First-in-Human Safety, Imaging, and Dosimetry of a Carbonic Anhydrase IX-Targeting Peptide, [Ga]Ga-DPI-4452, in Patients with Clear Cell Renal Cell Carcinoma.

[Ga]Ga-DPI-4452, a first-in-class carbonic anhydrase IX-binding radiolabeled peptide, is the imaging agent of a theranostic pair with [Lu]Lu-DPI-4452, developed for selecting and treating patients with carbonic anhydrase IX-expressing tumors. Here, [Ga]Ga-DPI-4452 imaging characteristics, dosimetry, pharmacokinetics, and safety were assessed in 3 patients with clear cell renal cell carcinoma. After [Ga]Ga-DPI-4452 administration, patients underwent serial full-body PET/CT imaging.

INCB050465 (Parsaclisib), a Novel Next-Generation Inhibitor of Phosphoinositide 3-Kinase Delta (PI3Kδ).

A medicinal chemistry effort focused on identifying a structurally diverse candidate for phosphoinositide 3-kinase delta (PI3Kδ) led to the discovery of clinical candidate INCB050465 (, parsaclisib). The unique structure of contains a pyrazolopyrimidine hinge-binder in place of a purine motif that is present in other PI3Kδ inhibitors, such as idelalisib (), duvelisib (), and INCB040093 (, dezapelisib). Parsaclisib () is a potent and highly selective inhibitor of PI3Kδ with drug-like ADME properties that exhibited an excellent in vivo profile as demonstrated through pharmacokinetic studies in rats, dogs, and monkeys and through pharmacodynamic and efficacy studies in a mouse Pfeiffer xenograft model.

(S)-4-(3-18F-fluoropropyl)-L-glutamic acid: an 18F-labeled tumor-specific probe for PET/CT imaging--dosimetry.

Unlabelled: The glutamic acid derivative (S)-4-(3-(18)F-Fluoropropyl)-l-glutamic acid ((18)F-FSPG, alias BAY 94-9392), a new PET tracer for the detection of malignant diseases, displayed promising results in non-small cell lung cancer patients. The aim of this study was to provide dosimetry estimates for (18)F-FSPG based on human whole-body PET/CT measurements.

Methods: (18)F-FSPG was prepared by a fully automated 2-step procedure and purified by a solid-phase extraction method.

Selective inhibition of IDO1 effectively regulates mediators of antitumor immunity.

Indoleamine 2,3-dioxygenase-1 (IDO1; IDO) mediates oxidative cleavage of tryptophan, an amino acid essential for cell proliferation and survival. IDO1 inhibition is proposed to have therapeutic potential in immunodeficiency-associated abnormalities, including cancer. Here, we describe INCB024360, a novel IDO1 inhibitor, and investigate its roles in regulating various immune cells and therapeutic potential as an anticancer agent.

Hydroxyamidine inhibitors of indoleamine-2,3-dioxygenase potently suppress systemic tryptophan catabolism and the growth of IDO-expressing tumors.

Malignant tumors arise, in part, because the immune system does not adequately recognize and destroy them. Expression of indoleamine-2,3-dioxygenase (IDO; IDO1), a rate-limiting enzyme in the catabolism of tryptophan into kynurenine, contributes to this immune evasion. Here we describe the effects of systemic IDO inhibition using orally active hydroxyamidine small molecule inhibitors.

INCB16562, a JAK1/2 selective inhibitor, is efficacious against multiple myeloma cells and reverses the protective effects of cytokine and stromal cell support.

Cytokines in the bone marrow of multiple myeloma patients activate Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathways in tumor cells and promote tumor growth, survival, and drug resistance. INCB16562 was developed as a novel, selective, and orally bioavailable small-molecule inhibitor of JAK1 and JAK2 markedly selective over JAK3. The specific cellular activity of the inhibitor was demonstrated by its potent and dose-dependent inhibition of cytokine-dependent JAK/STAT signaling and cell proliferation in the absence of effects on Bcr-Abl-expressing cells.

Combined inhibition of Janus kinase 1/2 for the treatment of JAK2V617F-driven neoplasms: selective effects on mutant cells and improvements in measures of disease severity.

