Henry F. VanBrocklin

6-[18F]Fluoro-l-m-tyrosine: metabolism, positron emission tomography kinetics, and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine lesions in primates

The tracer 6-[18F]fluoro-L-m-tyrosine (FMT) was studied with regard to its biochemistry and kinetics, as well as its utility in evaluating brain dopaminergic function in primates before and after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment using positron emission tomography (PET). Plasma analysis of FMT and its F18-labeled metabolites 6-fluoro-3-hydroxyphenylacetic acid (FPAC) and 6-fluoro-3-hydroxyphenylethylamine (FMA) during PET scanning enabled kinetic analysis of FMT uptake. A separate study examined brain FMT metabolism in MPTP-naive monkeys euthanized 60 or 120 min after FMT injection. Almost 60% of total plasma F-18 activity was associated with FPAC and FMA 120 min after FMT injection. The FMT signal accumulated preferentially in dopaminergic areas such as caudate and putamen. This bilateral FMT signal was disrupted after unilateral intracarotid artery (ICA) MPTP infusion which reduced ipsilateral striatal activity. A three compartment three kinetic rate constant model for FMT uptake revealed reduced FMT decarboxylation (k3) in ipsilateral caudate and putamen after unilateral MPTP although a further decrease was not evident after intravenous MPTP. FPAC was the major F-18 species in all brain regions except in cerebellum where FMT was predominant 60 min post-mortem. FPAC was most concentrated in dopaminergic areas whereas lower levels occurred in areas containing few dopamine terminals. These data demonstrate preferential FMT metabolism and F-18 retention in dopaminergic tissue and support the use of FMT to evaluate normal and abnormal dopaminergic function.

A novel MPTP primate model of Parkinson's disease: neurochemical and clinical changes

Positron emission tomography (PET) and the dopamine (DA) metabolism tracer, [18F]6-fluoro-L-m-tyrosine (FMT) were used to evaluate the relationship between DA metabolism and the clinical stage of parkinsonism monkeys following either unilateral ICA MPTP infusion or unilateral ICA MPTP infusion and subsequent varying sequential systemic doses of MPTP. Clinical stage corresponded to PET measures of striatal DA metabolism, showing the usefulness of the overlesioned hemiparkinsonian monkey as a stable model of various stages of Parkinsons disease (PD).

Assessment of cancer-associated biomarkers by positron emission tomography: Advances and challenges

Positron emission tomography (PET) provides a powerful means to non-invasively image and quantify protein expression and biochemical changes in living subjects at nano- and picomolar levels. As the field of molecular imaging develops, and as advances in the biochemistry, pharmacology, therapeutics, and molecular biology of disease are made, there is a corresponding increase in the number of clinically relevant, novel disease-associated biomarkers that are brought to the attention of those developing imaging probes for PET. In addition, due to the high specificity of the PET radiotracers being developed, there is a demand for PET cameras with higher sensitivity and resolution. This manuscript reviews advances over the past five years in clinical and pre-clinical PET instrumentation and in new PET probes and imaging methods associated with the latest trends in the molecular imaging of cancer. Included in the PET tracer review is a description of new radioligands for steroid receptors, growth factor receptors, receptor tyrosine kinases, sigma receptors, tumor-associated enzymes, gene reporter probes, markers for tumor hypoxia and metabolism, and sites associated with angiogenesis and cellular proliferation. The use of PET imaging in drug development, including the monitoring of cancer chemotherapy, also is discussed.

BEARS: radioactive ion beams at Berkeley

A light-isotope radioactive ion-beam capability has been added to the 88-in. Cyclotron at Lawrence Berkeley National Laboratory by coupling to the production cyclotron of the Berkeley Isotope Facility. The connection required the development and construction of a 350 m gas transport system between the two accelerators as well as automated cryogenic separation of the produced activity. The rst beam developed, 11C, has been successfully accelerated with an on-target intensity of 1]108 ions/s at energies of around 10 MeV/u. ( 2000 Elsevier Science B.V. All rights reserved.

