Biomedical subjects

Peter S Conti

Publications and source records attributed to Peter S Conti.

At least 37 records · Page 2Linked to original sources

PubMed2004

Direct comparison of radiolabeled probes FMAU, FHBG, and FHPG as PET imaging agents for HSV1-tk expression in a human breast cancer model.

2'-Deoxy-2'-fluoro-5-methyl-1-beta-D-arabinofuranosyluracil (FMAU), 9-(4-fluoro-3-hydroxy-methyl-butyl)guanine (FHBG) and 9-[(3-fluoro-1-hydroxy-2-propoxy)methyl]-guanine (FHPG) have been evaluated in a human breast cancer model as potential radiotracers for PET imaging of HSV1-tk gene expression. In vitro accumulation of [14C]FMAU, [18F]FHBG, and [18F]FHPG in HSV1-tk-expressing cells was 14- to 16-fold (p <.001), 9- to 13-fold (p <.001), and 2- to 3-fold (p <.05) higher than tk-negative control cells, respectively, between 30 and 240 min. Accumulation of FMAU and FHBG in vector-transduced cells was 10- to 14-fold and 6- to 10-fold higher than wild-type cells, respectively. At 2 hr, uptake of [(14)C]FMAU in tkpositive cells was 6.3-fold and 60-fold higher than [18F]FHBG and [18F]FHPG, respectively. In vivo, tumor uptake of [14C]FMAU in HSV1-tk-expressing cells was 3.7-fold and 5.5-fold (p <.001) higher than tk-negative control cells at 1 and 2 hr, respectively. Tumor uptake of [18F]FHBG was 4.2-fold and 12.6-fold higher (p <.001) than tk-negative cells at the same time points. Incorporation of [14C]FMAU in tk-positive tumor was 18-fold and 24-fold higher (p <.001) than [18F]FHBG at 1 and 2 hr, respectively. Micro-PET images support the biodistribution results and indicate that both [18F]FMAU and [18F]FHBG are useful for imaging HSV1-tk expression in breast cancer. Although FMAU demonstrates higher total incorporation (%dose/g) in tumor tissue compared with the other tracers, FHBG is superior in terms of specific accumulation in transfected cells at later time points.

Animals↗

PubMed2004

Micro-PET imaging of alphavbeta3-integrin expression with 18F-labeled dimeric RGD peptide.

The alphav integrins, which act as cell adhesion molecules, are closely involved with tumor invasion and angiogenesis. In particular, alphavbeta3 integrin, which is specifically expressed on proliferating endothelial cells and tumor cells, is a logical target for development of a radiotracer method to assess angiogenesis and anti-angiogenic therapy. In this study, a dimeric cyclic RGD peptide E[c(RGDyK)]2 was labeled with 18F (t(1/2) = 109.7 min) by using a prosthetic 4-[18F]fluorobenzoyl moiety to the amino group of the glutamate. The resulting [18F]FB-E[c(RGDyK)]2, with high specific activity (200-250 GBq/micromol at the end of synthesis), was administered to subcutaneous U87MG glioblastoma xenograft models for micro-PET and autoradiographic imaging as well as direct tissue sampling to assess tumor targeting efficacy and in vivo kinetics of this PET tracer. The dimeric RGD peptide demonstrated significantly higher tumor uptake and prolonged tumor retention in comparison with a monomeric RGD peptide analog [18F]FB-c(RGDyK). The dimeric RGD peptide had predominant renal excretion, whereas the monomeric analog was excreted primarily through the biliary route. Micro-PET imaging 1 hr after injection of the dimeric RGD peptide exhibited tumor to contralateral background ratio of 9.5 +/- 0.8. The synergistic effect of polyvalency and improved pharmacokinetics may be responsible for the superior imaging characteristics of [18F]FB-E[c(RGDyK)]2.

Animals↗

PubMed2004

microPET and autoradiographic imaging of GRP receptor expression with 64Cu-DOTA-[Lys3]bombesin in human prostate adenocarcinoma xenografts.

