First positronium image of the human brain in vivo

Positronium, an unstable atom consisting of an electron and a positron, is abundantly produced within the molecular voids of a patient’s body during positron emission tomography (PET) diagnosis. Its properties, such as its average lifetime between formation and annihilation into photons, dynamically respond to the submolecular architecture of the tissue and the partial pressure of oxygen molecules. However, the diagnostic information that positronium may deliver about early molecular alterations remains unavailable in clinics with state-of-the-art PET scanners. This study presents the first in vivo images of positronium lifetime in humans. We developed a dedicated J-PET system with multiphoton detection capability for imaging. The measurements of positronium lifetime were performed on a patient with a glioblastoma tumor in the brain. The patient was injected intratumorally with the 68Ga radionuclide attached to Substance-P, which accumulates in glioma cells, and intravenously with 68Ga attached to the PSMA-11 ligand, which is selective to glioma cells and salivary glands. The 68Ga radionuclide is routinely used in PET for detecting radiopharmaceutical accumulation and was applied for positronium imaging because it can emit an additional prompt gamma. The prompt gamma enables the determination of the time of positronium formation, while the photons from positronium annihilation were used to reconstruct the place and time of its decay. The determined positronium mean lifetime in glioblastoma cells is shorter than in salivary glands, which in turn is shorter than in healthy brain tissues, demonstrating for the first time that positronium imaging can be used to diagnose disease in vivo . This study also demonstrates that if current total-body PET systems were equipped with multiphoton detection capability and the 44Sc radionuclide was applied, it would be possible to perform positronium imaging at 6500 times greater sensitivity than achieved in this research. Therefore, it is anticipated that positronium imaging has the potential to bring a new quality of cancer diagnosis in clinics. ### Competing Interest Statement P. M. and G. M. are inventors on a patent related to this work [patent nos.: (Poland) PL 227658, (Europe) EP 3039453, and (United States) US 9,851,456], filed (Poland) 30 August 2013, (Europe) 29 August 2014, and (United States) 29 August 2014; published (Poland) 23 January 2018, (Europe) 29 April 2020, and (United States) 26 December 2017. The authors declare that they have no other competing interests. ### Clinical Trial NCT06211803 ### Funding Statement the Foundation for Polish Science through the TEAM POIR.04.04.00-00-4204/17 program; the National Science Centre of Poland through grants MAESTRO no. 2021/42/A/ST2/00423 and OPUS no. 2021/43/B/ST2/02150; the Ministry of Education and Science through grant no. SPUB/SP/490528/2021; the SciMat and qLife Priority Research Areas budget under the program Excellence Initiative - Research University at the Jagiellonian University, and Jagiellonian University project no. CRP/0641.221.2020 ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethical Committee at the Medical University of Warsaw (opinion from February 21, 2022 No. KB/16/2022) gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors