Dosimetry and first human experience with Zr-panitumumab.

Zr-panitumumab is a novel immuno-PET radiotracer. A fully humanized IgG2 antibody, panitumumab binds with high affinity to the extracellular ligand binding domain of EGFR. Immuno-PET with radiolabeled panitumumab is a non-invasive method that could characterize EGFR expression in tumors and metastatic lesions.

Clinical impact of PSMA-based F-DCFBC PET/CT imaging in patients with biochemically recurrent prostate cancer after primary local therapy.

Purpose: The purpose of our study was to assess F-DCFBC PET/CT, a PSMA targeted PET agent, for lesion detection and clinical management of biochemical relapse in prostate cancer patients after primary treatment.

Methods: This is a prospective IRB-approved study of 68 patients with documented biochemical recurrence after primary local therapy consisting of radical prostatectomy (n = 50), post radiation therapy (n = 9) or both (n = 9), with negative conventional imaging. All 68 patients underwent whole-body F-DCFBC PET/CT, and 62 also underwent mpMRI within one month.

18F-DCFBC Prostate-Specific Membrane Antigen-Targeted PET/CT Imaging in Localized Prostate Cancer: Correlation With Multiparametric MRI and Histopathology.

Purpose: To assess the ability of (N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-4-F-fluorobenzyl-L-cysteine) (F-DCFBC), a prostate-specific membrane antigen-targeted PET agent, to detect localized prostate cancer lesions in correlation with multiparametric MRI (mpMRI) and histopathology.

Methods: This Health Insurance Portability and Accountability Act of 1996-compliant, prospective, institutional review board-approved study included 13 evaluable patients with localized prostate cancer (median age, 62.8 years [range, 51-74 years]; median prostate-specific antigen, 37.

Imaging the Met Receptor Tyrosine Kinase (Met) and Assessing Tumor Responses to a Met Tyrosine Kinase Inhibitor in Human Xenograft Mouse Models with a [99mTc] (AH-113018) or Cy 5** (AH-112543) Labeled Peptide.

Developing an imaging agent targeting the hepatocyte growth factor receptor protein (Met) status of cancerous lesions would aid in the diagnosis and monitoring of Met-targeted tyrosine kinase inhibitors (TKIs). A peptide targeting Met labeled with [(99m)Tc] had high affinity in vitro (Kd = 3.3 nM) and detected relative changes in Met in human cancer cell lines.

Rapid synthesis of [18F]fluoroestradiol: remarkable advantage of microwaving over conventional heating.

16α-[(18)F]fluoroestradiol ([(18)F]FES) is known as a clinically important tracer in nuclear medicine as an estrogen receptor ligand for investigating primary and metastatic breast cancers. Synthesizing [(18)F]FES is a two-step process associated with [(18)F]fluoride incorporation to the precursor (3-methoxymethyl 16β,17β-epiestriol-O-cyclic sulfone) and subsequent hydrolysis of the [(18)F]fluorinated intermediate with 2 N HCl. The impact of microwave (MW) heating on both fluorination and hydrolysis reactions was investigated.

Synthesis and biological evaluation of panitumumab-IRDye800 conjugate as a fluorescence imaging probe for EGFR-expressing cancers.

To investigate panitumumab-IRDye800 as an intraoperative optical imaging agent for epidermal growth factor receptor (EGFR)-expressing cancers, we developed clinical-quality panitumumab-IRDye800 and evaluated its specificity and sensitivity to visualize tumors by fluorescence imaging in a variety of mouse xenograft models with different levels of EGFR-expression. Panitumumab was chemically conjugated to NIR-dye (Li-COR 800CW) at well-defined and limited substitution ratio (1:1-2) for the characterization of fluorescence signals. Yield and purity of the conjugate was 80±5% and 95±2% respectively (n= 6).

Preparation of clinical-grade (89) Zr-panitumumab as a positron emission tomography biomarker for evaluating epidermal growth factor receptor-targeted therapy.

Panitumumab is a fully human monoclonal antibody approved for the treatment of epidermal growth factor receptor (EGFR) positive colorectal cancer. Recently, panitumumab has been radiolabeled with (89) Zr and evaluated for its potential to be used as immuno-positron emission tomography (PET) probe for EGFR positive cancers. Interesting preclinical results published by several groups of researchers have prompted us to develop a robust procedure for producing clinical-grade (89) Zr-panitumumab as an immuno-PET probe to evaluate EGFR-targeted therapy.

Synthesis of Clinical-Grade [(18)F]-Fluoroestradiol as a Surrogate PET Biomarker for the Evaluation of Estrogen Receptor-Targeting Therapeutic Drug.

