Search PubMed⌕ Search

Biomedical subjects

M E Phelps

Publications and source records attributed to M E Phelps.

At least 37 records · Page 2Linked to original sources
PubMed2001

Human pharmacokinetic and dosimetry studies of [(18)F]FHBG: a reporter probe for imaging herpes simplex virus type-1 thymidine kinase reporter gene expression.

UNLABELLED: 9-[4-[(18)F]fluoro-3-(hydroxymethyl)butyl]guanine ([(18)F]FHBG) has been used as a reporter probe to image expression of herpes simplex virus type-1 thymidine kinase (HSV1-tk) reporter gene in living animals. Our aim was to study the kinetics, biodistribution, stability, dosimetry, and safety of [(18)F]FHBG in healthy human volunteers, preparatory to imaging patients undergoing HSV1-tk gene therapy. METHODS: [(18)F]FHBG was synthesized with a specific activity of 37,000--444,000 GBq/mmol and a radiochemical purity > 99%. Ten healthy volunteers consented to participate in the study. A transmission scan was obtained before bolus injection of 70.3--229.4 MBq [(18)F]FHBG into a hand vein, followed by dynamic PET imaging with 4 consecutive emission scans. Warmed hand-vein blood was withdrawn at various times after injection for blood time--activity measurements. Electrocardiography, blood pressure, and blood and urine pharmacologic parameters were measured before and after injection of the [(18)F]FHBG tracer (n = 5). The stability of [(18)F]FHBG in the urine was analyzed. Attenuation-corrected images were reconstructed using the ordered-subsets expectation maximization algorithm. Image region-of-interest time-activity data were used with the MIRD program to estimate absorbed radiation dosages. RESULTS: [(18)F]FHBG had rapid blood clearance; only 8.42% +/- 4.76% (mean +/- SD) of the peak blood activity remained at approximately 30 min. The average ratio of plasma activity to whole-blood activity during the study was 0.91 +/- 0.04. Penetration of [(18)F]FHBG across the blood-brain barrier was not observed. The primary routes of clearance were renal and hepatobiliary. High activities were observed in the bladder, gut, liver, and kidneys, but <0.0002% of the injected dose per gram was observed in other tissues. In the urine, 83% of activity 180 min after injection was stable [(18)F]FHBG. Blood and urine pharmacologic parameters did not change significantly after injection of the [(18)F]FHBG tracer. The bladder absorbed the highest radiation dose. CONCLUSION: [(18)F]FHBG has the desirable in vivo characteristics of stability, rapid blood clearance, low background signal, biosafety, and acceptable radiation dosimetry in humans. This study forms the foundation for using [(18)F]FHBG in applications to monitor HSV1-tk reporter gene expression.

Adult↗
PubMed2001

Impact of whole-body 18F-FDG PET on staging and managing patients with breast cancer: the referring physician's perspective.

UNLABELLED: FDG PET has emerged as an important clinical imaging modality for diagnosing and staging cancer. However, the impact of FDG PET on staging and managing patients with breast cancer from the referring physician's point of view is unknown. METHODS: The referring physicians of 160 breast cancer patients received standardized questionnaires inquiring if and how PET findings altered their patient's stage and their clinical management decisions. Management changes were classified as intermodality if the change was from one modality to another (e.g., medical to surgical, surgical to radiation, medical to no treatment, and vice versa) or as intramodality if the change was within the same modality (e.g., altered medical or radiotherapy approach). RESULTS: Fifty of the 160 surveys were completed (31% response rate). PET changed the clinical stage in 36% of patients (28% upstaged, 8% downstaged) and resulted in intermodality changes in 28% of patients and intramodality changes in 30% of patients. CONCLUSION: The results of this prospective survey show that FDG PET has a major impact on the management of breast cancer patients, influencing both clinical stage and management in more than 30% of patients.

Adult↗
PubMed2000

PET imaging of transgene expression.