UNLABELLED: Overexpression of gastrin-releasing peptide (GRP) receptor (GRPR) in both androgen-dependent (AD) and androgen-independent (AI) human neoplastic prostate tissues provides an attractive target for prostate cancer imaging and therapy. The goal of this study was to develop (64)Cu-radiolabeled GRP analogs for PET imaging of GRPR expression in prostate cancer xenografted mice. METHODS: [Lys(3)]bombesin ([Lys(3)]BBN) was conjugated with 1,4,7,10-tetraazadodecane-N,N',N",N"'-tetraacetic acid (DOTA) and labeled with the positron-emitting isotope (64)Cu (half-life = 12.8 h, 19% beta(+)). Receptor binding of DOTA-[Lys(3)]BBN and internalization of (64)Cu-DOTA-[Lys(3)]BBN by PC-3 prostate cancer cells were measured. Tissue biodistribution, microPET, and whole-body autoradiographic imaging of the radiotracer were also investigated in PC-3 (AI)/CRW22 (AD) prostate cancer tumor models. RESULTS: A competitive receptor- binding assay using (125)I-[Tyr(4)]BBN against PC-3 cells yielded a 50% inhibitory concentration value of 2.2 +/- 0.5 nmol/L for DOTA-[Lys(3)]BBN. Incubation of cells with the (64)Cu-labeled radiotracer showed temperature- and time-dependent internalization. At 37 degrees C, >60% of the tracer was internalized within the first 15 min and uptake remained constant for 2 h. Radiotracer uptake was higher in AI PC-3 tumor (5.62 +/- 0.08 %ID/g at 30 min after injection, where %ID/g is the percentage of injected dose per gram) than in AD CWR22 tumor (1.75 +/- 0.05 %ID/g at 30 min after injection). Significant accumulation of the activity in GRPR-positive pancreas was also observed (10.4 +/- 0.15 %ID/g at 30 min after injection). Coinjection of a blocking dose of [Lys(3)]BBN inhibited the activity accumulation in PC-3 tumor and pancreas but not in CWR22 tumor. microPET and autoradiographic imaging of (64)Cu-DOTA-[Lys(3)]BBN in athymic nude mice bearing subcutaneous PC-3 and CWR22 tumors showed strong tumor-to-background contrast. CONCLUSION: This study demonstrates that PET imaging of (64)Cu-DOTA-[Lys(3)]BBN is able to detect GRPR-positive prostate cancer.

Adenocarcinoma↗

PubMed2004

Pegylated Arg-Gly-Asp peptide: 64Cu labeling and PET imaging of brain tumor alphavbeta3-integrin expression.

UNLABELLED: The alphav-integrins, cell adhesion molecules that are highly expressed on activated endothelial cells and tumor cells but not on dormant endothelial cells or normal cells, present an attractive target for tumor imaging and therapy. We previously coupled a cyclic Arg-Gly-Asp (RGD) peptide, c(RGDyK), with 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA) and labeled the RGD-DOTA conjugate with 64Cu (half-life, 12.8 h; 19% beta+) for solid tumor targeting, with high tumor-to-background contrast. The rapid tumor washout rate and persistent liver and kidney retention of this tracer prompted us to optimize the tracer for improved pharmacokinetic behavior. In this study, we introduced a polyethylene glycol (PEG; molecular weight, 3,400) moiety between DOTA and RGD and evaluated the 64Cu-DOTA-PEG-RGD tracer for microPET imaging in brain tumor models. METHODS: DOTA was activated in situ and conjugated with RGD-PEG-NH2 under slightly basic conditions. alphavbeta3-Integrin-binding affinity was evaluated with a solid-phase receptor-binding assay in the presence of 125I-echistatin. Female nude mice bearing subcutaneous U87MG glioblastoma xenografts were administered 64Cu-DOTA-PEG-RGD, and the biodistributions of the radiotracer were evaluated from 30 min to 4 h after injection. microPET (20 min of static imaging at 1 h after injection) and then quantitative autoradiography were used for tumor visualization and quantification. The same tracer was also applied to an orthotopic U87MG model for tumor detection. RESULTS: The radiotracer was synthesized with a high specific activity (14,800-29,600 GBq/mmol [400-800 Ci/mmol]). The c(RGDyK)-PEG-DOTA ligand showed intermediate binding affinity for alphavbeta3-integrin (50% inhibitory concentration, 67.5 +/- 7.8 nmol/L [mean +/- SD]). The pegylated RGD peptide demonstrated rapid blood clearance (0.57 +/- 0.15 percentage injected dose [%ID]/g [mean +/- SD] at 30 min after injection and 0.03 +/- 0.02 %ID/g at 4 h after injection). Activity accumulation in the tumor was rapid and high at early time points (2.74 +/- 0.45 %ID/g at 30 min after injection), and some activity washout was seen over time (1.62 +/- 0.18 %ID/g at 4 h after injection). Compared with (64)Cu-DOTA-RGD, this tracer showed improved in vivo kinetics, with significantly reduced liver uptake (0.99 +/- 0.08 %ID/g vs. 1.73 +/- 0.39 %ID/g at 30 min after injection and 0.58 +/- 0.07 %ID/g vs. 2.57 +/- 0.49 %ID/g at 4 h after injection). The pegylated RGD peptide showed higher renal accumulation at early time points (3.51 +/- 0.24 %ID/g vs. 2.18 +/- 0.23 %ID/g at 30 min after infection) but more rapid clearance (1.82 +/- 0.29 %ID/g vs. 2.01 +/- 0.25 %ID/g at 1 h after injection) than 64Cu-DOTA-RGD. The integrin receptor specificity of this radiotracer was demonstrated by blocking of tumor uptake by coinjection with nonradiolabeled c(RGDyK). The high tumor-to-organ ratios for the pegylated RGD peptide tracer (at 1 h after injection: tumor-to-blood ratio, 20; tumor-to-muscle ratio, 12; tumor-to-liver ratio, 2.7; and tumor-to-kidney ratio, 1.2) were confirmed by microPET and autoradiographic imaging in a subcutaneous U87MG tumor model. This tracer was also able to detect an orthotopic brain tumor in a model in which U87MG cells were implanted into the mouse forebrain. Although the magnitude of tumor uptake in the orthotopic xenograft was lower than that in the subcutaneous xenograft, the orthotopic tumor was still visualized with clear contrast from normal brain tissue. CONCLUSION: This study demonstrated the suitability of a PEG moiety for improving the in vivo kinetics of a 64Cu-RGD peptide tracer without compromising the tumor-targeting ability and specificity of the peptide. Systematic investigations of the effects of the size and geometry of PEG on tumor targeting and in vivo kinetics will lead to the development of radiotracers suitable for clinical applications such as visualizing and quantifying alphav-integrin expression by PET. In addition, the same ligand labeled with therapeutic radionuclides may be applicable for integrin-targeted internal radiotherapy.

