Synthesis and evaluation of novel radioiodinated anthranilate derivatives for in vivo imaging of vascular endothelial growth factor receptor with single-photon emission computed tomography.

OBJECTIVE: Angiogenesis facilitates tumor survival and promotes malignancy. The vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) tyrosine kinase (TK) signaling pathway is a key factor mediating angiogenesis, suggesting that this pathway may be a target for diagnosis and therapy. In this study, we aimed to develop small molecule radioiodinated probes applicable for in vivo VEGFR imaging considering the versatility and usefulness of single-photon emission computed tomography (SPECT). METHODS: We designed and synthesized four radioiodinated anthranilate compounds (6a-d) based on the structure of an anticancer drug targeting VEGFR-TK. The inhibitory potencies of corresponding cold compounds 4a-d and in vitro stability of compounds 6a-d were assessed by cellular proliferation inhibition assays and radio thin-layer chromatography after incubation in neutral solution. In vivo biodistributions were evaluated by determining radioactivity in tissues of interest after intravenous injection of test compounds in tumor-bearing mice. In vitro and in vivo blocking experiments using a selective VEGFR-TK inhibitor and SPECT/computed tomography (CT) imaging were performed in tumor-bearing mice. RESULTS: The radioiodinated compounds 6a-d were obtained with more than 68.0% radiochemical yield and more than 95% radiochemical purity. Because compounds 4a-d showed high inhibitory potencies and compounds 6c and 6d showed high in vitro stability, 6c ([125I]m-NPAM) and 6d ([125I]p-NPAM) were further evaluated. Analysis of the in vivo biodistribution revealed a tumor to blood radioactivity ratio of greater than 4 at 24 h after [125I]p-NPAM administration. Accumulation of radioactivity in cultured tumor cells and tumor xenografts after [125I]p-NPAM administration was significantly blocked by inhibitor pretreatment. Tumors were clearly imaged at 24 h after [125I]p-NPAM injection with SPECT/CT in comparison to that in inhibitor-pretreated tumor-bearing mice. CONCLUSION: [125I]p-NPAM may have potential applications as a lead compound for future development of a clinically usable VEGFR imaging probe for SPECT.

[A case of relapsed neurosyphilis with progressive left hemiparesis].

A 52-year-old man presented with progressive dementia and left hemiparesis. He was treated for neurosyphilis at 44 years old in another hospital. An initial MRI revealed a widespread high-intensity area in the right temporal lobe on DWI. Findings on MRA were normal. He was treated initially with intravenous edaravone and glyceol, but neurological finding did not improved. Serological tests of serum and CSF demonstrated high titers of antibodies to Treponema pallidum. He was treated for relapsed neurosyphilis with daily penicillin G injections without improvement. Penicillin G was switched to erythromycin. After administration of erythromycin, neurological symptoms improved and MRI abnormality showed progression. This case could be considered as Lissauer form of general paresis because of left hemiparesis and MRI findings. Neurosyphilis should be considered in a case with revealing high density area in DWI.

[A case of intravascular malignant lymphoma with initial progressive non-specific neurological symptoms].

A 79-year-old woman was admitted to a nearby hospital for seven days due to low-grade fever, loss of appetite and general fatigue. She was diagnosed with normal condition and discharged. She was admitted to our hospital one week later with disturbed consciousness. Laboratory findings upon admission revealed anemia, elevated alanine amino transferase, elevated total birirubin and thrombocytopenia. Abdominal CT demonstrated multiple low intensity lesions in the liver. Enhanced brain CT revealed multiple lesions with increased signal intensity lesions in the white matter and cortex. The value of soluble IL-2 receptor antibody was 16,000U/ml. Intravascular lymphoma was suspected because of brain CT finding and IL-2 receptor antibody titer. Methylprednisolone pulse therapy was started considering her age and general condition, but she was died thirteen days after admission. Postmorten examination revealed widespread intravascular aggregation of malignant lymphoma cells in the liver, spleen, bone marrow, bladder, ovary and stomach indicating a diagnosis of an Asian variant of intravascular large B cell lymphoma (AIVL). Neurological abnormalities are not usually associated with AIVL, but this patient had rare AIVL presenting with initial progressive nonspecific neurological symptoms.