Purpose: Deregulation of the Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway is a hallmark for the Philadelphia chromosome-negative myeloproliferative diseases polycythemia vera, essential thrombocythemia, and primary myelofibrosis. We tested the efficacy of a selective JAK1/2 inhibitor in cellular and in vivo models of JAK2-driven malignancy.

Experimental Design: A novel inhibitor of JAK1/2 was characterized using kinase assays.

Design considerations for incorporating sodium iodide symporter reporter gene imaging into prostate cancer gene therapy trials.

This study was done to aid in the design of a phase I gene therapy trial in patients with prostate cancer. We determined the dosimetric characteristics of our reporter gene system when coupled with intravenous administration of radioactive sodium pertechnetate (Na(99m) TcO(4)) and determined the feasibility of using human sodium iodide symporter (hNIS) as a reporter gene to study the dynamics of adenoviral transgene expression in a large animal tumor. A replication-competent Ad5-yCD/mutTK(SR39) rep-hNIS adenovirus was injected into the prostate gland of dogs for dosimetry purposes, and into a canine soft tissue sarcoma (STS) for imaging purposes.

Structural insights into the design of nonpeptidic isothiazolidinone-containing inhibitors of protein-tyrosine phosphatase 1B.

Structural analyses of the protein-tyrosine phosphatase 1B (PTP1B) active site and inhibitor complexes have aided in optimization of a peptide inhibitor containing the novel (S)-isothiazolidinone (IZD) phosphonate mimetic. Potency and permeability were simultaneously improved by replacing the polar peptidic backbone of the inhibitor with nonpeptidic moieties. The C-terminal primary amide was replaced with a benzimidazole ring, which hydrogen bonds to the carboxylate of Asp(48), and the N terminus of the peptide was replaced with an aryl sulfonamide, which hydrogen bonds to Asp(48) and the backbone NH of Arg(47) via a water molecule.

Potent benzimidazole sulfonamide protein tyrosine phosphatase 1B inhibitors containing the heterocyclic (S)-isothiazolidinone phosphotyrosine mimetic.

Potent nonpeptidic benzimidazole sulfonamide inhibitors of protein tyrosine phosphatase 1B (PTP1B) were derived from the optimization of a tripeptide containing the novel (S)-isothiazolidinone ((S)-IZD) phosphotyrosine (pTyr) mimetic. An X-ray cocrystal structure of inhibitor 46/PTP1B at 1.8 A resolution demonstrated that the benzimidazole sulfonamides form a bidentate H bond to Asp48 as designed, although the aryl group of the sulfonamide unexpectedly interacts intramolecularly in a pi-stacking manner with the benzimidazole.

OLINDA/EXM: the second-generation personal computer software for internal dose assessment in nuclear medicine.

Unlabelled: The OLINDA/EXM version 1.0 personal computer code was created as a replacement for the widely used MIRDOSE3.1 code.

Microwave-assisted synthesis of 2,4,5-triaryl-imidazole; a novel thermally induced N-hydroxyimidazole N-O bond cleavage.

[reaction: see text] 2,4,5-Triaryl-imidazoles were synthesized directly from the keto-oxime in moderate to good yields via cyclization to the N-hydroxyimidazole and an unprecedented in situ thermal reduction of the N-O bond upon microwave irradiation at 200 degrees C for 20 min.

Radiation dosimetry results from a Phase II trial of ibritumomab tiuxetan (Zevalin) radioimmunotherapy for patients with non-Hodgkin's lymphoma and mild thrombocytopenia.

This was a 30-patient Phase II trial of reduced-dose (90)Y ibritumomab tiuxetan (Zevalin) RIT for patients with low-grade, follicular, or transformed B-cell NHL and mild thrombocytopenia. Patients were given an imaging dose of (111)In-labeled ibritumomab tiuxetan for dosimetry measurements. One week later, patients were administered a therapeutic dose of 0.

Radiation dosimetry results and safety correlations from 90Y-ibritumomab tiuxetan radioimmunotherapy for relapsed or refractory non-Hodgkin's lymphoma: combined data from 4 clinical trials.