Animals↗

PubMed2004

Synthesis and evaluation of 2'-deoxy-2'-18F-fluoro-5-fluoro-1-beta-D-arabinofuranosyluracil as a potential PET imaging agent for suicide gene expression.

UNLABELLED: 2'-deoxy-2'-(18)F-fluoro-5-fluoro-1-beta-D-arabinofuranosyluracil ((18)F-FFAU) has been synthesized and evaluated in HT-29 cells as a potential PET agent for herpes simplex virus type 1 thymidine kinase (HSV1-tk) gene expression. METHODS: 2-Deoxy-2-(18)F-fluoro-1,3,5-tri-O-benzoyl-alpha-D-arabinofuranose was prepared by the reaction of the respective 2-triflate with tetrabutylammonium (18)F-fluoride. The fluorosugar was converted to its 1-bromo derivative and coupled with protected 5-fluorouracil. The crude product was hydrolyzed in base and purified by high-performance liquid chromatography to obtain the (18)F-FFAU. In vitro studies were performed in HT-29 cells by incubation at various time points. In vivo studies including biodistribution and microPET were performed in tumor-bearing nude mice. RESULTS: The radiochemical yield was 20%-30% decay corrected with an average of 25% in 4 runs. Radiochemical purity was >99% and average specific activity was 85 GBq/micromol (2,300 mCi/micromol) (end of synthesis). In vitro accumulation of (3)H-FFAU in HSV1-tk-expressing cells was approximately 180-fold (P < 0.001) higher than that in the wild-type cells between 30 and 120 min. In vivo uptake of (3)H-FFAU in HSV1-tk-positive tumors at 2 h was approximately 8-fold (P < 0.001) higher than that in the control tumors. Tumor uptake (percentage injected dose per gram of tissue) and the uptake ratio (tk-positive to wild type) of (3)H-FFAU in tk-positive cells was higher compared with those of our earlier studies using 2'-(14)C-deoxy-2'-fluoro-5-methyl-1-beta-D-arabinofuranosyluracil ((14)C-FMAU) and 9-(4-(18)F-fluoro-3-hydroxymethylbutyl)guanine ((18)F-FHBG) in the same cell lines. microPET on tumor-bearing nude mice also demonstrated a very high uptake of (18)F-FFAU in tk-positive tumors compared with that of the control tumor without significant accumulation in other organs. CONCLUSION: These results demonstrate that (18)F-FFAU has superior biodistribution characteristics and significantly higher in vivo uptake in HSV1-tk-expressing tumor compared with previously studied agents.

Animals↗

PubMed2003

Kinetic modeling of 5-fluorouracil anabolism in colorectal adenocarcinoma: a positron emission tomography study in rats.

