Biodistribution and internal radiation dosimetry of a companion diagnostic radiopharmaceutical, [68Ga]PSMA-11, in subcutaneous prostate cancer xenograft model mice.

[68Ga]PSMA-11 is a prostate-specific membrane antigen (PSMA)-targeting radiopharmaceutical for diagnostic PET imaging. Its application can be extended to targeted radionuclide therapy (TRT). In this study, we characterize the biodistribution and pharmacokinetics of [68Ga]PSMA-11 in PSMA-positive and negative (22Rv1 and PC3, respectively) tumor-bearing mice and subsequently estimated its internal radiation dosimetry via voxel-level dosimetry using a dedicated Monte Carlo simulation to evaluate the absorbed dose in the tumor directly. Consequently, this approach overcomes the drawbacks of the conventional organ-level (or phantom-based) method. The kidneys and urinary bladder both showed substantial accumulation of [68Ga]PSMA-11 without exhibiting a washout phase during the study. For the tumor, a peak concentration of 4.5 ± 0.7 %ID/g occurred 90 min after [68Ga]PSMA-11 injection. The voxel- and organ-level methods both determined that the highest absorbed dose occurred in the kidneys (0.209 ± 0.005 Gy/MBq and 0.492 ± 0.059 Gy/MBq, respectively). Using voxel-level dosimetry, the absorbed dose in the tumor was estimated as 0.024 ± 0.003 Gy/MBq. The biodistribution and pharmacokinetics of [68Ga]PSMA-11 in various organs of subcutaneous prostate cancer xenograft model mice were consistent with reported data for prostate cancer patients. Therefore, our data supports the use of voxel-level dosimetry in TRT to deliver personalized dosimetry considering patient-specific heterogeneous tissue compositions and activity distributions.

In vivo preclinical assessment of novel 68Ga-labelled peptides for imaging of tumor associated angiogenesis using positron emission tomography imaging.

Formation and growth of metastases require a new vascular network. Angiogenesis plays an essential role in the expansion and progression of most malignancies. A high number of molecular pathways regulate angiogenesis, including vascular endothelial growth factor (VEGF), αvß3 integrin, matrix metalloproteinases (MMPs), or aminopeptidase N. The aim of this study is to involve new, easily accessible peptide sequences into the of neo-angiogenesis in malignant processes. Labelling of these peptide ligands with 68Ga enable PET imaging of neo-vascularization.

Prospective Within-Patient Assessment of the Impact of an Unlabeled Octreotide Pre-dose on the Biodistribution and Tumor Uptake of 68Ga DOTATOC as Assessed by Dynamic Whole-body PET in Patients with Neuroendocrine Tumors: Implications for Diagnosis and Therapy.

PURPOSE: Gastroenteropancreatic neuroendocrine tumors (GEP NETs) are often associated with high expression of somatostatin receptors (SSTRs) which allows for PET/CT imaging with radiolabeled somatostatin analogs such as 68Ga-DOTATOC. The interplay between 68Ga-DOTATOC and the synthetic somatostatin analogs commonly used to manage patient symptoms may lead to competition between the labelled and unlabeled peptides for receptor binding sites and current product labelling recommends patients be taken off somatostatin analogs before imaging. In this study, we prospectively investigated in human patients the effect of a pre-dose of octreotide, a short-acting somatostatin analog, on the distribution of 68Ga-DOTATOC in GEP NETs and normal organs. PROCEDURE: Research participants with GEP NETs were studied on two occasions using dynamic whole-body 68Ga-DOTATOC PET/CT. The two imaging studies were performed within 21 days of each other, using an identical acquisition protocol except for the administration of 50 µg of short-acting octreotide (pre-dose) immediately before the second PET/CT. Paired t-tests were used to compare tracer uptake with and without octreotide, for tumor and various normal organs. RESULTS: Seven participants with a mean age of 53 ± 10 years were studied. Octreotide pre-dosing decreased radiotracer uptake in the normal liver and spleen by 25 % (p = 0.04) and 47 % (p = 0.05) respectively but did not significantly change uptake in tumor (p = 0.53), red marrow (p = 0.12), kidneys (p =0.57), or pituitary gland (p = 0.27). CONCLUSIONS: Our data indicate SSTR imaging can be improved with a pre-dose of unlabeled octreotide given just prior to injection of the radiotracer. These data suggest there may be no need to discontinue somatostatin analog therapy prior to PET/CT with 68Ga-DOTATOC, allowing for a simpler, less disruptive patient protocol. This approach warrants further study in a variety of settings.

Assessment of Chemotherapy-Induced Organ Damage with Ga-68 Labeled Duramycin.