Unlabelled: Ibritumomab tiuxetan is an anti-CD20 murine IgG1 kappa monoclonal antibody (ibritumomab) conjugated to the linker-chelator tiuxetan, which securely chelates (111)In for imaging or dosimetry and (90)Y for radioimmunotherapy (RIT). Dosimetry and pharmacokinetic data from 4 clinical trials of (90)Y-ibritumomab tiuxetan RIT for relapsed or refractory B-cell non-Hodgkin's lymphoma (NHL) were combined and assessed for correlations with toxicity data.

Methods: Data from 179 patients were available for analysis.

Red marrow radiation dose adjustment using plasma FLT3-L cytokine levels: improved correlations between hematologic toxicity and bone marrow dose for radioimmunotherapy patients.

Unlabelled: Calculated red marrow absorbed dose in patients receiving radioimmunotherapy (RAIT) has not been highly predictive of the dose-limiting hematologic toxicity observed in many patient populations studied. Because patients receiving the same red marrow dose often experience different grades of toxicity, other factors might help predict the different grades of toxicity observed. One such factor may be the plasma FLT3-L (FMS-related tyrosine kinase 3 ligand, hematopoiesis stimulatory cytokine) level, which has been shown to be a better indicator of recovery of progenitor cells and, thus, red marrow radiosensitivity (because during the recovery period the progenitor cells are hyperproliferative and potentially more radiosensitive) for patients treated with previous chemotherapy than peripheral blood counts.

Sensitivity of model-based calculations of red marrow dosimetry to changes in patient-specific parameters.

We have investigated several of the key model parameters and assumptions involved in the calculation of red marrow absorbed dose in order to better understand the sensitivity of the predicted results to changes in these model features and the subsequent effect on correlations of the red marrow absorbed dose values with observed hematologic toxicity. Red marrow dose calculations based on measured blood activity concentrations (to determine red marrow cumulated activity) and measured total body cumulated activity have a mass-independent and mass-dependent term. Adjustments for patient mass should be made in these calculations when patients' lean body masses are more than 10% different from that in the assumed standard models.

Calculating the absorbed dose from radioactive patients: the line-source versus point-source model.

Unlabelled: In calculations of absorbed doses from radioactive patients, the activity distribution in such patients is generally assumed to be an unattenuated point source and the dose to exposed individuals at a given distance is therefore calculated using the inverse square law. In many nuclear medicine patients, the activity distribution is widely dispersed and does not simulate a point source. In these cases, a line-source model is proposed to more accurately reflect this extended activity distribution.

Radiation dose distributions in normal tissue adjacent to tumors containing (131)I or (90)Y: the potential for toxicity.

Unlabelled: Given the relatively large tumor-absorbed doses reported for patients receiving radionuclide therapy, particularly radioimmunotherapy, and the relatively long pathlength of the nonpenetrating emissions of some radionuclides being used for these therapies, there exists the possibility of large absorbed doses to tissues adjacent to, surrounded by, or surrounding these tumors. Because tumors can occur adjacent to critical organs or tissues, such as arteries, nerves, pericardium, and the walls of the organs of the gastrointestinal tract, large absorbed doses to these normal tissues can lead to acute complications.

Methods: In this study, the Monte Carlo radiation transport code MCNP4b was used to simulate the deposition of energy from emissions of 2 radionuclides of interest, (131)I and (90)Y, to assess the possible magnitude of the absorbed doses in tissues adjacent to tumors.

Radiation dosimetry results for Zevalin radioimmunotherapy of rituximab-refractory non-Hodgkin lymphoma.

Background: Zevalin consists of a murine anti-CD20 monoclonal antibody (ibritumomab) conjugated to the linker-chelator tiuxetan, which securely chelates indium-111 ((111)In) for imaging and dosimetry and yttrium-90 ((90)Y) for radioimmunotherapy (RIT). Previous trials involving rituximab-naïve patients have demonstrated excellent targeting of Zevalin to CD20+ B-cell non-Hodgkin lymphoma with minimal uptake in normal organs. The purpose of this trial was to perform (111)In-Zevalin imaging in patients with rituximab-refractory tumors to determine normal organ dosimetry.

Radioactivity appearing at landfills in household trash of nuclear medicine patients: much ado about nothing?

The U.S. NRC in 1997 removed its arbitrary 1.