Drug uptake and anabolism by tumors are prerequisites of response to 5-fluorouracil (5-FU). Positron emission tomography (PET) with 5-[(18)F]FU (PET/5-[(18)F]FU) is potentially useful for noninvasive measurement of these processes, but is severely hampered by rapid catabolism of 5-[(18)F]FU in vivo. This study explored the combined use of PET/5-[(18)F]FU and eniluracil (5-ethynyluracil), a potent inhibitor of 5-FU catabolism, to measure the pharmacokinetics of 5-FU uptake and metabolism in tumors. Rats bearing a s.c. implanted rat colon tumor were given eniluracil and injected i.v. with 5-[(18)F]FU. Dynamic PET and arterial blood sampling were performed 0-2 h. Tumors (n = 5) were then rapidly excised, frozen, and analyzed for labeled metabolites by high performance liquid chromatography. Tumor TACs were analyzed by compartmental modeling. Compartments were identified with molecular species by comparison with ex vivo assays. Tumor extracellular fluid volume was determined in a separate group of rats. Kinetic analysis indicated partial trapping of (18)F within tumors 0-2 h after injection. Tumor time-activity curves conformed closely to a catenary 3-compartment, 5-parameter model. The model yielded values for 5-FU clearance from plasma into the trap that agreed closely with those reported previously for gastrointestinal tumors from a PET/5-[(18)F]FU + eniluracil study in humans. Tumor extracellular fluid volume as measured with (99m)Tc DTPA [(3.1 +/- 0.2) x 10(-1) ml/g; n = 5] agreed well with the distribution volume for compartment 1 of the 3-compartment, 5-parameter model [(3.7 +/- 0.3) x 10(-1) ml/g; n = 5], thus indicating that compartment 1 corresponds to tumor extracellular space. Compartment 3 closely matched the combined magnitudes of (18)F fluoronucleoside (FN) triphosphates and macromolecules in all of the cases, and compartment 2 was quantitatively consistent with the sum of intracellular 5-FU, FNs, and FN mono- and diphosphates. These observations show that PET/5-[(18)F]FU combined with an inhibitor of 5-FU catabolism and compartmental modeling is capable of quantifying the following for 5-FU in tumors: distribution volume in the extracellular space, cell transport, size and turnover rate of an intermediate intracellular pool, and formation of a long-lived intracellular pool comprising FN triphosphates + macromolecules. Such information could be useful in predicting tumor response to 5-FU, formulating protocols that increase delivery of 5-FU into tumor cells, and modulating 5-FU kinetics to overcome tumor resistance.

Adenocarcinoma↗

PubMed2003

Receptor mediated uptake of a radiolabeled contrast agent sensitive to beta-galactosidase activity.

Radiolabeling of the MRI contrast agent 1-[2-(beta-galactopyranosyloxy)propyl]-4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane with (111)In, and its evaluation is reported. Radiolabeling was performed in acetate buffer with 50-78% radiochemical yield. In vitro studies revealed that the asialoglycoprotein receptor-poor cell line MH1C1 has low uptake, while the receptor-rich cell lines BNL-CL2 and Hep G2 have higher uptake. In vivo, the uptake of the compound in receptor-rich organ liver was very high. Blocking the receptor in vivo, reduced liver uptake by 90% suggesting that the compound localizes in receptor-enriched tissues by binding to the asialoglycoprotein receptor.

Animals↗

PubMed2002

Diagnostic utility of FDG PET in multiple myeloma.

OBJECTIVE: Very little information is available regarding the diagnostic utility of positron emission tomography with [(18)F]fluorodeoxyglucose (FDG PET) in multiple myeloma. Our objective was to further define the role of FDG PET in the clinical assessment of patients with multiple myeloma. DESIGN AND PATIENTS: Nine whole-body PET scans (45 min after intravenous administration of 370-555 MBq FDG) were performed in six patients (age 38-62 years, 5 males) with multiple myeloma for evaluation of the extent of disease at the time of initial diagnosis (n=3) and for assessment of therapy response (n=3). Three patients had PET scans both before and after therapy. Prior treatments included chemoradiation therapy (n=2) and chemotherapy with autologous bone marrow transplantation (n=1). Correlative imaging data were available in all patients and included skeletal radiographic survey (n=6), bone scan (n=3), and spinal CT or MRI (n=4), and were all obtained within 3 months of the PET study. Validation was by clinical or imaging follow-up. RESULTS: In three patients with both pre- and post-therapy PET scans, PET demonstrated a favorable treatment response, by showing a decline in lesion metabolic activity (n=1), or progression of disease, by showing development of new lesions or higher lesion glucose metabolism (n=2), concordant with the clinical evaluation, while the other imaging studies showed no discernible interval changes. PET detected multiple hypermetabolic lesions in one patient with a negative bone scan and concordant positive skeletal radiographic survey. Bone scans underestimated the extent of disease in two other patients in comparison with PET. PET also detected a few early marrow lesions with subtle radiographic changes while all radiographically aggressive lytic lesions corresponded to intense hypermetabolism on PET. CONCLUSION: PET can detect early marrow involvement of multiple myeloma and is useful in assessing the extent of active disease at the time of initial presentation and in evaluating treatment response.

Adult↗

PubMed2002

Incidental colonic fluorodeoxyglucose uptake: correlation with colonoscopic and histopathologic findings.

PURPOSE: To evaluate the pattern and degree of incidental colonic fluorodeoxyglucose (FDG) uptake in patients without colorectal carcinoma who underwent whole-body FDG positron emission tomography (PET) for other purposes and compare them with colonoscopic and/or histopathologic findings. MATERIALS AND METHODS: Cases of 27 patients without known history of colorectal carcinoma who were referred for evaluation with whole-body FDG PET and displayed incidental colonic uptake were reviewed retrospectively. Colonoscopy was performed in 10 patients; histopathologic analysis, in two; and both, in 15. The colonic FDG uptake patterns were nodular-focal, nodular-multifocal, segmental, and diffuse. The FDG uptake level was scored with a four-point scale in relation to hepatic uptake. Binomial distribution was used to calculate 95% CIs for the probability of finding an abnormality at histologic examination, as predicted by findings at FDG PET. RESULTS: Colonoscopic findings in eight patients with a diffuse uptake pattern were normal. Thirteen patients with nodular high FDG uptake had pathologic findings. Six (22%) of the 27 patients were not suspected of having a malignancy, and seven had benign neoplasms. With a 95% CI, nodular high FDG uptake implies at least a 79% chance that histopathologic findings may be abnormal. Colitis was seen in five of six patients with a segmental pattern of high FDG uptake. CONCLUSION: Colonoscopy is a reasonable next step for further diagnostic examination of patients who display nodular high FDG uptake in the colon. Diffuse FDG uptake often is associated with normal findings at colonoscopy, while segmental high uptake may imply inflammation.