Synthesis of 4-(3′-[125I]iodoanilino)-6,7-dialkoxyquinazolines: radiolabeled epidermal growth factor receptor tyrosine kinase inhibitors

The preparation of two radioiodinated analogs of the epidermal growth factor receptor tyrosine kinase (EGFrTK) inhibitor PD153035 (4-(3-bromoanilino)-6,7-dimethoxyquinazoline) are reported herein. The two analogs, 4-(3-[ 125 I]iodoanilino)-6,7-dimethoxyquinazoline and 4-(3-[ 125 I]iodoanilino)-6,7-diethoxyquinazoline, were synthesized via iododestannylation of the corresponding 4-(3-trimethylstannylanilino)-6,7-dialkoxyquinazolines to form the desired 1-125 labeled products in good yield, high radiochemical purity (>99%) and high specific activity.

Synthesis of 3H labeled dihydrorotenone

The catalytic tritiation of rotenone results in the preparation of two products, the expected tritiated 6′,7′-dihydrorotenone ([3H]DHR) and tritiated 6′,7′-dihydrorotenol ([3H]DHR-ol). The ratio of [3H]DHR to [3H]DHR-ol is 9 to 1. Reversed-phase HPLC provided the purified [3H]DHR and [3H]DHR-ol with estimated specific activities of 45 and 60 Ci/mmol, respectively.

High Pressure H2 18O Target for the Production of [18F]Fluoride Ion

Positron emission tomography (PET) plays an important role in clinical research as well as an ever increasing role in the diagnosis and staging of several disease states. The expansion of PET will demand the production of greater quantities of short-lived radiopharmaceuticals and thus the need for increased isotope production. In order to meet the supply needs of the PET community, new methods must be developed to economically achieve the required quantities of short-lived isotopes using the current in-house isotope production equipment (cyclotrons, accelerators) or low cost, low energy accelerators.

BEARS: A radioactive ion beam initiative at LBNL

BEARS is an initiative to develop a radioactive ion-beam capability at Lawrence Berkeley National Laboratory. The aim is to produce isotopes at an existing medical cyclotron and to accelerate them at the 88″ Cyclotron. To overcome the 300-meter physical separation of these two accelerators, a carrier-gas transport system will be used. At the terminus of the capillary, the carrier gas will be separated and the isotopes will be injected into the 88″ Cyclotron’s Advanced Electron Cyclotron Resonance ion source. The first radioactive beams to be developed will include 20-min 11C and 70-sec 14O, produced by (p, n) and (p, α) reactions on low-Z targets. Tests at the 88″ Cyclotron lead to projections of initial 11C beams of 2×108u200aions/sec 14O beams of 1×106u200aions/sec. Construction of BEARS is expected to be completed in the spring of 1999.

Preparation of fluorine-18 gas from an 11 MeV cyclotron: a target system for the CTI RDS 111 cyclotron

Abstract A fully operational 18 F -fluorine gas production system for the CTI model RDS 111 cyclotron turret target system is presented. The system design and merger with the existing CTI model RDS 112-style fluorine system and experiments toward the optimization of production parameters will be included.

BEARS: Radioactive ion beams at LBNL

BEARS (Berkeley Experiments with Accelerated Radioactive Species) is an initiative to develop a radioactive ion-beam capability at Lawrence Berkeley National Laboratory. The aim is to produce isotopes at an existing medical cyclotron and to accelerate them at the 88 inch Cyclotron. To overcome the 300-meter physical separation of these two accelerators, a carrier-gas transport system will be used. At the terminus of the capillary, the carrier gas will be separated and the isotopes will be injected into the 88 inch Cyclotron`s Electron Cyclotron Resonance (ECR) ion source. The first radioactive beams to be developed will include 20-min {sup 11}C and 70-sec {sup 14}O, produced by (p,n) and (p,{alpha}) reactions on low-Z targets. A test program is currently being conducted at the 88 inch Cyclotron to develop the parts of the BEARS system. Preliminary results of these tests lead to projections of initial {sup 11}C beams of up to 2.5 {times} 10{sup 7} ions/sec and {sup 14}O beams of 3 {times} 10{sup 5} ions/sec.