododexetimide: A SPECT imaging agent for cholinergic muscarinic neuroreceptors. 1. Nucl. Med. 36, 1332-1338. 3. Budinger T. F. (1974) Quantitative nuclear medicine imaging application of computers to the gamma camera and whole-body scanner. In: Progress in Atomic Medicine: Vol. 4. Recent Advances m Nuclear Medicine (Edited by Lawrence J. H.), pp. 41-130. Academic Press, New York. K., Stocklin G., Laufer P., Hebold I., Pawlik 4. Coenen H. H., Wienhard G. and Heiss W-D. (1988) PET Measurement of D, and S, receptor binding of 3-N-([2’-‘“F]fluoroethyl)spiperone in haboon brain. Eur. J. Nucl. Med. 14, 80-87. 5. Cutler P. D., Schwartz S. W., Anderson C. J., Connett J. M., Welch M. J., Philpott G. W. and Siegel B. A. (1995) Dosimetry of copper-64labeled monoclonal antibody lA3 as determined hy PET imaging of the torso. .J. Nucl. Med. 36, 2363-2371. 6. Cutler P. D., Dehdashtl F., Siegel B. A., Downer J. B. and Welch M. J. (1996) Investigatmn of a prostate ligand 16P-[‘sF]fluoro-5ti-dihydrotestosterone for stagmg of prostate carcinoma. J. Nucl. Med. 37, 87P. 7. Dewey S. L., Smith G. S., Logan J., Brodie J. D., Fowler J. S. and Wolf A. P. (1993) Striatal binding of the PET radioligand “C-raclopride is altered by drugs that modify synaptic dopamine level. Synapse 13, 350-356. 8. Dey H. M., Seihyl J. P., Stubbs J. B., Zoghbi S. S., Baldwin R. M., Smith E. O., Zuhal I. G., Zea-Ponce Y., Olson C., Chamey D. S., Hoffer P. B. and Innis R. B. (1994) Human biodistrihution and dosimetry of the SPECT benzodiazepme receptor radioligand iodine-123-iomazenil. J. Nucl. Med. 35, 399-404. 9. Eckerman K. F., Christy M., Warner G. G., Watson E. E. and Schlafke-Stelson A. T. (1981) Dosimetric evaluation of brain scanning agents. Proceedings of the Third International Radiopharmaceutical Dosimetry Symposium (Edited by Coffey, J. L. and Cloutier, R. J.), pp. 527-540. Proceedings of a conference held at Oak Ridge, TN, Ott 7-10, 1980. HHS Publication FDA 81-8166.

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