A vital step in transgenic animal study and gene therapy is the ability to assay the extent of transgene expression. Unfortunately, classic methods of assaying transgene expression require biopsies or death of the subject. We are developing techniques to noninvasively and repetitively determine the location, duration, and magnitude of transgene expression in living animals. This will allow investigators and clinicians to assay the effectiveness of their particular experimental and therapeutic paradigms. Of radionuclide (single photon emission computed tomography, positron emission tomography [PET]), optical (green fluorescent protein, luciferase), and magnetic (magnetic resonance imaging) approaches, only the radionuclide approach has sufficient sensitivity and quantitation to measure the expression of genes in vivo. We describe the instrumentation involved in high resolution PET scanning. We also describe the principles of PET reporter gene/reporter probe in vivo imaging, the development of two in vivo reporter gene imaging systems, and the validation of our ability to noninvasively, quantitatively, and repetitively image gene expression in murine viral gene transfer and transgenic models. We compare the two reporter gene systems and discuss their utility for the study of transgenic animals and gene therapies. Finally, we mention alternative approaches to image gene expression by using radiolabeled antibody fragments to image specific proteins and radiolabeled oligonucleotides to image RNA messages directly.

Animals↗
PubMed2000

Positron emission tomography provides molecular imaging of biological processes.

Diseases are biological processes, and molecular imaging with positron emission tomography (PET) is sensitive to and informative of these processes. This is illustrated by detection of biological abnormalities in neurological disorders with no computed tomography or MRI anatomic changes, as well as even before symptoms are expressed. PET whole body imaging in cancer provides the means to (i) identify early disease, (ii) differentiate benign from malignant lesions, (iii) examine all organs for metastases, and (iv) determine therapeutic effectiveness. Diagnostic accuracy of PET is 8-43% higher than conventional procedures and changes treatment in 20-40% of the patients, depending on the clinical question, in lung and colorectal cancers, melanoma, and lymphoma, with similar findings in breast, ovarian, head and neck, and renal cancers. A microPET scanner for mice, in concert with human PET systems, provides a novel technology for molecular imaging assays of metabolism and signal transduction to gene expression, from mice to patients: e.g., PET reporter gene assays are used to trace the location and temporal level of expression of therapeutic and endogenous genes. PET probes and drugs are being developed together-in low mass amounts, as molecular imaging probes to image the function of targets without disturbing them, and in mass amounts to modify the target's function as a drug. Molecular imaging by PET, optical technologies, magnetic resonance imaging, single photon emission tomography, and other technologies are assisting in moving research findings from in vitro biology to in vivo integrative mammalian biology of disease.

Alzheimer Disease↗
PubMed2000

High-resolution microPET imaging of carcinoembryonic antigen-positive xenografts by using a copper-64-labeled engineered antibody fragment.

Rapid imaging by antitumor antibodies has been limited by the prolonged targeting kinetics and clearance of labeled whole antibodies. Genetically engineered fragments with rapid access and high retention in tumor tissue combined with rapid blood clearance are suitable for labeling with short-lived radionuclides, including positron-emitting isotopes for positron-emission tomography (PET). An engineered fragment was developed from the high-affinity anticarcinoembryonic antigen (CEA) monoclonal antibody T84.66. This single-chain variable fragment (Fv)-C(H)3, or minibody, was produced as a bivalent 80 kDa dimer. The macrocyclic chelating agent 1,4,7, 10-tetraazacyclododecane-N,N',N", N"'-tetraacetic acid (DOTA) was conjugated to the anti-CEA minibody for labeling with copper-64, a positron-emitting radionuclide (t(1/2) = 12.7 h). In vivo distribution was evaluated in athymic mice bearing paired LS174T human colon carcinoma (CEA positive) and C6 rat glioma (CEA negative) xenografts. Five hours after injection with (64)Cu-DOTA-minibody, microPET imaging showed high uptake in CEA-positive tumor (17.9% injected dose per gram +/- 3.79) compared with control tumor (6.0% injected dose per gram +/- 1.0). In addition, significant uptake was seen in liver, with low uptake in other tissues. Average target/background ratios relative to neighboring tissue were 3-4:1. Engineered antibody fragments labeled with positron-emitting isotopes such as copper-64 provide a new class of agents for PET imaging of tumors.

Animals↗
PubMed2000

Cerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer's disease.