Adult↗

PubMed2002

Administration guidelines for radioimmunotherapy of non-Hodgkin's lymphoma with (90)Y-labeled anti-CD20 monoclonal antibody.

90Y-ibritumomab tiuxetan is a novel radioimmunotherapeutic agent recently approved for the treatment of relapsed or refractory low-grade, follicular, or CD20+ transformed non-Hodgkin's lymphoma (NHL). (90)Y-ibritumomab tiuxetan consists of a murine monoclonal antibody covalently attached to a metal chelator, which stably chelates (111)In for imaging and (90)Y for therapy. Both health care workers and patients receiving this therapy need to become familiar with how it differs from conventional chemotherapy and what, if any, safety precautions are necessary. Because (90)Y is a pure beta-emitter, the requisite safety precautions are not overly burdensome for health care workers or for patients and their families. (90)Y-ibritumomab tiuxetan is dosed on the basis of the patient's body weight and baseline platelet count; dosimetry is not required for determining the therapeutic dose in patients meeting eligibility criteria similar to those used in clinical trials, such as <25% lymphomatous involvement of the bone marrow. (111)In- and (90)Y-ibritumomab tiuxetan are labeled at commercial radiopharmacies and delivered for on-site dose preparation and administration. Plastic and acrylic materials are appropriate for shielding during dose preparation and administration; primary lead shielding should be avoided because of the potential exposure risk from bremsstrahlung. Because there are no penetrating gamma-emissions associated with the therapy, (90)Y-ibritumomab tiuxetan is routinely administered on an outpatient basis. Furthermore, the risk of radiation exposure to patients' family members has been shown to be in the range of background radiation, even without restrictions on contact. There is therefore no need to determine activity limits or dose rate limits before patients who have been treated with (90)Y radioimmunotherapy are released, as is necessary with patients who have been treated with radiopharmaceuticals that contain (131)I. Standard universal precautions for handling body fluids are recommended for health care workers and patients and their family members after (90)Y-ibritumomab tiuxetan administration. In summary, (90)Y-ibritumomab tiuxetan introduces (90)Y into clinical practice and expands the role nuclear medicine plays in the care of patients with cancer. Understanding the unique properties of this novel radioimmunoconjugate will facilitate its safe and effective use.

Antibodies, Monoclonal↗

PubMed2002

Comparison of radiolabeled nucleoside probes (FIAU, FHBG, and FHPG) for PET imaging of HSV1-tk gene expression.

UNLABELLED: The efficacy of 3 radiolabeled probes of current interest for imaging herpes simplex virus type 1 thymidine kinase (HSV1-tk) expression in vivo with PET, including (124)I- or (131)I-labeled 2'-fluoro-2'-deoxy-1-beta-D-arabinofuranosyl-5-iodouracil (FIAU), (18)F-labeled 9-[4-fluoro-3-(hydroxymethyl)butyl]guanine (FHBG), and (18)F-labeled 9-[3-fluoro-1-hydroxy-2-propoxymethyl]guanine (FHPG), was compared. METHODS: Two established rat glioma cell lines, stably transduced RG2TK+ and wild-type RG2, were used for paired comparisons of probe accumulation in vitro and for paired comparisons of subcutaneous xenografts produced from these cell lines in athymic rnu/rnu rats. RESULTS: The in vitro paired probe uptake (0-3 h) comparisons in RG2TK+ cells showed that FIAU accumulation was 15-fold greater than that of FHBG and 41-fold greater than that of FHPG. The net accumulation rate values (+/-SD) calculated for RG2TK+ cells were 0.317 +/- 0.066, 0.022 +/- 0.001, and 0.0077 +/- 0.0003 mL/min/g cells for FIAU, FHBG, and FHPG, respectively. These results and similar uptake studies in RG2 wild-type cells suggest a possible cell membrane transport limitation for FHBG and FHPG. The paired 2-h in vivo uptake studies produced similar differences in RG2TK+ xenografts for FIAU and FHBG (1.22 +/- 0.21 vs. 0.074 +/- 0.49 %dose/g) and for FIAU and FHPG (1.27 +/- 0.14 vs. 0.023 +/- 0.008 %dose/g). These differences were clearly visible on the images. FIAU accumulation at 24 h was 1.53 +/- 0.40 %dose/g. Plasma clearance was FHBG > FHPG >> FIAU. The FIAU images showed significant stomach and some intestinal background radioactivities, whereas hepatobiliary and intestinal background activities were very high for the guanosine analogs (FHBG > FHPG). Dynamic imaging showed early ( approximately 10 min) selective localization of FIAU in RG2TK+ xenografts, whereas FHBG and FHPG are being cleared from the HSV1-tk transduced and wild-type xenografts over the initial 2-h imaging period. CONCLUSION: The in vitro and in vivo results (including the PET images) show that FIAU is a substantially more efficient probe than FHBG or FHPG for imaging HSV1-tk expression, with greater sensitivity and contrast as well as lower levels of abdominal background radioactivity at 2 and 24 h.

