Comparison of Bolus and Infusion Methods for Receptor Quantitation: Application to [¹⁸F]Cyclofoxy and Positron Emission Tomography

Abstract

Summary:Positron emission tomography studies with the opiate antagonist [18F]cyclofoxy ([18F]CF) were per formed in baboons. Bolus injection studies demonstrated initial uptake dependent on blood flow. The late uptake showed highest binding in caudate nuclei, amygdala, thal amus, and brainstem and the least accumulation in cere bellum. By 60 min postinjection, regional brain radioac tivity cleared at the same rate as metabolite-corrected plasma, i.e., transient equilibrium was achieved. Com partmental modeling methods were applied to time activity curves from brain and metabolite-corrected plasma. Individual rate constants were estimated with poor precision. The model estimate of the total volume of distribution (VT), representing the ratio of tissue radioac tivity to metabolite-corrected plasma at equilibrium, was reliably determined. The apparent volume of distribution Va significantly overestimated V T and produced artifi cially high image contrast. These differences were pre dicted by compartment model theory and were caused by a plasma clearance rate that was close to the slowest tissue clearance rate. To develop a simple method to mea sure V T' an infusion protocol consisting of bolus plus continuous infusion (B/I) of CF was designed and applied in a separate set of studies. The Va values from the B/I studies agreed with the V T values from both B/I and bolus studies. This infusion approach can produce accurate re ceptor measurements and has the potential to shorten scan time and simplify the acquisition and processing of scan and blood data.

SPECT Quantification of [123I]Iomazenil Binding to Benzodiazepine Receptors in Nonhuman Primates: I. Kinetic Modeling of Single Bolus Experiments

“…, 1988) and peak equilibrium methods (Farde et aI., 1986). We followed Carson et al (1992) by using the term transient equilibrium to designate the method that relies upon the measure of V a ( t ) when this value becomes constant (i.e. , when brain and plasma activity are decreasing at the same rate).…”

“…Thus, a transient equilib rium state was not observed during the time frame of these experiments. Carson et al (1992) recently demonstrated that the transient equilibrium method overestimates the BP unless the brain washout (as estimated by k 2 ' or al) is much faster than A 3 ' In deed, at 300 min, the value of V a ( t ) was higher than that of VT . Thus, even if longer experimental times had allowed attainment of a transient equilibrium state in regions such as the striatum, this analysis would have overestimated VT • The peak equilibrium method is superior to the transient equilibrium method, at least theoretically,.…”

Buprenorphine-Induced Changes in Mu-Opioid Receptor Availability in Male Heroin-Dependent Volunteers A Preliminary Study

“…These data suggest that relatively low degrees of occupancy are needed to induce clinically significant effects (Kling et al 1997). However, this study was conducted utilizing [ 18 F]cyclofoxy, which is a non-selective OR and kappa receptor marker (Carson et al 1993), and therefore the receptor availability measure calculated does not refer to one but two receptor sites. Since methadone has much higher affinity for mu than for kappa receptor sites (Kristensen et al 1995), the use of a non-selective radiotracer would underestimate changes in OR availability.…”

Effects of Blood Flow on [11C]Raclopride Binding in the Brain: Model Simulations and Kinetic Analysis of PET Data

“…Since the plasma drug concentration is not usually held con stant [generally the drug is administered as a bolus injection, although recently Carson et al (1993) have proposed an infusion protocol for e8p]cyclo foxy to maintain a constant plasma level], the tis sue/plasma drug ratio does not represent the true DV but also contains factors representing the loss of drug from plasma (Logan et aI., 1990 ;Carson et aI., 1993). Por this reason, when using a bolus in jection of tracer, the DV must be determined using compartmental modeling (finding values for individ ual kinetic parameters for a specified model) or graphically (not assuming a specified model) (Logan et aI., 1990).…”