The major known genetic risk for Alzheimer's disease (AD), apolipoprotein E-4 (APOE-4), is associated with lowered parietal, temporal, and posterior cingulate cerebral glucose metabolism in patients with a clinical diagnosis of AD. To determine cognitive and metabolic decline patterns according to genetic risk, we investigated cerebral metabolic rates by using positron emission tomography in middle-aged and older nondemented persons with normal memory performance. A single copy of the APOE-4 allele was associated with lowered inferior parietal, lateral temporal, and posterior cingulate metabolism, which predicted cognitive decline after 2 years of longitudinal follow-up. For the 20 nondemented subjects followed longitudinally, memory performance scores did not decline significantly, but cortical metabolic rates did. In APOE-4 carriers, a 4% left posterior cingulate metabolic decline was observed, and inferior parietal and lateral temporal regions demonstrated the greatest magnitude (5%) of metabolic decline after 2 years. These results indicate that the combination of cerebral metabolic rates and genetic risk factors provides a means for preclinical AD detection that will assist in response monitoring during experimental treatments.

Aged↗
PubMed2000

Dynamic changes in cerebral glucose metabolism in conscious infant monkeys during the first year of life as measured by positron emission tomography.

Recently, advances in spatial resolution have provided the opportunity to utilize positron emission tomography (PET) to examine local cerebral metabolic rates for glucose (lCMR(glc)) in large animals noninvasively, thereby allowing repeated lCMR(glc) measurements in the same animal. Previous studies have attempted to describe the ontogeny of cerebral glucose metabolism in anesthetized nonhuman primates using [18F]fluorodeoxyglucose (FDG) and PET. However, the use of sedation during the tracer uptake period may influence lCMR(glc). This study was conducted to describe lCMR(glc) in conscious infant vervet monkeys (Cercopithecus aethiops sabaeus) during the first year of life utilizing FDG-PET. Cross-sectional studies (n=23) displayed lowest and highest lCMR(glc) in all structures at the 2-3 and 8-9 month age groups, respectively. The metabolic pattern suggested an increase in lCMR(glc) values between 2 and 8 months of age with decreased metabolism observed at 10-12 months of age in all regions. Peak lCMR(glc) values at 8 months were an average of 84+/-24% higher than values seen at the youngest age examined quantitatively (2-3 months). The regions of greatest and smallest increases in lCMR(glc) at 8 months were the cerebellar hemispheres (90%) and the thalamus (39%), respectively. Longitudinal analysis in 4 animals supported this developmental pattern, demonstrating the ability to detect changes in cerebral glucose metabolism within animals and the potential for FDG-PET in nonhuman primate models of brain maturation. By determining the normative profile of lCMR(glc) during development in monkeys, future application of FDG-PET will provide the opportunity to longitudinally assess the effects of environmental or pharmacological intervention on the immature brain.

Aging↗
PubMed2000

Seeing is believing: non-invasive, quantitative and repetitive imaging of reporter gene expression in living animals, using positron emission tomography.

The ability to monitor reporter gene expression in living animals and in patients will permit longitudinal examinations both of somatically transferred DNA in experimental animals and patients and of transgenic constructs expressed in experimental animals. If investigators can non-invasively monitor the organ and tissue specificity, the magnitude and the duration of gene expression from somatically transferred DNA and from transgenes, conceptually new experimental paradigms will be possible. If clinicians can non-invasively monitor the location, extent and duration of somatically transferred genes, they will be better able to determine the correlations between expression of therapeutic genes and clinical outcomes. We have developed two reporter gene systems for in vivo reporter gene imaging in which the protein products of the reporter genes sequester positron-emitting reporter probes. The "PET reporter gene" dependent sequestration of the "PET reporter probes" is subsequently measured in living animals by Positron Emission Tomography (PET). We describe here the principles of PET reporter gene/PET reporter probe in vivo imaging, the development of two imaging systems, and the validation of their ability to non-invasively, quantitatively and repetitively image reporter gene expression in murine viral gene transfer and transgenic models.

Animals↗
PubMed2000

Long-term methamphetamine-induced decreases of [(11)C]WIN 35,428 binding in striatum are reduced by GDNF: PET studies in the vervet monkey.