Animals↗

PubMedDate not supplied

Longitudinal microPET imaging of brain tumor growth with F-18-labeled RGD peptide.

PURPOSE: EMD 121974, a potent cyclic RGD peptide inhibitor of alphav-integrins, demonstrated effectiveness in suppressing brain tumor growth in both preclinical models and phases I/II clinical trials. The ability to non-invasively evaluate alphav-integrin expression provides a novel and unique way to better understand brain tumor angiogenesis in relationship to alphav-integrin expression, and allow for direct assessment of anti-integrin treatment efficacy. PROCEDURES: We developed a F-18-labeled RGD peptide [F-18]FB-RGD and performed serial microPET imaging scans to follow brain tumor growth and angiogenesis as a function of time in an orthotopic U87MG glioblastoma xenograft model in athymic nude mice. RESULTS: The tumor was barely visible on microPET at the size of <or=1.5 mm diameter at which time no angiogenesis was evident on histological examination. When tumor started to grow exponentially by day 35 the activity accumulation in the brain tumor also increased accordingly, with best tumor-to-brain contrast seven weeks after inoculation of 10(5) U87MG cells into the mice forebrain. CONCLUSIONS: Longitudinal microPET imaging and [F-18]FB-RGD provides the sensitivity and resolution to visualize and quantify anatomical variations during brain tumor growth and angiogenesis, most likely through interaction with alphav-integrins expressed on tumor cells and angiogenic tumor vessels.

Animals↗

PubMedDate not supplied

2-deoxy-2-[F-18]fluoro-D-glucose-positron emission tomography/computed tomography imaging evaluation of esophageal cancer.

We evaluated the clinical utility of 2-deoxy-2-[F-18]fluoro-D-glucose (FDG)-positron emission tomography (PET)/computed tomography (CT) on the precise localization of pathologic foci and exclusion of normal variants in the imaging evaluation of patients with esophageal carcinoma. Combined PET/CT scans were performed in 60 patients (50 males, 10 females, age range 47-84 years) with history of esophageal carcinoma either at the time of initial diagnosis (group I, n=14) or for surveillance and/or detection of recurrent and metastatic disease (group II, n=46). Prior treatments included esophagectomy with gastric pull-up (n=23), surgery and chemotherapy (n=3), surgery and chemoradiation therapy (n=10), chemotherapy alone (n=5), radiation therapy alone (n=2), and chemoradiation without surgery (n=3). Diagnostic validation was by tissue sampling in three patients and clinical/radiological follow-up for up to 1.5 years in the remaining patients. In group I, discordant abnormalities were noted in seven patients. PET demonstrated hypermetabolism in normal-size lymph nodes on CT in three patients that were considered likely true positive in view of concurrent existence of other adjacent enlarged hypermetabolic lymph nodes in the same nodal basin. Hypometabolic incidental CT abnormalities of up to 1-cm lung nodules were noted in three patients and pleural effusion in one patient, which were considered true negative in view of no change on follow-up PET/CT studies. In group II, both PET and CT showed concordant abnormalities in 23 patients. The precise image fusion of hypermetabolism in a liver lesion allowed a diagnostic CT-guided biopsy in one patient. PET demonstrated true positive hypermetabolic abnormalities in four patients that localized to structures, which were normal by noncontrast CT criteria, and true negative in one patient with hepatic fatty deposits. PET showed decline in metabolic activity of the primary lesion in one patient after chemotherapy, while the corresponding CT abnormality remained unchanged. PET/CT image fusion provided relevant complementary diagnostic information in 14 patients with discordant findings (23% of total) that resulted in biopsy in three cases, institution of chemotherapy in four cases, and a wait-and-watch strategy in seven cases. In conclusion, our findings add to the current body of literature that suggests that FDG-PET/CT scanning may improve the imaging evaluation of patients with esophageal cancer by providing complementary structural-metabolic information. In particular, our findings support the notion that PET/CT may be the most appropriate imaging modality in the evaluation of patients of esophageal cancer that may impact patient management.

Aged↗

PubMedDate not supplied

2-Deoxy-2-[18F]fluoro-D-glucose-positron emission tomography and positron emission tomography/computed tomography diagnosis of patients with recurrent papillary thyroid cancer.

