FDDNP-PET scanning can differentiate persons with mild cognitive impairment from those with Alzheimer's disease and those with no cognitive impairment. This technique is potentially useful as a noninvasive method to determine regional cerebral patterns of amyloid plaques and tau neurofibrillary tangles.
Microreactor technology has shown potential for optimizing synthetic efficiency, particularly in preparing sensitive compounds. We achieved the synthesis of an [
18
F]fluoride-radiolabeled molecular imaging probe, 2-deoxy-2-[
18
F]fluoro-
d
-glucose ([
18
F]FDG), in an integrated microfluidic device. Five sequential processes—[
18
F]fluoride concentration, water evaporation, radiofluorination, solvent exchange, and hydrolytic deprotection—proceeded with high radio-chemical yield and purity and with shorter synthesis time relative to conventional automated synthesis. Multiple doses of [
18
F]FDG for positron emission tomography imaging studies in mice were prepared. These results, which constitute a proof of principle for automated multistep syntheses at the nanogram to microgram scale, could be generalized to a range of radiolabeled substrates.
Senile plaques (SPs) and neurofibrillary tangles (NFTs) are hallmark pathologies accompanying the neurodegeneration involved in Alzheimer's disease (AD), for which beta-amyloid (Abeta) peptide is a major constituent of SPs. Our laboratories previously developed the hydrophobic, fluorescent molecular-imaging probe 2-(1-(6-[(2-[(18)F]fluoroethyl)(methyl)amino]-2-naphthyl)ethylidene)malononitrile ([(18)F]FDDNP), which crosses the blood-brain barrier and determines the localization and load of SPs and NFTs in vivo in AD patients. In this report, we used fluorimetric and radioactive binding assays to determine the binding affinities of FDDNP and its analog, 1-(6-[(2-[(18)F]fluoroethyl)(methyl)amino]naphthalen-2-yl)ethanone ([(18)F]FENE), to synthetic fibrils of Abeta(1-40). FDDNP and FENE both appeared to bind to two kinetically distinguishable binding sites on Abeta(1-40) fibrils. Fluorescence titrations yielded apparent K(d) values of 0.12 and 0.16 nm for high-affinity binding sites for FDDNP and FENE, respectively, and apparent K(d) values of 1.86 and 71.2 nm for the low-affinity binding sites. The traditional radioactive binding assays also produced apparent K(d) values in the low nanomolar range. The presence of two kinetically distinguishable binding sites for FDDNP and FENE suggests multiple binding sites for SPs and identifies the parameters that allow for the structural optimization of this family of probes for in vivo use. The high-affinity binding of the probes to multiple binding sites on fibrils are consistent with results obtained with digital autoradiography, immunohistochemistry, and confocal fluorescence microscopy using human brain specimens of AD patients.
SUMMARY
Background
A 57 years old male had been diagnosed with grade III/IV glioblastoma multiforme. The patient had then enrolled in an adoptive cellular immunotherapy trial. The trial involved infusion of ex vivo expanded autologous cytolytic CD8+ T cells (CTLs), genetically engineered to express the interleukin-13 zetakine gene (therapeutic gene, encoding a receptor protein that targets the T cells to the tumor cells), and the Herpes Simplex virus 1 thymidine kinase (HSV1-tk) suicide gene/positron emission tomography (PET) imaging reporter gene.
Investigations
Whole-body and brain PET scan with 9-[4-[18F]Fluoro-3-(hydroxymethyl)butyl]guanine ([18F]FHBG) to detect HSV1-tk expressing CTLs, and safety monitoring following injection of [18F]FHBG.
Diagnosis
Magnetic resonance imaging detection of grade III/IV glioblastoma multiforme plus recurrence of two tumors after resection of the initial tumor.
Management
Surgical resection of original glioblastoma tumor, enrollment in CTL therapy trial, re-resection of glioma recurrence, infusion of approximately 1 X 109 CTL into the site of tumor re-resection, and [18F]FHBG PET scan to detect infused CTLs.
A B S T R A C T PurposeEvaluation of treatment effects in malignant brain tumors is challenging because of the lack of reliable response predictors of tumor response. This study examines the predictive value of positron emission tomography (PET) using [18 F] fluorothymidine (FLT), an imaging biomarker of cell proliferation, in patients with recurrent malignant gliomas treated with bevacizumab in combination with irinotecan.
Patients and MethodsPatients with recurrent malignant gliomas treated with biweekly cycles of bevacizumab and irinotecan were prospectively studied with FLT-PET at baseline, after 1 to 2 weeks, and after 6 weeks from start of treatment. A more than 25% reduction in tumor FLT uptake as measured by standardized uptake value was defined as a metabolic response. FLT responses were compared with response as shown by magnetic resonance imaging (MRI) and patient survival.
ResultsTwenty-one patients were included, and 19 were assessable for metabolic response evaluation with FLT-PET. There were nine responders (47%) and 10 nonresponders (53%). Metabolic responders survived three times as long as nonresponders (10.8 v 3.4 months; P ϭ .003), and tended to have a prolonged progression-free survival (P ϭ .061). Both early and later FLT-PET responses were more significant predictors of overall survival (1 to 2 weeks, P ϭ .006; 6 weeks, P ϭ .002), compared with the MRI responses (P ϭ .060 for both 6-week and best responses).
ConclusionFLT-PET as an imaging biomarker seems to be predictive of overall survival in bevacizumab and irinotecan treatment of recurrent gliomas. Whether FLT-PET performed as early as 1 to 2 week after starting treatment is as predictive as the study indicates at 6 weeks warrants further investigation.
Monitoring immune function using molecular imaging could significantly impact the diagnosis and treatment evaluation of immunological disorders and therapeutic immune responses. Positron Emission Tomography (PET) is a molecular imaging modality with applications in cancer and other diseases. PET studies of immune function have been limited by a lack of specialized probes. We identified [18F]FAC (1-(2′-deoxy-2′-[18F]fluoroarabinofuranosyl) cytosine) by differential screening as a new PET probe for the deoxyribonucleotide salvage pathway. [18F]FAC enabled visualization of lymphoid organs and was sensitive to localized immune activation in a mouse model of anti-tumor immunity. [18F]FAC microPET also detected early changes in lymphoid mass in systemic autoimmunity and allowed evaluation of immunosuppressive therapy. These data support the use of [18F]FAC PET for immune monitoring and suggest a wide range of clinical applications in immune disorders and in certain types of cancer.
We are developing quantitative assays to repeatedly and noninvasively image expression of reporter genes in living animals, using positron emission tomography (PET). We synthesized positron-emitting 8
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