The effects of glial cell line-derived neurotrophic factor (GDNF) pretreatment on methamphetamine (METH)-induced striatal dopamine system deficits in the vervet monkey were characterized with [(11)C]WIN 35,428 (WIN)-positron emission tomography (PET). WIN, a cocaine analog that binds to the dopamine transporter (DAT), was used to provide an index of striatal dopamine terminal integrity. In two subjects, GDNF (200 microg/40 microl) was injected into the caudate and putamen unilaterally vs. saline contralaterally. After 1-2 weeks, + and -GDNF striatal WIN-PET binding values were equivalent as calculated by multiple time graphic analysis, suggestive of an absence of unilateral DAT up-regulation. Three other subjects (n = 3) received GDNF injections into the caudate and putamen unilaterally and one week later, were administered METH HCl (2 x 2 mg/kg; i.m., 24 hours apart; a neurotoxic dosage for this species). At 1 week post-METH, WIN-PET studies showed that mean WIN binding was decreased by 72% in the +GDNF and by 92% in the -GDNF striatum relative to pre-drug assessment values. Thus, GDNF pretreatment reduced the extent of METH-induced decreases in WIN binding. Subsequent WIN-PET studies (1.5-9-month range) showed a protracted recovery of WIN binding in each striatum, indicative of long-term but partially reversible METH neurotoxicity. Further, at each time point, WIN binding remained relatively higher in the +GDNF vs. -GDNF striatum. These results provide further evidence that the adult non-human primate brain remains responsive to exogenously administered GDNF and that this pharmacotherapy approach can counteract aspects of neurotoxic actions associated with methamphetamine.

Animals↗
PubMed2000

A mutant herpes simplex virus type 1 thymidine kinase reporter gene shows improved sensitivity for imaging reporter gene expression with positron emission tomography.

We are developing assays for noninvasive, quantitative imaging of reporter genes with positron emission tomography (PET), for application both in animal models and in human gene therapy. We report here a method to improve the detection of lower levels of PET reporter gene expression by utilizing a mutant herpes simplex virus type 1 thymidine kinase (HSV1-sr39tk) as a PET reporter gene. The HSV1-sr39tk mutant was identified from a library of site-directed mutants. Accumulation (net uptake) of the radioactively labeled substrates [8-(3)H]penciclovir ([8-(3)H]PCV), and 8-[(18)F]fluoropenciclovir (FPCV) in C6 rat glioma cells expressing HSV1-sr39tk is increased by a factor of approximately 2.0 when compared with C6 cells expressing wild-type HSV1-tk. The increased imaging sensitivity of HSV1-sr39tk when FPCV is used is also demonstrated in vivo both with tumor cells stably transfected with either HSV1-tk or HSV1-sr39tk, and after hepatic delivery of HSV1-tk or HSV1-sr39tk by using adenoviral vectors. The use of HSV1-sr39tk as a PET reporter gene and FPCV as a PET reporter probe results in significantly enhanced sensitivity for imaging reporter gene expression in vivo.

Acyclovir↗
PubMed2000

Synthesis of 8-[(18)F]fluoroguanine derivatives: in vivo probes for imaging gene expression with positron emission tomography.

A new method for the preparation of 8-[(18)F]fluoroguanine derivatives based on a direct radiofluorination reaction has been developed. The radiofluorination of ganciclovir (1a) with [(18)F]F(2) was carried out in absolute ethanol in the presence of tetraethylammonium hydroxide at room temperature to give 8-[(18)F]fluoroganciclovir (3a) in an approximately 1% radiochemical yield. Similarly, 8-[(18)F]fluoropenciclovir (3b), 8-[(18)F]fluoroacyclovir (3c), and 8-[(18)F]fluoroguanosine (3d) were synthesized from penciclovir (1b), acyclovir (1c), and guanosine (1d), respectively, using [(18)F]F(2). The structural analyses of the final products (3a, 3b, 3c, and 3d) were carried out after (18)F decay by (1)H, (13)C, and (19)F nuclear magnetic resonance and high resolution mass spectroscopy.

