Although 18 F-labeled NaF was the first widely used agent for skeletal scintigraphy, it quickly fell into disuse after the introduction of 99m Tc-labeled bone-imaging agents. Recent comparative studies have demonstrated that 18 F-fluoride PET is more accurate than 99m Tc-diphosphonate SPECT for identifying both malignant and benign lesions of the skeleton. Combining 18 Ffluoride PET with other imaging, such as CT, can improve the specificity and overall accuracy of skeletal 18 F-fluoride PET and probably will become the routine clinical practice for 18 Ffluoride PET. Although 18 F-labeled NaF and 99m Tc-diphosphonate have a similar patient dosimetry, 18 F-fluoride PET offers shorter study times (typically less than 1 h), resulting in a more efficient workflow, improved patient convenience, and faster turnarounds of reports to the referring physicians. With the widespread availability of PET scanners and the improved logistics for the delivery of 18 Several decades before the introduction of modern PET systems, 18 F-labeled NaF was recognized as an excellent radiopharmaceutical for skeletal imaging (1). 18 F-Fluoride has the desirable characteristics of high and rapid bone uptake accompanied by very rapid blood clearance, which results in a high bone-to-background ratio in a short time. High-quality images of the skeleton can be obtained less than an hour after the intravenous administration of 18 Flabeled NaF. 18 F-labeled NaF became widely used for skeletal scintigraphy after its introduction by Blau and others in the early 1960s (2) and was approved for clinical use by the U.S. Food and Drug Administration in 1972. One limitation of 18 F-fluoride scintigraphy was the relatively high energy of the 511-keV annihilation photons produced by decay of 18 F. This high energy necessitated imaging with rectilinear scanners equipped with relatively thick NaI(Tl) crystals and precluded the use of Anger-type g-cameras. This technical limitation, combined with the widespread availability of 99 Mo/ 99m Tc generators, encouraged the development of 99m Tc-labeled bone agents.In the early 1970s, 99m Tc-labeled polyphosphates and then 99m Tc-labeled pyrophosphate were introduced as bone-imaging agents. With readily available 99m Tc, bone scintigraphy quickly became one of the most commonly performed nuclear medicine imaging procedures (3). When it became apparent that pyrophosphate impurities or degradation products were responsible for most of the bone-imaging properties of 99m Tc-labeled polyphosphates, 99m Tc-polyphosphates were abandoned in favor of 99m Tcpyrophosphate (4). However, skeletal imaging with 99m Tcpyrophosphate was limited by prolonged clearance from the circulation. During this same period, 99m Tc-labeled diphosphonates were introduced for skeletal scintigraphy. These compounds demonstrated higher skeletal uptake, faster blood-pool clearance, and better in vivo stability than did either polyphosphates or pyrophosphate. With the successful development of kit-based 99m Tc-diphosphonate radiopharmaceuticals and ...

Tissues with high metabolic rates often use lipid as well as glucose for energy, conferring a survival advantage during feast and famine.1 Current dogma suggests that high-energy consuming photoreceptors depend on glucose.2,3 Here we show that retina also uses fatty acids (FA) β-oxidation for energy. Moreover, we identify a lipid sensor Ffar1 that curbs glucose uptake when FA are available. Very low-density lipoprotein receptor (VLDLR), expressed in tissues with a high metabolic rate, facilitates the uptake of triglyceride-derived FA.4,5 Vldlr is present in photoreceptors.6 In Vldlr−/− retinas, Ffar1, sensing high circulating lipid levels despite decreased FA uptake5, suppresses glucose transporter Glut1. This impaired glucose entry into photoreceptors results in a dual lipid/glucose fuel shortage and reduction in the Krebs cycle intermediate α-ketoglutarate (KG). Low α-KG levels promote hypoxia-induced factor-1α (Hif1a) stabilization and vascular endothelial growth factor (Vegfa) secretion by starved Vldlr−/− photoreceptors, attracting neovessels to supply fuel. These aberrant vessels invading normally avascular photoreceptors in Vldlr−/− retinas are reminiscent of retinal angiomatous proliferation (RAP), a subset of neovascular age-related macular degeneration (AMD)7, associated with high vitreous VEGF levels in humans. Dysregulated lipid and glucose photoreceptor energy metabolism may therefore be a driving force in neovascular AMD and other retinal diseases.

Nuclear medicine is composed of two complementary areas, imaging and therapy. Positron emission tomography (PET) and single-photon imaging, including single-photon emission computed tomography (SPECT), comprise the imaging component of nuclear medicine. These areas are distinct in that they exploit different nuclear decay processes and also different imaging technologies. In PET, images are created from the 511 keV photons produced when the positron emitted by a radionuclide encounters an electron and is annihilated. In contrast, in single-photon imaging, images are created from the γ rays (and occasionally X-rays) directly emitted by the nucleus. Therapeutic nuclear medicine uses particulate radiation such as Auger or conversion electrons or β − or α particles. All three of these technologies are linked by the requirement that the radionuclide must be attached to a suitable vector that can deliver it to its target. It is imperative that the radionuclide remain attached to the vector before it is delivered to its target as well as after it reaches its target or else the resulting image (or therapeutic outcome) will not reflect the biological process of interest. Radiochemistry is at the core of this process, and radiometals offer radiopharmaceutical chemists a tremendous range of options with which to accomplish these goals. They also offer a wide range of options in terms of radionuclide half-lives and emission properties, providing the ability to carefully match the decay properties with the desired outcome. This Review provides an overview of some of the ways this can be accomplished as well as several historical examples of some of the limitations of earlier metalloradiopharmaceuticals and the ways that new technologies, primarily related to radionuclide production, have provided solutions to these problems.