No abstract

The copper-mediated nucleophilic radiobromination of aryl boron precursors with a radiobromide ion is a novel radiolabeling method that is efficient and robust. High radiochemical conversion (RCC) was observed using a variety of solvents, temperatures and catalysts. The reaction is also clean and is feasible for purification to obtain high chemical and radiochemical purity. This method provides a very useful route for the preparation of radiobrominated pharmaceuticals, including a radiobromine labeled PARP-1 inhibitor, and it is a valuable addition to the family of copper-mediated radiolabeling processes.

Synopsis Hypoxia imaging has applications in functional recovery in ischemic events such as stroke and myocardial ischemia, but especially in tumors in which hypoxia can be predictive of treatment response and overall prognosis. Recently there has been development of imaging agents utilizing positron emission tomography for non-invasive imaging of hypoxia. Many of these PET agents have come to the forefront of hypoxia imaging. Halogenated PET nitroimidazole imaging agents labeled with 18F (t1/2 = 110 m) and 124I (t1/2 = 110 m) have been under investigation for the last 25 years, with radiometal agents (64Cu-ATSM) being developed more recently. This review focuses on these positron emission tomography imaging agents for hypoxia.

For PET radionuclides, the radioactivity of a sample can be conveniently measured by a dose calibrator. These devices depend on a "calibration setting number", but many recommended settings from manuals were interpolated based on standard sources of other radionuclide(s). We conducted HPGe gamma-ray spectroscopy, resulting in a reference for determining settings in two types of vessels containing one of several PET radionuclides. Our results reiterate the notion that in-house, experimental calibrations are recommended for different radionuclides and vessels.

Background: There remains an unmet need for molecularly targeted imaging agents in multiple myeloma (MM). The integrin, very late antigen-4 (VLA4), is differentially expressed in malignant MM cells as well as in the pathogenic inflammatory microenvironmental cells. [ 64 Cu]Cu-CB-TE1A1P-LLP2A ( 64 Cu-LLP2A) is a VLA4 targeted, high-affinity radiopharmaceutical with promising utility for managing patients diagnosed with MM. Here, we evaluated safety and human radiation dosimetry of 64 Cu-LLP2A for potential use in MM patients.Methods: Single dose [ nat Cu]Cu-LLP2A (Cu-LLP2A) tolerability and toxicity study was performed in CD-1 (Hsd:ICR) male and female mice. 64 Cu-LLP2A was synthesized in accordance with the good manufacturing practice compliant procedures. Three MM and six healthy participants underwent 64 Cu-LLP2A-PET/CT or PET/MR scans up to three time points to help determine tracer biodistribution, pharmacokinetics and radiation dosimetry. Time-activity curves were plotted for each participant. Mean organ absorbed doses and effective doses were calculated using the Organ Level INternal Dose Assessment (OLINDA) software. Tracer bioactivity was evaluated via cell binding assays and metabolites from human blood samples were analyzed with analytical radio-high performance liquid chromatography. When feasible, VLA4 expression was evaluated in the biopsy tissues using 14-color flow cytometry.Results: 150-fold mass excess of the desired imaging dose was tolerated well in male and female CD-1 mice (no observed adverse effect level (NOEL)). Time-activity curves from human imaging data showed rapid tracer clearance from blood via kidneys and bladder. The effective dose of 64 Cu-LLP2A in humans was 0.036 ± 0.006 mSv/MBq, and spleen had the highest organ uptake of 0.142 ± 0.034 mSv/MBq. Among all tissues, the red marrow demonstrated highest residence time. Image quality analysis supports early imaging time (4-5 h post injection of the radiotracer) as optimal. Cell studies showed statistically significant blocking for the tracer produced for all of the human studies (82.42 ± 13.47%). Blood metabolism studies confirmed a stable product peak (> 90%) up to 1 h post-injection of the radiopharmaceutical. No clinical or laboratory adverse events related to 64 Cu-LLP2A were observed in the human participants.Conclusions: 64 Cu-LLP2A exhibited a favorable dosimetry and safety profile for use in humans.