Acyclovir↗
PubMed2000

In vivo imaging of neuronal activation and plasticity in the rat brain by high resolution positron emission tomography (microPET).

The study of neural repair and neuroplasticity in rodents would be enhanced by the ability to assess neuronal function in vivo. Positron emission tomography (PET) is used to study brain plasticity in humans, but the limited resolution and sensitivity of conventional scanners have generally precluded the use of PET to study neuroplasticity in rodents. We now demonstrate that microPET, a PET scanner developed for use with small animals, can be used to assess metabolic activity in different regions of the conscious rodent brain using [18F]fluorodeoxyglucose (FDG) as the tracer, and to monitor changes in neuronal activity. Limbic seizures result in dramatically elevated metabolic activity in the hippocampus, whereas vibrissal stimulation results in more modest increases in FDG uptake in the contralateral neocortex. We also show that microPET can be used to study lesion-induced plasticity of the brain. Cerebral hemidecortication resulted in diminished relative glucose metabolism in the neostriatum and thalamus ipsilateral to the lesion, with subsequent, significant recovery of metabolic function. These studies demonstrate that microPET can be used for serial assessment of metabolic function of individual, awake rats with a minimal degree of invasiveness, and therefore, has the potential for use in the study of brain disorders and repair.

Age Factors↗
PubMed2000

Nigrostriatal reduction of aromatic L-amino acid decarboxylase activity in MPTP-treated squirrel monkeys: in vivo and in vitro investigations.

Aromatic L-amino acid decarboxylase (AAAD) activity was examined in vivo with positron emission tomography (PET) using 6-[18F]fluoro-L-DOPA (FDOPA) in squirrel monkeys lesioned with graded doses of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In vitro biochemical determinations of AAAD activity in caudate, putamen, substantia nigra, and nucleus accumbens were performed in the same animals to establish a direct comparison of in vivo and in vitro measurements. In vivo and in vitro AAAD activities in caudate/ putamen were substantially reduced in animals treated with the highest dose of MPTP (2.0 mg/kg). The percent change in the striatal FDOPA uptake (K(i)) and decarboxylation rate constant (k3) values resulting from MPTP treatment showed highly significant correlations with in vitro-determined AAAD activities. However, decarboxylase rates within individual animals presented as approximately 10-fold difference between in vivo and in vitro values. Lower in vivo k3 measurements may be attributed to several possibilities, including transport restrictions limiting substrate availability to AAAD within the neuron. In addition, reductions in AAAD activity in the substantia nigra did not parallel reductions in AAAD activity within the striatum, supporting the notion of a nonlinear relationship between nigrostriatal cell degeneration and terminal losses. This work further explores the role of AAAD in Parkinson's disease, a more important factor than previously thought.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2000

Dissociation of cerebral glucose metabolism and level of consciousness during the period of metabolic depression following human traumatic brain injury.

Utilizing [18F]fluorodeoxyglucose positron emission tomography (FDG-PET), we studied the correlation between CMRglc and the level of consciousness within the first month following human traumatic brain injury. Forty-three FDG-PET scans obtained on 42 mild to severely head-injured patients were quantitatively analyzed for the determination of regional cerebral metabolic rate of glucose (CMRglc). Reduction of cerebral glucose utilization, defined as a CMRglc of < or =4.9 mg/100 g/min, was present regionally in 88% of the studies. The prevalence of global cortical CMRglc reduction was higher in severely head-injured patients (86% versus 67% mild-moderate), although the absolute magnitude was similar across the injury severity spectrum (mean CMRglc 3.9 +/- 0.6 mg/100 g/min). The level of consciousness, as measured by the Glasgow Coma Scale, correlated poorly with the global cortical CMRglc value (r = 0.08; p = 0.63). With regards to severity of head injury, this correlation was worst for the severely injured (r = -0.11; p = 0.58) and better for the mildly injured patients (r = 0.50; p = 0.07). In most cases, intraparenchymal hemorrhagic lesions were associated with either focal CMRglc reduction or elevation. It is concluded that the etiologies of CMRglc reduction are likely multifactorial given the complex nature of traumatic brain injury and that the reduction of CMRglc represents a fundamental pathobiologic state following head injury that is not tightly coupled to level of consciousness.