OBJECTIVE: 2-Deoxy-2-[F-18]fluoro-D-glucose positron emission tomography (FDG-PET) has an established role in restaging of various cancers, including papillary and undifferentiated thyroid carcinoma, but detection rates are variable in the published literature. We were therefore prompted to review our experience with FDG-PET in detection of recurrent papillary thyroid cancer (PTC). METHODS: This is a retrospective study (April 1, 1995-March 31, 2005) of 21 patients with histologic diagnosis of PTC who had PET examinations. The group included seven men and 14 women, with age range of 26-75 years (average 50 +/- 16). The PET scan request was triggered by rising levels of thyroglobulin (Tg) in the presence of a negative iodine-131 scan. RESULTS: Recurrent/metastatic disease was identified by PET in 16 (76%) of the 21 patients with PTC. The sensitivity and specificity of FDG-PET for disease detection in this cohort were 88.2% [95% confidence interval (CI), 65.7-96.7] and 75% (95% CI, 30.1-95.4), respectively. The Tg levels were 1.0-10.4 ng/ml (average, 4.52 ng/ml) in the patients with negative PET scans and 1.0-38 ng/ml (average, 16.8 ng/ml) in patients with positive scans. The lesions were located in the cervical lymph nodes (8), thyroid bed (4), lungs (4), and mediastinal lymph nodes (2). CONCLUSION: Our study confirms the feasibility of PET in detection of residual/recurrence of PTC, with sensitivity of 88.2% (95% CI, 65.7-96.7) and specificity of 75% (95% CI, 30.1-95.4). Detectable levels of Tg, even in the presence of negative I-131 scan or anatomic imaging, should prompt restaging with FDG-PET.

Adult↗

PubMedDate not supplied

Detection of occult medullary thyroid cancer recurrence with 2-deoxy-2-[F-18]fluoro-D-glucose-PET and PET/CT.

PURPOSE: 2-deoxy-2-[F-18]fluoro-D-glucose (FDG)-positron emission tomography (PET) has an established role in restaging of various cancers, including papillary and undifferentiated thyroid carcinoma. However, controversies exist regarding its ability to reliably assess recurrent medullary thyroid cancer (MTC). We were therefore prompted to review our experience with FDG-PET for detection of occult MTC. METHODS: This is a retrospective study (Apr 1, 1997-Mar 31, 2004) of 13 patients with histologic diagnosis of MTC, who had PET examinations. The group included six men and seven women, 15-62 years old (average: 48+/-13). The PET scan request was triggered by rising levels of calcitonin and negative anatomical imaging studies. RESULTS: Recurrent/metastatic disease was identified by PET in seven (54%) of the 13 patients. The lesions were located in superior mediastinum (4), cervical lymph nodes (3), thyroid bed (2), lung (1) and liver (1). The calcitonin levels ranged from 52 to 5,090 pg/ml (average: 1,996 pg/ml) in patients with negative PET scans and from 132 to 9,500 pg/ml (average: 3,757 pg/ml) in patients with positive studies. The sensitivity and specificity of FDG-PET for disease detection in this cohort were 85.7% (95% CI: 48.7-97.4) and 83.3% (95% CI: 43.6-96.9), respectively. CONCLUSION: Our findings suggest a significant role for FDG-PET in patients with suspected MTC recurrence, with sensitivity of 85.7% and specificity of 83.3% for disease detection. FDG-PET provides additional information in a significant fraction of cases (54%) and could be used for restaging of patients with MTC and elevated levels of biomarkers (calcitonin). Additional studies are necessary to further evaluate the role of FDG-PET in MTC.

Adolescent↗

PubMedDate not supplied

MicroPET imaging of breast cancer alphav-integrin expression with 64Cu-labeled dimeric RGD peptides.

