Biodistribution and dosimetry of the carbon-11 labelled PARP1-selective PET radiopharmaceutical [11C]AZ14193391.

Poly (ADP-ribose) polymerase-1 (PARP1) inhibitors are used for treatment of advanced breast, ovarian, and prostate cancer with germline or somatic BRCA1/2 mutations. However, not all patients respond to these drugs, and therapy-predictive biomarkers are needed to optimise the benefit-risk balance. The 11C-labelled PARP1-selective radiopharmaceutical [11C]AZ14193391 has emerged as a promising radioligand to identify eligible patients. The aim of this study was to investigate the safety and to determine the biodistribution and dosimetry of [11C]AZ14193391. A secondary aim was to investigate the parametric bootstrap method to determine time-integrated activity coefficients (TIACs), absorbed doses, and effective dose. Ten participants (5 breast, 3 ovarian, 2 prostate cancer) were injected with 5.7 MBq/kg [11C]AZ14193391. Participants underwent five positron emission tomography (PET) acquisitions, ranging from the base of the skull to the proximal femur, at approximately 0, 10, 20, 30, and 45 min post-injection. Participants were monitored for changes in vital signs and were contacted 24 h after injection. No adverse events occurred. Visual evaluation of PET images showed high activity concentrations in the gastrointestinal tract, liver, kidneys, red marrow, pancreas, salivary glands, and spleen. Organs were segmented on a low-dose computed tomography image with an automatic segmentation tool (TotalSegmentator extension in 3D Slicer). The segmentations were reviewed and corrected based on the PET images. Time-activity curve (TAC) fits were determined with two TAC fit methods: 1) individual and 2) parametric bootstrap, to calculate TIACs. Absorbed doses and effective dose were determined with IDAC-Dose 2.1 from eleven source organs. Mean effective dose was estimated to be 5.0 (SD = 0.3) µSv/MBq with individual TAC fits and 5.0 (SE = 0.1) µSv/MBq with parametric bootstrap TAC fits. The organs receiving the highest mean absorbed doses per injected activity were liver, kidneys, and spleen. Gallbladder, red marrow, salivary glands, and spleen showed continued accumulation during the PET acquisitions. Imaging with [11C]AZ14193391 is feasible and safe. Our results suggest that the radiation-induced risk is low, warranting further studies to evaluate the potential benefits of this diagnostic approach. The parametric bootstrap method estimated the population variability in the effective dose, but not in the TIACs. Ongoing recruitment Human Pharmacology (phase I) trial in Sweden including cancer patients in the age range (18-64) years. Karolinska University Hospital. https://euclinicaltrials.eu/ctis-public/view/2022-502918-87-00 : Registry identifier: EU CT 2022-502918-87-00; Date of registration: 2023-08-17.