Biodistribution, dosimetry, and temporal signal-to-noise ratio analyses of normal and cancer uptake of [68Ga]Ga-P15-041, a gallium-68 labeled bisphosphonate, from first-in-human studies.

INTRODUCTION: [68Ga]Ga-P15-041 ([68Ga]Ga-HBED-CC-BP) is a novel bone-seeking PET radiotracer that can be generator-produced. We undertook a Phase 0/I clinical trial to assess its potential for imaging bone metastases in prostate cancer including assessment of radiotracer biodistribution and dosimetry. METHODS: Subjects with prostate cancer and known or suspected osseous metastatic disease were enrolled into one of two arms: dosimetry or dynamic. Dosimetry was performed with 6 whole body PET acquisitions and urine collection spanning 3 h; normal organ dosimetry was calculated using OLINDA/EXM. Dynamic imaging included a 60 min acquisition over a site of known or suspected disease followed by two whole body scans. Bootstrapping and subsampling of the acquired list-mode data were conducted to recommend image acquisition parameters for future clinical trials. RESULTS: Up to 233 MBq (6.3 mCi) of [68Ga]Ga-P15-041 was injected into 12 enrolled volunteers, 8 in dosimetry and 4 in dynamic cohorts. Radiotracer accumulated in known bone lesions and cleared rapidly from blood and soft tissue. The highest individual organ dose was 0.135 mSv/MBq in the urinary bladder wall. The average effective dose was 0.0173 ± 0.0036 mSv/MBq. An average injected activity of 166.5 MBq (4.5 mCi) resulted in absorbed dose estimates of 22.5 mSv to the urinary bladder wall, 8.2 mSv to the kidneys, and an effective dose of 2.9 mSv. Lesion signal to noise ratios on images generated from subsampled data were significantly higher for injected activities above 74 MBq (2 mCi) and were also significantly higher for imaging at 90 min than at 180 min post-injection. CONCLUSIONS: Dosimetry estimates are acceptable and [68Ga]Ga-P15-041 uptake characteristics in patients with confirmed bone metastases support its continued development. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: Use of [68Ga]Ga-P15-041 would not require cyclotron infrastructure for manufacturing and distribution, allowing for improved patient access to a promising PET bone imaging agent.

New F-18 prosthetic group via oxime coupling.

A novel fluorine-18 prosthetic ligand, 5-(1,3-dioxolan-2-yl)-2-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)pyridine [(18)F]2, has been synthesized. The prosthetic ligand is formed in high radiochemical yield (rcy = 71 ± 2%, n = 3) with excellent radiochemical purity (rcp = 99 ± 1%, n = 3) in a short reaction time (10 min). [(18)F]2 is a small, neutral, organic complex, easily synthesized in four steps from a readily available starting material. It can be anchored onto a target molecule containing an aminooxy functional group under acidic conditions by way of an oxime bond. We report herein two examples [(18)F]23 and [(18)F]24, potential imaging agents for ß-amyloid plaques, which were labeled with this prosthetic group. This approach could be used for labeling proteins and peptides containing an aminooxy group. Biodistribution in male ICR mice for both oxime labeled complexes [(18)F]23 and [(18)F]24 were compared to that of the known ß-amyloid plaque indicator, [(18)F]-AV-45, florbetapir 1. Oximes [(18)F]23 and [(18)F]24 are larger in size and therefore should reduce the blood-brain barrier (BBB) penetration. The brain uptake for oxime [(18)F]23 appeared to be reduced, but still retained some capability to cross the BBB. Oxime [(18)F]24 showed promising results after 2 min post injection (0.48% dose/gram); however, the uptake increased after 30 min post injection (0.92% dose/gram) suggesting an in vivo decomposition/metabolism of compound [(18)F]24. We have demonstrated a general protocol for the fluoride-18 labeling with a new prosthetic ligand [(18)F]2 that is tolerant toward several functional groups and is formed via chemoselective oxime coupling.