Evan Morris CLA 2008 Imaging Drugs in the Brain with PET

Oct 31, 2008

Paper 1 ”Imaging Dopamine…” Wagner et al. Science, 1983

Summary: what did they do?  (3 sentences max)

• Used PET and 11C-NMSP to image Dopamine D2 receptors in human and baboon brains, in vivo
• Use images of cerebellum (very few D2 receptors) to measure uptake (non-specific mechanisms) alone.
• Used injection of 11C-NMSP with co-injection of NMSP (no radioactivity) as means of measuring non-specific uptake of tracer (receptors are mostly blocked by cold tracer) in target region (striatum, aka. “caudate”).
• Achievement of note: first ever images of human D2 receptor distribution.
• Historical note: very poor spatial resolution compared to modern PET machines.

Talking points:  (for example)

• Experimental: PET scan with BOLUS injection of tracer or tracer+cold ligand
• first ever human scan, combination of results from high and low specific activity injections
• only model here is implicit: namely that specific binding can be extinguished by blocking of all receptors with cold tracer.
• generally applicable method.

Question: (try the following formats)

• I understand that they want to image D2 receptors with a D2 tracer, but why do they inject cold tracer as well? Answer: To get a measure of nonspecific binding.

Relevance: If such tracers can be displaced by endogenous neurotransmitters, we can use this procedure to measure activation of dopamine.

keywords:

caudate, basal ganglia, cerebellum, specific activity, neuroleptic,

Paper 2 “A quantitative model for the …”, Mintun et al, 1984 Ann Neurol

Summary: what did they do?  (3 sentences max)

• First mathematical model to describe uptake of dopamine receptor tracer, 18F-spiperon with PET. Model derived from mass balances on each compartment.
• Model stipulates 3 compartments (blood, extravascular space, bound to extravascular (dopamine) receptors). Nowadays, we would not call the blood a compartment.
• Introduction of parameter, “BP” = B_max/K_D, called “binding potential.”
• Introduces terms for fraction of tracer that is “free” in either blood (f1) or extravascular space (f2).

Talking points:  (for example)

• Model assumes that transport across blood-brain-barrier is wholly diffusive (based on Crone, Renkin work which should have been cited).
• low specific activity injection is used as a test of the specific binding of the tracer: i.e., is it “blockable” or “displaceable”.
• Claims that only certain parameters can be estimated. Issue of parameter identifiability. If SA is high, then molar injection is low -> binding term:

k₁ f₂ C₂ (B_max – C₃) simplifies to k₁ f₂ C₂ B_max

hence, we certainly could not hope to estimate k₁ separately from B_max (nowadays we call this term “k₃”

• Clams that even k₁ and k_-1 cannot be estimated separately and hence BP is best choice but gives no evidence.
• f1 and f2 terms assume that the fraction is constant (ie., that free and not-free tracer in each compartment are in fast equilibrium with each other so that the particular fractions are maintained.
• claims that fluid volume fraction in brain is 79%. This is quite far from the accepted value of 95-96%.
• Analogizes BP to what is commonly measured in vitro.
• Need measured input function to drive ODE model.
• model equations are continuous, instantaneous --- but PET measured discrete averages (or sums) over each frame time. How to reconcile model and data (ought to integrate model).
• As with Wagner paper, Mintun uses comparison between cerebellum and basal ganglia to demonstrate specific binding of tracer.
• term “flux” usually refers to transport of moles per time PER surface area.
• should have used WEIGHTED fitting of data to model.

Question: (try the following formats)

• I understand that they want to model uptake of tracer over time. Why do they have to “assume constant radioactivity during scan (his term for “time frame”)? Answer. PET measurements are sums over Dt. The model gives C2, C3 at each instant in t. Need to reconcile the two.

Relevance: If such models can be extended to account for role of endogenous neurotransmitters, we can use them to quantify activation of dopamine through its effect on tracer uptake.

keywords:

spiperone, diffusive, parameter estimation, Binding Potential