PURPOSE: Alphavbeta3 and alphavbeta5 integrins are cell adhesion molecules that play a vital role in tumor angiogenesis and metastasis. The ability to visualize and quantify integrin expression in vivo will foster our understanding of the role of integrins alphavbeta3 and alphavbeta5 in tumor angiogenesis and allow for direct assessment of anti-angiogenic treatment efficacy based on integrin antagonists. This study compared the tumor targeting characteristics of two dimeric 64Cu-labeled RGD peptide agonists of alphavbeta3 integrin. PROCEDURES: Dimeric RGD peptides E[c(RGDyK)]2 and E[c(RGDfK)]2 were conjugated with 1,4,7,10-tetraazadodecane-N,N',N",N"'-tetraacetic acid (DOTA) and labeled with positron emitter 64Cu(t(1/2)=12.8 h, beta+=19%). Both 64Cu-DOTA-E[c(RGDyK)]2 and 64Cu-DOTA-E[c(RGDfK)]2 were used in biodistribution, microPET imaging and whole-body autoradiography studies in athymic female nude mice with orthotopically growing MDA-MB-435 breast carcinoma xenografts. RESULTS: At all time points, activity accumulation of 64)Cu-DOTA-E[c(RGDyK)]2 in tumors was significantly higher compared to the D-Phe analog. Liver uptake of the D-Tyr derivative was lower than the D-Phe derivative at early time points but the difference became marginal with time. Overall, 64Cu-DOTA-E[c(RGDyK)]2 yielded better position emission tomography (PET) images in orthotopic MDA-MB-435 bearing mice than did 64Cu-DOTA-E[c(RGDfK)]2. Both radiotracers had alphav-integrin specific tumor activity accumulation, as demonstrated by significant reduction of uptake with a coinjected blocking dose of c(RGDyK). CONCLUSIONS: The radiolabeled dimeric RGD peptides 64Cu-DOTA-E[c(RGDyK)]2 and 64Cu-DOTA-E[c(RGDfK)]2 have high and specific tumor uptake in a human breast cancer tumor xenograft, with the D-Tyr derivative showing better in vivo kinetics than the D-Phe derivative, most likely due to the increased hydrophilicity of the D-Tyr. Both dimeric peptides showed better tumor retention than the previously tested monomeric RGD counterparts, presumably because of bivalency and increase in apparent molecular size.

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PubMedDate not supplied

MicroPET and autoradiographic imaging of breast cancer alpha v-integrin expression using 18F- and 64Cu-labeled RGD peptide.

Cell adhesion molecules alphavbeta3 and alphavbeta5 play a pivotal role in tumor angiogenesis and metastasis. Antiangiogenic therapy by using small peptide antagonists of alphav-integrins slows tumor growth and prevents tumor spread. The ability to visualize and quantify integrin expression will enable selection of appropriate patients for clinical trials, following determination of treatment efficacy and development of new potent drugs. We have previously labeled cyclic RGD peptide c(RGDyK) with 125I and 18F and applied the radiotracers to both subcutaneous and orthotopic brain tumor models. Here we conjugated c(RGDyK) with 1,4,7,10-tetraaza-1,4,7,10-tetradodecane-N,N',N' ',N' "-tetraacetic acid (DOTA) and labeled the DOTA-RGD conjugate with 64Cu (t1/2) = 12.8 h, 19% beta+) in high radiochemical purity and specific activity. The tumor targeting ability and in vivo kinetics of 64Cu-DOTA-RGD was compared with [18F]FB-RGD and 125I-RGD in orthotopic MDA-MB-435 breast cancer model. All three radiotracers revealed fast blood clearance and high tumor-to-blood and tumor-to-muscle ratios. 125I-RGD had higher tumor uptake than the corresponding 18F and 64Cu analogues. [18F]FB-RGD indicated a fast tumor washout rate and an unfavorable hepatobiliary excretion pathway, resulting in significant activity accumulation in gallbladder and intestines. 64Cu-DOTA-RGD had prolonged tumor retention (1.44 +/- 0.09 %ID/g at 4 h postinjection) and persistent uptake in the liver. All three tracers revealed receptor specific tumor accumulation which were illustrated by effective blocking via coinjection with a blocking dose of c(RGDyK). Static microPET imaging and whole-body autoradiography showed strong contrast from the contralateral background. In conclusion, overall molecular charge and characteristics of radiolabels have profound effects on tumor accumulation and in vivo kinetics of radiolabeled RGD peptide. Further modification of the RGD peptide and optimization of the tracer for prolonged tumor uptake and improved in vivo kinetics are being explored.

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PubMedDate not supplied

Evaluation of 2'-deoxy-2'-flouro-5-methyl-1-beta-D-arabinofuranosyluracil as a potential gene imaging agent for HSV-tk expression in vivo.

2'-Deoxy-2'-flouro-5-methyl-1-beta-D-arabinofuranosyluracil (FMAU) has been evaluated in HT-29 cells as a potential positron emission tomography (PET) radiotracer for imaging HSV-tk gene expression in vivo. In vitro experiments demonstrate that the accumulation of [14C]-FMAU in HSV-tk-expressing cells is 2.4-fold (p < .02), 4.0-fold (p < .001), and 5.3-fold (p < .001) higher than the wild-type cells at 1, 3, and 5 hr, respectively. In vivo studies revealed that the tumor uptake in HSV-tk-expressing cells was 2.3-fold (p < .001), 3.0-fold (p < .001), and 5.5-fold (p < .001) higher than the control cells at 1, 2, and 5 hr, respectively. FMAU was found to be more sensitive compared to our earlier studies using 9-[(3-18F-fluoro-1-hydroxy-2-propoxy)methyl]-guanine ([18F]-FHPG) and 9-(4-[18F]-fluoro-3-hydroxy-methylbutyl)guanine ([18F]-FHBG) in the same cell lines, although, the specificity was less than FHBG. These results suggest that while FMAU labeled with PET isotopes may be useful for imaging HSV-tk-expressing tumors in vivo, multitracer studies across additional tumor models are necessary in order to identify an optimal PET radiotracer.

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