Adult↗
PubMed2000

Striatal kinetic modeling of FDOPA with a cerebellar-derived constraint on the distribution of volume of 30MFD: a PET investigation using non-human primates.

The peripherally born metabolite of FDOPA, 3-O-Methyl-FDOPA (3OMFD), crosses the blood-brain barrier, thus complicating positron emission tomography-FDOPA (PET-FDOPA) data analysis. In previous reports the distribution volume (DV) of 3OMFD was constrained to unity. We have recently shown that the forward transport rate-constant of FDOPA (K(S1)) and the cerebellum-to-plasma ratio (C(b)/C(p)), a measure for the DV of 3OMFD, are functions of plasma large neutral amino acid (LNAA) concentration. Given large interstudy and intersubject differences in plasma LNAA levels, variations in the DV of 3OMFD are significant. In this report, the authors propose a constraint on the DV of 3OMFD that accounts for these variations. Dynamic PET-FDOPA scans were performed on 12 squirrel monkeys and 12 vervet monkeys. Two sets of constraints were employed on the compartmental model--M1 or M2. In M1, the striatal DV of 3OMFD was constrained to unity; in M2, the striatal DV of 3OMFD was constrained to an estimate derived from the cerebellum. Striatal and cerebellar time-activity curves were fitted using FDOPA and 3OMFD plasma input functions. The estimate of K(S1) and that of the compartmental FDOPA uptake-constant (K(i)), both obtained using M2, were adjusted to values corresponding to average LNAA levels. Finally, K(i) was compared with the graphical uptake-constant (PK(j)). With the use of constraint M2, intersubject variability of squirrel monkey k(S3) and K(i) was reduced by 45% and 53%, respectively; and for vervet monkeys, by 54% and 44%, respectively. Intersubject variability of K(1) and K(i) was further reduced after correction for variations in intersubject plasma LNAA levels (for squirrel monkeys, by 67% and 41%; for vervet monkeys, by 40% and 36%, respectively). K(i) correlation to PK(i) was enhanced to identity. Finally, average cerebellar k(C2) estimates were more than 2.5-fold higher than striatal k(S2) estimates (P < 0.0001). In modeling of PET-FDOPA data, it cannot be assumed that the DV of 3OMFD is unity. The cerebellar-derived constraint furnishes a reliable estimate for the DV of 3OMFD. Invoking the constraint and correcting for variations in plasma LNAA significantly reduced interstudy and intersubject variations in parameter estimates.

Animals↗
PubMed2000

Regulation of myocardial blood flow response to mental stress in healthy individuals.

Mental stress testing has been proposed as a noninvasive tool to evaluate endothelium-dependent coronary vasomotion. In patients with coronary artery disease, mental stress can induce myocardial ischemia. However, even the determinants of the physiological myocardial blood flow (MBF) response to mental stress are poorly understood. Twenty-four individuals (12 males/12 females, mean age 49 +/- 13 yr, range 31-74 yr) with a low likelihood for coronary artery disease were studied. Serum catecholamines, cardiac work, and MBF (measured quantitatively with N-13 ammonia and positron emission tomography) were assessed. During mental stress (arithmetic calculation) MBF increased significantly from 0.70 +/- 0.14 to 0.92 +/- 0.21 ml x min(-1) x g(-1) (P < 0.01). Mental stress caused significant increases (P < 0.01) in serum epinephrine (26 +/- 16 vs. 42 +/- 17 pg/ml), norepinephrine (272 +/- 139 vs. 322 +/- 136 pg/ml), and cardiac work [rate-pressure product (RPP) 8,011 +/- 1,884 vs. 10,416 +/- 2,711]. Stress-induced changes in cardiac work were correlated with changes in MBF (r = 0.72; P < 0.01). Multiple-regression analysis revealed stress-induced changes in the RPP as the only significant (P = 0.0001) predictor for the magnitude of mental stress-induced increases in MBF in healthy individuals. Data from this group of healthy individuals should prove useful to investigate coronary vasomotion in individuals at risk for or with documented coronary artery disease.

Adult↗