PURPOSE: Evaluation of [68Ga]NODAGA-duramycin as a positron emission tomography (PET) tracer of cell death for whole-body detection of chemotherapy-induced organ toxicity. PROCEDURES: Tracer specificity of Ga-68 labeled NODAGA-duramycin was determined in vitro using competitive binding experiments. Organ uptake was analyzed in untreated and doxorubicin, busulfan, and cisplatin-treated mice 2 h after intravenous injection of [68Ga]NODAGA-duramycin. In vivo data were validated by immunohistology and blood parameters. RESULTS: In vitro experiments confirmed specific binding of [68Ga]NODAGA-duramycin. Organ toxicities were detected successfully using [68Ga]NODAGA-duramycin PET/X-ray computed tomography (CT) and confirmed by immunohistochemistry and blood parameter analysis. Organ toxicities in livers and kidneys showed similar trends in PET/CT and immunohistology. Busulfan and cisplatin-related organ toxicities in heart, liver, and lungs were detected earlier by PET/CT than by blood parameters and immunohistology. CONCLUSION: [68Ga]NODAGA-duramycin PET/CT was successfully applied to non-invasively detect chemotherapy-induced organ toxicity with high sensitivity in mice. It, therefore, represents a promising alternative to standard toxicological analyses with a high translational potential.

Synthesis, molecular structure, and validation of metalloprobes for assessment of MDR1 P-glycoprotein-mediated functional transport.

UNLABELLED: The human genome is known to consist of 49 ATP-binding cassette (ABC) transporter genes. Among these ABC proteins, overexpression of multidrug resistance (MDR1) P-glycoprotein (Pgp/ABCB1) is the best characterized barrier to successful chemotherapeutic treatments, impacts pharmacokinetics of numerous recognized drugs, and is also quickly emerging as an important target in the development of neurodegenerative diseases. Therefore, there exists an urgent need to seek radiopharmaceuticals, incorporated with generator-produced radionuclides to assist their widespread deployment, for noninvasive assessment of Pgp-mediated functional transport activity in vivo. METHODS: gallium(III) complexes (5a and 5b) possessing octahedral geometry were synthesized, analytically characterized, and evaluated for their potential to serve as probes of Pgp-mediated functional transport activity in cellulo and in vivo. While unlabeled compounds (5a and 5b) were examined via cell cytotoxicity assays, the (67)Ga-labeled counterparts (6a and 6b) were evaluated via cell transport studies and quantitative biodistribution studies in mdr1a/1b((-/-)) gene-deleted mice and their wild-type (WT) counterparts. RESULTS: cytotoxicity data of 5a and 5b displayed profiles modified by the expression of Pgp in drug-resistant cells. (67)Ga-metalloprobes (6a and 6b) showed high accumulation in human epidermal carcinoma drug-sensitive KB-3-1 cells (Pgp-), human breast carcinoma MCF-7 (Pgp-) cells; an inhibitor (LY335979, 1 microM) induced accumulation in multidrug resistant (MDR, Pgp+) KB-8-5, KB-8-5-11 cells, and stably transfected MCF-7/MDR1 cells, thus demonstrating their ability to interrogate Pgp-mediated functional transport activity in cellulo. In mdr1a/1b((-/-)) gene-deleted mice, the (67)Ga-metalloprobe (6b) showed 8-fold greater brain uptake and retention compared with WT counterparts and no significant difference in blood pharmacokinetics. CONCLUSION: molecular imaging of the functional transport activity of MDR1 Pgp (ABCB1) with (67/68)Ga-metalloprobes could enable non-invasive monitoring of the blood-brain barrier, tumors, and tissues in vivo.

Usefulness of pulmonary vascular leakiness assessment in interstitial pneumonitis.

STUDY OBJECTIVE: Pulmonary vascular leakiness of (67)Ga-circulating transferrin in interstitial pneumonitis (IP) was estimated by our previously described method, and its ability to evaluate disease activity was compared with conventional (67)Ga scintigraphy. DESIGN: Using 30-min dynamic scanning data after IV injection of (67)Ga citrate, the exponential equilibration coefficient of (67)Ga between the intravascular and pulmonary interstitial compartments was calculated and defined as the leak index (LI). Pulmonary (67)Ga uptake was assessed by gallium index, determined by conventional static images taken 48 h after (67)Ga citrate injection. SETTING: Hospitalized patients. PARTICIPANTS: The study population consisted of 17 control patients and 20 patients with IP. RESULTS: The mean LI in patients with IP was significantly higher than in the control group (p < 0.0001), whereas no significant increase in gallium index was noted between the IP group and the control group. No significant correlation was found between gallium index and LI among all study participants. Mean LI in patients with active IP was significantly higher than in patients with stable IP (p = 0.0024). CONCLUSIONS: An increase in pulmonary vascular leakiness was found in patients with IP. LI may be useful to assess the disease activity.