Plasma Pharmacokinetics, Whole-Body Distribution, Metabolism, and Radiation Dosimetry of ⁶⁸Ga Bombesin Antagonist BAY 86-7548 in Healthy Men

Abstract

This first-in-human study investigated the safety, tolerability, metabolism, pharmacokinetics, biodistribution, and radiation dosimetry of 68 Ga-bombesin antagonist 68 Ga-DOTA-4-amino-1-carboxymethylpiperidine-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH 2 . Methods: Five healthy men underwent dynamic whole-body PET/CT after an intravenous injection of BAY 86-7548 (138 6 5 MBq). Besides total radioactivity, plasma samples were analyzed by radio-high-performance liquid chromatography for metabolism of the tracer. Dosimetry was calculated using the OLINDA/EXM software. Results: Three radioactive plasma metabolites were detected. The proportion of unchanged BAY 86-7548 decreased from 92% 6 9% at 1 min after injection to 19% 6 2% at 65 min. The organs with the highest absorbed doses were the urinary bladder wall (0.62 mSv/MBq) and the pancreas (0.51 mSv/MBq). The mean effective dose was 0.051 mSv/MBq. BAY 86-7548 was well tolerated by all subjects. Conclusion: Intravenously injected BAY 86-7548 is safe, and rapid metabolism is demonstrated. A 150-MBq injection of BAY 86-7548 results in an effective dose of 7.7 mSv, which could be reduced to 5.7 mSv with frequent bladder voids.Key Words: dosimetry; 68 Ga; PET; pharmacokinetics; radiometabolism; whole-body distribution J Nucl Med 2013; 54:867-872 DOI: 10.2967/jnumed.112.114082 Prost ate cancer (PCa) is the second most common cancer in men globally (1) and the most common cancer in developed countries (2). However, conventional imaging techniques such as ultrasound, contrast-enhanced CT, or MR imaging have limited sensitivity and specificity for detecting primary, metastatic, and recurrent PCa (3). PET/CT plays an important role in the attempt to improve and individualize therapeutic approaches in oncology. The most widely used tracer, 18 F-FDG, shows a high excretion in the urinary bladder and demonstrates generally an unsatisfactory uptake in PCa, especially in the early phase (4,5). Tracers that depict lipid metabolism such as 11 C-choline and 11 C-acetate have already been applied for imaging PCa, but they accumulate also in prostatic hyperplasia, with overlapping uptake in benign and malignant intraprostatic lesions (6-8). Consequently, there is an urgent need for more PCa-specific tracers.Gastrin-releasing peptide receptors (GRPr) are highly overexpressed in a variety of human tumors including PCa (9). Preclinical data suggest the possibility of a high PCa-specific signal with radiolabeled bombesin analogs targeting GRPr (10). These analogs could potentially provide better and more specific diagnosis than 18 F-FDG or tracers such as 11 C-choline or 11 C-acetate.68 Ga-DOTA-4-amino-1-carboxymethylpiperidine-D-PheGln-Trp-Ala-Val-Gly-His-Sta-Leu-NH 2 (BAY 86-7548; also known as RM2) is a bombesin antagonist with high GRPr affinity. The purpose of this first-in-human study was to investigate the safety, tolerability, metabolism, pharmacokinetics, biodistribution, and radiation dosimetry of BAY 86-7548 in healthy volunteers receiving an intravenous injection of this a...

N-Terminal Modifications Improve the Receptor Affinity and Pharmacokinetics of Radiolabeled Peptidic Gastrin-Releasing Peptide Receptor Antagonists: Examples of 68Ga- and 64Cu-Labeled Peptides for PET Imaging

“…We further continued with the antagonist DOTA-4-amino-1-carboxymethyl-piperidine-D-Phe-Gln-Trp-Ala-Val-Gly-HisSta-Leu-NH 2 (RM2), indicating that 111 In-RM2 and 68 Ga-RM2 are good candidates for clinical SPECT and PET studies (9). The firstin-human study showed that the intravenous injection of 68 Ga-RM2 is safe, but rapid metabolism is demonstrated (35). Nevertheless, clinical studies by us (G. Wieser, I. Popp, H.R.…”

Preclinical Comparison of Al18F- and 68Ga-Labeled Gastrin-Releasing Peptide Receptor Antagonists for PET Imaging of Prostate Cancer

“…Several GRPR antagonists have since been developed by the modification of C-terminal residues of GRPR agonists, including the statinbased BBN analog, JMV594 (H-D-Phe-Gln-Trp-Ala-Val-GlyHis-Sta-Leu-NH 2 ) (15). 68 Ga-labeled GRPR antagonists were developed for PET imaging, showing good targeting properties in preclinical studies (12,(16)(17)(18) and recently also in clinical trials (19,20). Clinical evaluation of the 68 Ga-labeled GRPR antagonist BAY86-7548 ( 68 Ga-DOTA-4-amino-1-carboxymethylpiperidine-D-Phe-Gln-TrpAla-Val-Gly-His-Sta-Leu-NH 2 ) has shown a specificity, sensitivity, and accuracy of 88%, 81%, and 83%, respectively, for the detection of primary PCa.…”

Bombesin-Targeted PET of Prostate Cancer

“…The addition of the positively charged spacer 4-amino-1-carboxymethyl-piperidine led to RM2 (DOTA-4-amino-1-carboxymethyl-piperidine-DPhe-Gln-Trp-AlaVal-Gly-His-Sta-Leu-NH 2 ) (15). 68 Ga-labeled RM2 was widely studied in different PC cell lines and tumor models and is currently in clinical studies (16,17).…”