QUANTIFICATION OF MUSCARINIC CHOLINERGIC RECEPTORS WITH [C-11] NMPB AND POSITRON-EMISSION-TOMOGRAPHY - METHOD DEVELOPMENT AND DIFFERENTIATION OF TRACER DELIVERY FROM RECEPTOR-BINDING
Jk. Zubieta et al., QUANTIFICATION OF MUSCARINIC CHOLINERGIC RECEPTORS WITH [C-11] NMPB AND POSITRON-EMISSION-TOMOGRAPHY - METHOD DEVELOPMENT AND DIFFERENTIATION OF TRACER DELIVERY FROM RECEPTOR-BINDING, Journal of cerebral blood flow and metabolism, 18(6), 1998, pp. 619-631
Quantification of human brain muscarinic cholinergic receptors was inv
estigated with the use of [C-11]N-methyl-4-piperidyl benzylate (NMPB)
and positron emission tomography (PET). Whole-brain uptake of NMPB at
90 to 110 minutes after intravenous injection was approximately 10% of
the administered dose. The initial cerebral distribution of NMPB corr
esponded to the pattern of cerebral perfusion; however, at progressive
ly longer postinjection intervals, regional distinctions consistent wi
th muscarinic receptor binding were evident: activity at 90 to 110 min
utes postinjection was highest in the striatum and cerebral cortex, in
termediate in the thalamus and pens, and lowest in the cerebellum. Aft
er the development of a chromatographic system for isolation of authen
tic [C-11]NMPB in plasma, tracer kinetic modeling was used to estimate
receptor binding from the cerebral and arterial plasma tracer time-co
urses. Ligand transport rate and receptor-binding estimates were obtai
ned with the use of compartmental models and analytical methods of var
ying complexity, including a two-parameter pixel-by-pixel-weighted int
egral approach and regional least-squares curve-fitting analyses emplo
ying both two- and three-compartment model configurations. In test-ret
est experiments, precision of the methods and their abilities to disti
nguish altered ligand delivery from binding in occipital cortex during
an audiovisual presentation were evaluated. Visual stimulation increa
sed the occipital blood-to-brain NMPB transport rate by 25% to 46% in
estimates arising from the various approaches. Weighted integral analy
ses resulted in lowest apparent transport changes and in a concomitant
trend toward apparent binding increases during visual activation. The
regional least-squares procedures were superior to the pixel-by-pixel
method in isolating the effects of altered tracer delivery from recep
tor-binding estimates, indicating larger transport effects and unalter
ed binding. Precision was best (less than 10% test-retest differences)
for the weighted integral analyses and was somewhat lower in the leas
t-squares analyses (10-25% differences), The authors conclude that pix
el-by-pixel-weighted integral analyses of NMPB distribution introduce
transport biases into receptor-binding estimates. Similar confounding
effects also are predicted in noncompartmental analyses of delayed rad
iotracer distribution. The use of regional nonlinear least-squares fit
ting to two-and three-compartment models, although more labor intensiv
e, provides accurate distinction of receptor-binding estimates from tr
acer delivery with acceptable precision in both intra-and intersubject
comparisons.