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Biodistribution and Dosimetry of ^99mTc-RP527, a Gastrin-Releasing Peptide (GRP) Agonist for the Visualization of GRP Receptor–Expressing Malignancies

Division of Nuclear Medicine, University Hospital Ghent, Ghent; Department of Radiopharmacy and Department of Biomedical Physics and Radiation Protection, University Ghent, Ghent, Belgium; and Resolution Pharmaceuticals Inc., Mississauga, Ontario, Canada

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION CONCLUSION REFERENCES

 
The aim of this study was to determine the human biodistribution and radiation dosimetry of ^99mTc-RP527, a promising radioligand for the visualization of gastrin-releasing peptide (GRP) receptor–expressing human malignancies. Methods: Whole-body scans were obtained up to 48 h after intravenous injection of 555 MBq ^99mTc-RP527 in each of 6 subjects. Blood samples were taken at various times up to 48 h after injection. Urine was collected up to 48 h after injection for calculation of renal clearance and whole-body clearance. Time–activity curves were generated for the thyroid, heart, breasts in women, testes in men, and liver by fitting the organ-specific geometric mean counts, obtained from regions of interest, on the respective images as a function of the time after injection. The MIRD formulation was applied to calculate the absorbed radiation dose for various organs. Results: The serial whole-body images showed rapid hepatobiliary excretion, resulting in low background and potentially high-contrast imaging of the thoracic region. Imaging of abdominal tumors may prove problematic, however, because of the extensive bowel activity. ^99mTc-RP527 was predominantly cleared by the kidneys and to a lesser extent by the gastrointestinal tract. The mean excretion in the urine (±SD) at 48 h after injection was 58.3 ± 5.4 percentage of the injected activity corrected for decay to the time of injection. The highest absorbed doses were received by the excretory organs (i.e., the urinary bladder and gallbladder wall). The average effective dose of ^99mTc-RP527 was estimated to be 0.0095 mSv/MBq. Conclusion: The biodistribution of ^99mTc-RP527 revealed low lung, myocardial, and liver uptake, which allowed early imaging of the supradiaphragmatic region with a favorable dosimetry (including effective dose) for administered activities required for SPECT imaging.

Key Words: ^99mTc-RP527 • biodistribution • dosimetry

	INTRODUCTION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION CONCLUSION REFERENCES

 
Gastrin-releasing peptide (GRP) belongs to the family of bombesin-like peptides (BLPs) that includes the amphibian peptide bombesin as well as the mammalian counterpart GRP and neuromedin B (1). Aside from their physiologic role (e.g., stimulation of secretion of gastrin and pancreatic enzymes and gallbladder contraction) (2,3), BLPs have been shown to play a role in various tumor models and human cancer (4–13).

In humans, both GRP and GRP antagonists mediate their action through the membrane-bound G-protein–coupled GRP receptor (GRP-R) (14). GRP receptors have been detected in various types of human carcinoma (15–17). The presence or absence of receptors on tumor cells, including GRP-R, as well as their level of expression have been correlated with cancer prognosis in several settings (18–22).

In analogy to the diagnosis of somatostatin receptor–expressing tumors in vivo with somatostatin receptor scintigraphy, in vivo GRP-R scintigraphy may be a potentially valuable tool to visualize and semiquantitate tumor GRP expression in a noninvasive way. This may allow prediction of therapy responsiveness to GRP antagonists and in vivo prognosis stratification. ^99mTc-RP527 is a targeting peptide derived from bombesin linked at its N-terminus through a linker group to a peptide sequence that chelates ^99mTc. ^99mTc-RP527 binds GRP-Rs with similar affinity to bombesin and is taken up by prostate, pancreas, and breast tumor tissue in animal models as well as in humans in vivo (23,24). This article reports on its biodistribution and dosimetry in humans.

