Evaluation of a bimodal, matched pair theranostic agent targeting prostate-specific membrane antigen.

Background: Prostate cancer affects 1 in 6 men, and it is the second‑leading cause of cancer-related death in American men. Surgery is one of the main treatment modalities for prostate cancer, but it often results in incomplete resection margins or complete resection that leads to nerve damage and undesirable side effects. In the present work, we have developed a new bimodal tracer, NODAGA-sCy7.

Albumin-Binding Lutetium-177-Labeled LLP2A Derivatives as Theranostics for Melanoma.

Very late antigen-4 (VLA-4) is a transmembrane integrin protein that is highly expressed in aggressive forms of metastatic melanoma. A small-molecule peptidomimetic, LLP2A, was found to have a low pM affinity binding to VLA-4. Because LLP2A itself does not inhibit cancer cell proliferation and survival, it is an ideal candidate for the imaging and delivery of therapeutic payloads.

Development and biodistribution studies of As-labeled trithiol RM2 bioconjugates for prostate cancer: Comparison of [As]As-trithiol-Ser-Ser-RM2 vs. [As]As-trithiol-Glu-Ser-RM2.

Introduction: Recent progress with the production of As (2.49 Mev β (64%), 3.33 Mev β (16%), 834 keV γ (81%), t: 26 h) and As (0.

Development of Heterobivalent Theranostic Probes Having High Affinity/Selectivity for the GRPR/PSMA.

In this study, we describe the development of heterobivalent [DUPA-6-Ahx-([In]In-DO3A)-8-Aoc-BBN ANT] and [DUPA-6-Ahx-([Lu]Lu-DO3A)-8-Aoc-BBN ANT] radiotracers that display very high selectivity/specificity for gastrin-releasing peptide receptor (GRPR)-/prostate-specific membrane antigen (PSMA)-expressing cells. These studies include metallation, purification, characterization, and in vitro and in vivo evaluation of the new small-molecule-/peptide-based radiopharmaceuticals having utility for imaging and potentially therapy. Competitive displacement binding assays using PC-3 cells and LNCaP cell membranes showed high binding affinity for the GRPR or the PSMA.

Design, synthesis and evaluation of In labeled DOTA-conjugated tetrapeptides having high affinity and selectivity for mu opioid receptors.

Introduction: Peripheral mu (μ) opioid receptors are implicated in pain, bowel dysfunction and the progression of certain cancers. In an effort to identify radioligands well suited for imaging these peripheral sites, we have prepared and evaluated four hydrophilic In labeled DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) conjugated μ tetrapeptides.

Methods: Peptides were prepared by solid-phase techniques, using orthogonal strategies to achieve branching to DOTA, and then characterized by HPLC, mass spectroscopy and amino acid analysis.

Cocaine occupancy of sigma1 receptors and dopamine transporters in mice.

Activation of sigma1 (σ1) receptors contributes to the behavioral and toxic effects of (-)-cocaine. We studied a key step, the ability of (-)-cocaine to occupy σ1 receptors in vivo, using CD-1(®) mice and the novel radioligand [(125) I]E-N-1-(3'-iodoallyl)-N'-4-(3",4"-dimethoxyphenethyl)-piperazine ([(125) I]E-IA-DM-PE-PIPZE). (-)-Cocaine displayed an ED50 of 68 μmol/kg for inhibition of specific radioligand binding in whole brain, with values between 73 and 80 μmol/kg for heart, lung, and spleen.

Relationship between cerebral sigma-1 receptor occupancy and attenuation of cocaine's motor stimulatory effects in mice by PD144418.

Psychostimulant effects of cocaine are mediated partly by agonist actions at sigma-1 (σ1) receptors. Selective σ1 receptor antagonists attenuate these effects and provide a potential avenue for pharmacotherapy. However, the selective and high affinity σ1 antagonist PD144418 (1,2,3,6-tetrahydro-5-[3-(4-methylphenyl)-5-isoxazolyl]-1-propylpyridine) has been reported not to inhibit cocaine-induced hyperactivity.

A selective sigma-2 receptor ligand antagonizes cocaine-induced hyperlocomotion in mice.

Cocaine functions, in part, through agonist actions at sigma-1 (σ1 ) receptors, while roles played by sigma-2 (σ2 ) receptors are less established. Attempts to discriminate σ2 receptor-mediated effects of cocaine in locomotor hyperactivity assays have been hampered by the lack of potent and selective antagonists. Certain tetrahydroisoquinolinyl benzamides display high σ2 receptor affinity, and excellent selectivity for binding to σ2 over σ1 receptors.

Laminin receptor specific therapeutic gold nanoparticles (198AuNP-EGCg) show efficacy in treating prostate cancer.

Systemic delivery of therapeutic agents to solid tumors is hindered by vascular and interstitial barriers. We hypothesized that prostate tumor specific epigallocatechin-gallate (EGCg) functionalized radioactive gold nanoparticles, when delivered intratumorally (IT), would circumvent transport barriers, resulting in targeted delivery of therapeutic payloads. The results described herein support our hypothesis.

Synthesis, radioiodination and in vitro and in vivo sigma receptor studies of N-1-allyl-N´-4-phenethylpiperazine analogs.

Introduction: Sigma-1 (σ(1)) receptor radioligands are useful for basic pharmacology studies and for imaging studies in neurology, psychiatry and oncology. We derived a hybrid structure, N-1-allyl-N´-4-phenethylpiperazine, from known ligands TPCNE and SA4503 for use as a scaffold for development of radioiodinated σ(1) receptor ligands.

Methods: E-and Z-N-1-(3'-iodoallyl)-N´-4-(3″,4″-dimethoxyphenethyl)-piperazine (E-1 and Z-1), N-1-allyl-N´-4-(3',4'-dimethoxyphenethyl)-piperazine (2) and E-N-1-(3'-iodoallyl)-N´-4-(3″-methoxy-4'´-hydroxyphenethyl)-piperazine (3) were synthesized.

Radioactive gold nanoparticles in cancer therapy: therapeutic efficacy studies of GA-198AuNP nanoconstruct in prostate tumor-bearing mice.

Unlabelled: Biocompatibility studies and cancer therapeutic applications of nanoparticulate beta-emitting gold-198 (198Au; beta(max) = 0.96 MeV; half-life of 2.7 days) are described.

Development of high-specific-activity (68)Ga-labeled DOTA-rhenium-cyclized alpha-MSH peptide analog to target MC1 receptors overexpressed by melanoma tumors.

Introduction: A previous report on (68)Ga-1,4,7,10-tetraazacyclodedecane-N,N',N'',N'''-tetraacetic acid (DOTA)-Re(Arg(11))CCMSH was shown to indicate the imaging agent's potency for early detection of metastatic melanoma. However, the main limiting factor to developing high-specific-activity (68)Ga-DOTA-Re(Arg(11))CCMSH is the short half-life of (68)Ga, which precludes further purification of the agent. To circumvent this problem, we incorporated the microwave technique to rapidly radiolabel the peptide with (68)Ga, thereby allowing enough time to include high-performance liquid chromatography (HPLC) purification in the overall procedure.