Pharmacokinetics of radiotracers in human plasma during positron emission tomography

Abstract

Many radiopharmaceuticals for positron emission tomography (PET) are substantially metabolized in peripheral organs. Pharmacological treatments intended to alter cerebral metabolism might also alter radiotracer metabolism, consequently altering the cerebral uptake. First-order rate constants for the metabolism of PET tracers can be calculated by a linear graphical method from the precursor and metabolite concentrations measured in plasma extracts fractionated by HPLC. We tested the effects of specific pharmacological challenges on the plasma kinetics of six tracers used for PET studies of neurotransmission. The rate of O-methylation of circulating [(18)F]fluorodopa, a tracer of dopa decarboxylase activity in brain, was unaffected by pretreatment with amantadine, an antagonist of glutamate receptors. [(11)C]Deprenyl, a tracer of monoamine oxidase activity, was rapidly metabolized to [(11)C]methamphetamine and polar metabolites in healthy volunteers. The net rate constant of this metabolism was three times higher in a group of subjects under treatment for epilepsy, consistent with induction of hepatic microsomal enzymes by antiepileptic drugs. [(11)C]Sch 23390, a ligand for dopamine D1 receptors, was rapidly metabolized to polar metabolites. The net rate constant of metabolism was unaffected by pretreatment with lorazepam. [(11)C]-(S)-Nicotine, a ligand for nicotinic receptors, was rapidly metabolized to [(11)C]-(S)-cotenine, which is less polar than the parent compound. Pretreatment with mazindol, a dopamine uptake inhibitor, was without effect on peripheral metabolism of [(11)C]-(S)-nicotine. [(11)C]WIN 35,428, a tropane derivative which labels dopamine uptake sites, was metabolized to a nonpolar metabolite, but so slowly that the rate constant of this process could not be calculated. [(11)C]Raclopride, a ligand for dopamine D2 receptors, was first metabolized to a nonpolar metabolite, which then yielded two hydrophilic metabolites. The initial metabolic step was substantially blocked by pretreatment with amphetamine, possibly indicative of competitive inhibition of microsomal oxidation. Together, these results indicate that the linear graphic method is useful for estimating the kinetics of the plasma metabolism of many widely used PET tracers. Drug-drug interactions were revealed in subjects treated with specific pharmacological agents prior to tracer administration.

Estimating neurotransmitter kinetics with ntPET: A simulation study of temporal precision and effects of biased data

“…Therefore, when using the ART method, we recommend that metabolite correction be performed unless tracer metabolism is known to be very limited. Population-based corrections may not be adequate because rates of tracer metabolism can be highly variable between subjects (Gillings et al, 2001;Ishiwata et al, 1998) and can be influenced by drug treatments (Cumming et al, 1999). We speculate that the complexity of the ntPET models, in particular the desired endpoint (a full characterization of the NT response), makes the method more sensitive to biases in the TIF than conventional PET models.…”

Comparison of 2β-Carbomethoxy-3β-(4-[18F]Fluorophenyl)Tropane and N-(3-[18F]Fluoropropyl)-2β-Carbomethoxy-3β-(4-Fluorophenyl)Nortropane, Tracers for Imaging Dopamine Transporter in Rat

“…All three possible 18 [8,10,19] as a consequence of the N-dealkylation reaction [35]. In humans, polar metabolites of [ 11 C]β-CFT were almost absent, and a nonpolar metabolite, proposed to be a labelled 2β-carboxylic acid, was detected.…”

“…In humans, polar metabolites of [ 11 C]β-CFT were almost absent, and a nonpolar metabolite, proposed to be a labelled 2β-carboxylic acid, was detected. The N-dealkylation reaction was reported to proceed much more rapidly in monkeys than in humans [35]. Non-polar metabolites are usually more likely to cross the blood-brain barrier and contribute to radioactivity concentrations in the brain.…”

Radiosynthesis and Validation of 18F-FP-CMT, a Phenyltropane with Superior Properties for Imaging the Dopamine Transporter in Living Brain

“…23 Using the plasma time-activity curves calculated from the untransformed 18 F-FP-CMT and its single hydrophilic metabolite, the fractional rate constants for whole body tracer metabolism (k 0 ; 1/minute) and for elimination from plasma of the metabolite (k À 1 ; 1/minute) were calculated by linear regression analysis as described previously. 24 From the initial 1-minute blood sample, a 50 mL portion of plasma was transferred to a Roti-Spin tube (MWCO ¼ 10 kDa, Carl Roth, Karlsruhe, Germany), and then centrifuged at 10,000 g; the radioactivity in a 20 mL portion of the ultrafiltrate was measured in the gamma counter, and the free fraction was calculated relative to the total radioactivity in the entire plasma sample.…”