	MATERIALS AND METHODS

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Radiopharmaceutical Synthesis
^99mTc-RP527 labeling was performed using a kit formulation; the reaction mixture contains 0.1 mL stannous chloride (2 mmol/L), 0.1 mL sodium gluconate (60 mmol/L), 1,850–2,035 MBq ^99mTcO₄ in 0.3 mL sodium chloride (0.9%), 0.5 mL sodium chloride (0.9%), and 100 µg RP527. After 35 min in a boiling water bath, the reaction mixture was allowed to cool to room temperature and injected on a high-performance liquid chromatography system using a gradient of ethanol, water, and acetic acid. The radiolabeled peptide was collected at 45 min, and the collected eluent was diluted with 10 mL sodium chloride (0.9%). The overall yield of the radiosynthesis was approximately 30% with a radiochemical purity of 90% and a specific activity of 4.32 TBq/Gmmol.

Subjects
This study was approved by the Medical Ethics Committee of the University Hospital Ghent and performed according to good clinical practice. Six individuals (3 men, 3 women; mean age, 46 y; age range, 24–73 y) were included in the study. All subjects gave their written informed consent for participation in the study. All volunteers were free from illness on the basis of screening by medical history, physical examination, serum chemical analyses, complete blood cell count, and urinalysis. Because of safety concerns, all chemical analyses were repeated during the experiment and the results were compared to their baseline (screening) values.

Imaging
Subjects were positioned supine with their arms alongside their body. Whole-body images were obtained using a triple-head gamma camera (Irix; Picker International, Cleveland Heights, OH) equipped with low-energy, high-resolution, parallel-hole collimators. The energy peak was centered at 140 keV with a 15% window. Whole-body planar images were acquired at approximately 30 min and 1, 3, 6, 24, and 48 h after injection. Acquisition was performed simultaneously in anterior and posterior positions with a scan speed of 11.4 cm/min. The matrix size was 256 x 1,024 pixels.

Urine Sampling
For all subjects, all voided urine from the time of injection until 48 h after injection was collected. The subjects were requested to collect urine before each emission scan and at home ad libitum. For each voiding, the urine was collected in a separate container, and the volume and time of voiding were recorded. For each void time, two 1-mL urine aliquots were sampled, and radioactivity was counted in a NaI(T1) counter (Cobra; Packard Instrument Co., Downers Grove, IL) after the counting efficiency of the system had been determined. The amount of radioactivity in the urine at each void time was expressed as percentage of the injected activity corrected for decay to the time of injection (%IA) of ^99mTc-RP527.

Blood Sampling
Blood samples were taken at 15 s, 30 s, 45 s, 1 min, 1 min 15 s, 1 min 30 s, 2 min, 5 min, 7 min 30 s, 10 min, 12 min, 15 min, 20 min, 30 min, 55 min, 2 h, 4 h, 6 h, 24 h, and 48 h after injection of the tracer. Duplicate 1-mL aliquots from each blood sample were assayed for ^99mTc radioactivity as described above. Total blood volume and, consequently, activity were calculated using a total blood volume based on body weight and height (25) and expressed as %IA.

Dosimetry
Image Analysis.
For quantification of radioactivity uptake after injection of ^99mTc-RP527, regions of interest (ROIs) over the total body and organs of interest were drawn manually on the earliest images, and the shapes and sizes (i.e., number of pixels) were kept constant over all subsequent images. Correction for background counts was performed using a region over the shoulder and subtracting the mean counts per pixel in the background ROI from the mean counts per pixel in each organ’s ROI to yield net counts in each organ. For each ROI (i.e., each organ), the geometric mean, corrected for physical decay, of total anterior and posterior counts was calculated. The total-body geometric mean activity calculated on the first image (1 h after injection) was taken as the total injected activity, considering that no urine was excreted before the first whole-body scan. The activity in the total body and different organs was expressed as %IA calculated by the following equation: (geometric mean net counts in organ or total body)/(geometric mean counts in first total body) x 100.

