Experiment assessment of mass effects in the rat: implications for small animal PET imaging

Abstract

In vivo imaging using positron emission tomography (PET) is important in the development of new radiopharmaceuticals in rodent animal models for use as biochemical probes, diagnostic agents, or in drug development. We have shown mathematically that, if small animal imaging studies in rodents are to have the same "quality" as human PET studies, the same number of coincidence events must be detected from a typical rodent imaging "voxel" as from the human imaging voxel. To achieve this using the same specifi activity preparation, we show that roughly the same total amount of radiopharmaceutical must be given to a rodent as to a human subject. At high specifi activities, the mass associated with human doses, when administered to a rodent, may not decrease the uptake of radioactivity at non saturable sites or sites where an enzyme has a high capacity for a substrate. However, in the case of binding sites of low density such as receptors, the increased mass injected could saturate the receptor and lead to physiologic effects and non-linear kinetics. Because of the importance of the mass injected for small animal PET imaging, we experimentally compared high and low mass preparations using ex vivo biodistribution and phosphorimaging of three compounds: 2-fluoro-2-deoxyglucos (FDG), 6-fluoro-L-metatyrosin (FMT) and one receptor-directed compound, the serotonin 5HT 1A receptor ligand, trans-4-fluoro-N-{2-[4-(2-methoxylphenyl piperazino]ethyl}-N-(2-pyridyl) cyclohexane-carboxamide (FCWAY). Changes in the mass injected per rat did not affect the distribution of FDG, FMT, and FCWAY in the range of 0.6 -1.9 nmol per rat. Changes in the target to nontarget ratio were observed for injected masses of FCWAY in the range of ϳ5-50 nmol per rat. If the specifi activity of such compounds and/or the sensitivity of small animal scanners are not increased relative to human studies, small animal PET imaging will not correctly portray the "true" tracer distribution. These difficultie will only be exacerbated in animals smaller than the rat, e.g., mice.

Hepatic arterial infusion enhances DOTATOC radiopeptide therapy in patients with neuroendocrine liver metastases

“…It has been previously observed that tumor uptake of DOTATOC is influenced by the total amount of administered peptide which depends on receptor occupancy (de Jong et al 1999, Müller et al 2007. Such mass effects are often more relevant in receptor targeted drugs compared with metabolized drugs (Jagoda et al 2004). Unfortunately, the risk of receptor saturation increases when the agent is delivered directly into the arterial supply of the tumor.…”

Augmented Acquisition of Cocaine Self-Administration and Altered Brain Glucose Metabolism in Adult Female but not Male Rats Exposed to a Cannabinoid Agonist during Adolescence

“…Tomographic images were reconstructed using a 3D subset expectation maximization algorithm (3D-OSEM) (20 iterations, 5 subsets), which results in a spatial resolution of 1.65 mm full-width at half-maximum (FWHM) isotropic. The usefulness of this piPET imaging device has been previously reported (Jagoda et al, 2004).…”

Detection of Visual Activation in the Rat Brain Using 2-deoxy-2-[18F]fluoro-d-glucose and Statistical Parametric Mapping (SPM)

“…The energy window was 300 650 keV, and decay and dead time corrections were applied. The usefulness of the piPET imaging device has been reported elsewhere [17].…”