16 α -[(18)F]-fluoroestradiol ([(18)F]FES), a steroid-based positron emission tomography (PET) tracer, has emerged as a dependable tracer for the evaluation and management of estrogen receptor-positive (ER+) breast cancer patients. We have developed a fully automatic, one-pot procedure for the synthesis of [(18)F]FES using the Eckert & Ziegler (E & Z) radiomodular system. After [(18)F]fluorination, the intermediate was hydrolyzed with 2.

Zirconium-89 labeled panitumumab: a potential immuno-PET probe for HER1-expressing carcinomas.

Introduction: Anti-HER1 monoclonal antibody (mAb), panitumumab (Vectibix) is a fully human mAb approved by the FDA for the treatment of epidermal growth factor receptor (EGFR, HER1)-expressing colorectal cancers. By combining the targeted specificity of panitumumab with the quantitative in vivo imaging capabilities of PET, we evaluated the potential of (89)Zr-DFO-panitumumab PET/CT imaging and performed non-invasive, in vivo imaging of HER1 expression and estimated human dosimetry.

Methods: Panitumumab was radiolabeled with (89)Zr using a derivative of desferrioxamine (DFO-Bz-NCS) and with (111)In using CHX-A" DTPA as bifunctional chelators.

Metallic radionuclides in the development of diagnostic and therapeutic radiopharmaceuticals.

Metallic radionuclides are the mainstay of both diagnostic and therapeutic radiopharmaceuticals. Therapeutic nuclear medicine is less advanced but has tremendous potential if the radionuclide is accurately targeted. Great interest exists in the field of inorganic chemistry for developing target specific radiopharmaceuticals based on radiometals for non-invasive disease detection and cancer radiotherapy.

Structure modulated electronic contributions to metalloenediyne reactivity: synthesis and thermal Bergman cyclization of MLX2 compounds.

The synthesis of novel metalloendiyne complexes MLRX(2) (where L = 1,4-dibenzyl/diethyl-1,4-diaza-cyclododec-8-ene-6,10-diyne, X = halogen) are reported with their X-ray crystal structures and thermal Bergman cyclization temperatures. Two distinct types of constructs are obtained; the Zn(II) compounds are tetrahedral, while the Cu(II) and the Pd(II) compounds are all distorted- or square-planar. Each possesses structurally similar enediyne conformations and critical distances (3.

Synthesis and evaluation of near-infrared (NIR) dye-herceptin conjugates as photoacoustic computed tomography (PCT) probes for HER2 expression in breast cancer.

We are evaluating PCT imaging in conjunction with NIR dye labeled Herceptin antibody for noninvasive assessment of HER2 expression in tumors. Herceptin was labeled with Alexa Fluor-750 amine reactive dye for characterization of photoacoustic and fluorescence signals. Measurements were performed in solution and after incubation in cultured cell lines that were positive or negative in expression of HER2.

A geometric switching approach toward thermal activation of metalloenediynes.

Tetradentate metalloenediynes with strong imine and weaker thioether coordination serve as a geometrically non-rigid switch to drive thermal Bergman cyclization.

Metalloenediynes: advances in the design of thermally and photochemically activated diradical formation for biomedical applications.

The remarkable discovery of the enediyne antitumor antibiotics almost two decades ago has led to significant developments in the systematic design and study of simple synthetic enediyne constructs and their Bergman cyclization reactivities. Advances in understanding both the geometric and electronic factors that are important in influencing the activation barrier to formation of the potent 1,4-phenyl diradical intermediate in simple organic enediynes have been made as a first step to the development of synthetic agents for biomedical uses. Progress in these areas has also served as a benchmark and guideline for a new wave of inorganic metalloenediyne constructs that display variable and wide-ranging reactivity or stability depending upon the geometric or electronic structure of the resulting complex.

Isolation of electronic from geometric contributions to Bergman cyclization of metalloenediynes.

Conformationally constrained ethylene-diamine metalloenediyne compounds exhibit alkyne termini separations that are constant and independent of metal center geometry. Ancillary chloride ligand electron donation into the Bergman cyclization reaction coordinate, however, dramatically influences the observed temperatures.

Pyridylazole chelation of oxorhenium(V) and imidorhenium(V). Rates and trends of oxygen atom transfer from Re(V)O to tertiary phosphines.

The concerned azoles are 2-(2-pyridyl)benzoxazole (pbo) and 2-(2-pyridyl)benzthiazole (pbt). These react with ReOCl(3)(PPh(3))(2) in benzene, affording Re(V)OCl(3)(pbo) and Re(V)OCl(3)(pbt), which undergo facile oxygen atom transfer to PPh(2)R (R = Ph, Me) in dichloromethane solution, furnishing Re(III)(OPPh(2)R)Cl(3)(pbo) and Re(III)(OPPh(2)R)Cl(3)(pbt). The oxo species react with aniline in toluene solution, yielding the imido complexes Re(V)(NPh)Cl(3)(pbo) and Re(V)(NPh)Cl(3)(pbt).