[^67/68Ga]Sarabesin 3: Preclinical evaluation in GRPR-expressing models - First successful clinical PET/CT imaging of prostate cancer metastases

Objectives We have previously reported on [^99mTc]Demobesin 1, a GRPR (gastrin releasing peptide receptor)-antagonist displaying high and specific uptake in human PC-3 xenografts in mice. By replacing the N₄-chelator with DOTA, Sarabesin 3 has been obtained, suitable for labeling with a variety of medically appealing radiometals, such as the preeminent PET radionuclide ⁶⁸Ga.

Methods ^67/68Ga-radioligands were analyzed by HPLC. Blood collected 5 min post injection (pi) in mice was tested by HPLC. Biodistribution was studied in SCID mice bearing PC-3 xenografts at 1, 4 (with/without 40 nmol [Tyr⁴]BBN for GRPR-blockade) and 24 h pi. PET/CT images were acquired in a prostate cancer patient (≈300 MBq; 20 nmol).

Results [⁶⁷Ga]Sarabesin 3 showed high metabolic stability with ≈90% remaining intact in mice at 5 min pi. In SCID mice bearing PC-3 xenografts it showed very high and receptor-specific tumor uptake (40.0±6.9%ID/g at 4 h pi vs. 7.4±1.6%ID/g at 4 h pi - GRPR-blockade group). Background activity cleared rapidly via the kidneys even from the strongly GRPR-positive pancreas (16.8%ID/g at 24 h pi). In contrast, tumor values remained at exceptionally high levels at 24 h pi (27%ID/g) resulting in increasingly high tumor to non-tumor-ratios. In a first prostate cancer patient, [⁶⁸Ga]Sarabesin 3 rapidly localized in abdominal lymph node metastases, previously identified by ¹⁸F-choline, leading to high contrast visualization of metastatic lesions with PET/CT without causing adverse effects.

Conclusions [⁶⁸Ga]Sarabesin 3 displays high, specific and rapid localization in PC-3 xenografts in mice combined with a fast background clearance. This excellent profile translated well in a first prostate cancer patient, revealing the potential of antagonist-based radiotracers to image GRPR-positive cancer with PET/CT.