Dosimetric Calculations.
For each individual, time–activity curves were generated for the thyroid, heart, breasts in women, testes in men, liver, and whole body. Using in-house curve-fitting software, time–activity curves were generated for these organs by biexponential fits. Two routes of excretion were considered: urinary and fecal excretion. The fecal excretion was predicted using data from the source organs, the urinary excretion, and the material excreted by the liver. Of the material excreted by the liver, 30% was assumed to flow directly in the small intestine. Activity in the small intestine was assumed to follow the gastrointestinal kinetic model in International Commission on Radiobiological Protection Publication 30 (26). Activity in the intestines was assumed to pass through the various segments at standard rates, with mean transit times of 4 h for the small intestine, 13 h for the upper large intestine, and 24 h for the lower large intestine. The transfer rate coefficient from the gallbladder to the small intestine was taken to be 1.8 h^-1, derived by taking the mean of average emptying rates reported by others (27).

Source organ residence times were determined from analytic integration of the time–activity curves. Residence times were then used to determine target organ radiation doses based on the MIRD methodology (28) for the normal adult (29) using the MIRDOSE software package (30).

	RESULTS

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After injection of approximately 555 MBq ^99mTc-RP527 (maximum, 3 ng/kg per subject), no short-term adverse or subjective effects were noted in any of the subjects. Their vital signs remained stable throughout the experiment. Moreover, no meaningful changes were observed in any of the clinical laboratory assays performed on the blood and urine specimens obtained at 1, 6, 24, and 48 h after administration of the radioligand when compared with baseline findings. Figure 1 presents whole-body images of a male and female subject showing the biodistribution of radioactivity on injection of ^99mTc-RP527 at different time points after injection. The whole-body images obtained between 30 min and 24 h after injection show most of the activity distributed in the bladder, liver, gallbladder, and intestines, reflecting the known urinary and hepatobiliary excretion of peptides. Although the kidneys were not visualized in all subjects, there was activity in the urinary bladder in all subjects, indicating prompt excretion through the renal system. Uptake in the brain, myocardium, and lungs was low. There was a diffuse uptake and retention of radioactivity in the normal breast tissue in women as well as in the testes in men. Although images at 24 and 48 h after injection were of low quality (attributed to low counting statistics), these images showed most of the remaining activity distributed in the intestines. Figure 2 presents averaged ROI data, over all subjects (expressed as %IA), of the biodistribution of ^99mTc-RP527 in the total body and in various organs at the different points in time. Clearance of radioactivity from blood and organs fitted a biexponential curve. Assays of blood samples showed that the elimination of activity from the blood was initially fast: by 20 min after injection, <20% of the injected dose remained in the blood. The mean calculated half-life was 1.5 min (first exponent).

View larger version (33K): [in this window] [in a new window]   FIGURE 1. Anterior whole-body images obtained from man (A) and woman (B) at 30 min and 1, 3, 6, and 24 h after injection.

View larger version (20K): [in this window] [in a new window]   FIGURE 2. Time–activity curves for total body (wb), various organs, and blood, calculated from direct measurements of counts in organ-specific ROIs or in blood. Physical decay-corrected data (expressed as %IA) are averaged over 6 subjects, except for breasts (n = 3) and testes (n = 3). Error bars represent 1 SD. Units of abscissa and ordinate are time (h) and %IA, respectively. Respective biexponential functions obtained for various ROIs and whole body are whole body, y = 38.16e-0.00001xt + 65.90e-0.00569xt (r = 0.96528); heart, y = 0.18e-0.0005xt + 1.19e-0.0140xt (r = 0.99898); liver, y = 2.36e-0.0003xt + 10.17e-0.0154xt (r = 0.99893); scrotum, y = 0.19e-0.0002xt + 0.77e-0.0083xt (r = 0.99015); thyroid, y = 0.12e-0.0004xt + 0.41e-0.0156xt (r = 0.99881); breasts, y = 0.03e-0.0002xt + 0.28e-0.0069xt (r = 0.99705); and blood, y = 23.57e-0.1842xt + 18.44e-0.0163xt (r = 0.99963).

	DISCUSSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION CONCLUSION REFERENCES

In humans, ^99mTc-RP527 was cleared rapidly from circulation: by 20 min after injection, <20% of the injected dose remained in the blood. The mean calculated blood clearance half-life of 1.5 min for ^99mTc-RP527 is comparable with the 2.2 min for unlabeled bombesin reported in men (32). Low brain, lung, and myocardial uptake and rapid hepatobiliary excretion of ^99mTc-RP527 resulted in excellent imaging conditions for the supradiaphragmatic region, even at early time points (1 h) after injection. On the other hand, in addition to a predominant urinary clearance, ^99mTc-RP527 was also cleared enterohepatically, resulting in a high accumulation of radioactivity affecting interpretation of the abdominal region.

Of interest is the visualization of the breasts in women and the testes in men. Visualization of the breasts is in keeping with the known bombesin-like immunoreactivity shown in mammary glands of various species (33,34), indicating that bombesin or GRP may be involved in the regulation of mammary cell proliferation and differentiation. Data by Halmos et al. (35) showing a highly positive correlation (r = 0.671; P < 0.005) between the binding capacity of high-affinity (Tyr4)-bombesin binding sites and estrogen receptor levels and between the concentration of low-affinity (Tyr4)-bombesin binding sites and peptide receptor levels (r = 0.541; P < 0.005) in biopsies of human breast carcinoma suggest a possible interaction with other receptor systems.

In primates, a bombesin-like peptide resulting from alternate splicing of the GRP gene has been detected in testis. In vitro, GRP at a concentration of 100 nmol/L, added after ionophore treatment, enhanced significantly (P < 0.05) human sperm motility, capacitation, zona binding, and acrosome reaction, thus supporting a role for BLPs in the regulation of sperm cell proliferation and differentiation (36). In this regard, the visualization of the testes in all 3 male subjects after injection of ^99mTc-RP527 suggests the presence of a currently unidentified human testicular BLP receptor. Because NMB-R gene expression is prominent in mouse testis and the BRS-3 receptor has been shown to be expressed in rat testis, it is possible that different subtypes of bombesin receptors mediate the same response in different species (37).

The MIRDOSE software provides a calculation of the effective dose as defined in International Commission on Radiological Protection (ICRP) Publication 60 (38). On the basis of the mean effective dose of 9.5 x 10^-3 mSv/MBq obtained in this study, patients and volunteers could easily be investigated with 555 MBq ^99mTc-RP527, allowing both planar and SPECT imaging. The corresponding effective dose of 5.27 mSv is equal to the reported average effective dose per patient from nuclear medicine procedures in Europe (39) and only half of the 10-mSv upper-limit average effective dose of category IIa of the World Health Organization and category IIb of the ICRP (40). Because the highest dose is received by the bladder wall, frequent voiding will reduce the absorbed dose to the urinary bladder. Given the 1% probability for severe hereditary disorders in the offspring per Sv received by the testis, the associated risk related to injection of 555 MBq ^99mTc-RP527 is <1 per 10,000. This risk is low compared with the 1.6% prevalence of naturally occurring genetic disorders (38).

	CONCLUSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION CONCLUSION REFERENCES

 
The biodistribution of ^99mTc-RP527 showed low lung, myocardial, and liver uptake, which allowed early imaging of the supradiaphragmatic region with a dosimetry favorable for clinical SPECT imaging.

	ACKNOWLEDGMENTS

 
This work is supported by grant 0035.01 from the National Fund for scientific research.

	FOOTNOTES

 
Received Jan. 31, 2001; revision accepted Jul. 16, 2001.

For correspondence contact: Christophe Van de Wiele, MD, PhD, University Hospital Ghent, De Pintelaan 185, B-9000 Ghent, Belgium.

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