Paper 1 Imaging Dopamine Receptors.. in the Living Human Brain, Wagner et al. Science, 1983

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

• Goal: to use 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 non-specific uptake of tracer.
• Used injection of 11C-NMSP with co-injection of cold 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).
• paradigm: PET study; single bolus injection of tracer
• diseases of interest: schizophrenia, Parkinson’s, claim is that dopamine receptors are up or down in those disease
• drugs mentioned: neuroleptics (for treating schizophrenia)
• Phenomenon being imaged: receptor binding leads to preferential retention of tracer in striatum vs rest of brain
• target: dopamine D2 receptors
• tracer: 11C-NMSP
• 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. Recall our discussion last week: nonspecific binding is defined as not-displaceable whereas specific binding is. When all the specific binding is displaced, we are left with the nonspecific.
• Why did this paper get into Science but the Mintun paper (which was submitted first, also had baboons, and was MORE quantitative) was published in a lesser journal?

Relevance: If such tracers can be displaced by endogenous neurotransmitters, we might be able to use this procedure to measure alterations in levels of endogenous dopamine in drug abuse.

keywords:

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

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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-spiperone 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. We don’t estimate its concentration, we measure it.
• 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).
• paradigm: PET; single bolus injection
• tracer: 18F-spiperone
• diseases:??
• target: dopamine D2 receptors
• innovations: mathematical model, recognizing that not all parameters are identifiable but the combination BP might be; using simulations to test the correlation between parameters

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. (Just like Wagner et al.)
• 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 because tracer concentration is low (assuming specific activity is high) and C₃ << B_max

Finally, we certainly could not hope to estimate k₁ separately from B_max (nowadays we call this WHOLE 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.
• “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. This is an 18F tracer so we could scan for much longer than with 11C tracer. Don’t know if that matters.

keywords:

spiperone, diffusive, parameter estimation, Binding Potential

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Paper 3 Farde et al, “Quantitative Analysis of D2 dopamine receptor binding in living human brain by PET”, Science 1985?

This is the first “Drug occupancy study with PET”

tracer: 11C-raclopride

target: D2 dopamine receptor

disease: schizophrenia

Innovation: estimated Bmax and Kd in healthy controls, assumed that Bmax would be same in schizophrenia so that lower 11C-raclopride binding observed in schizophrenics could be attributed directly to occupancy of receptors.

Assumptions that Bmax is stable has now been disproved in many diseases

Assumption that Kd is same in HC and disease is weak

Assumption (implied, never mentioned) that we can compare 24 yr old healthies to 50 yr old schizophrenics is now laughable. D2 receptors have been shown to decline with age.

Claims that equilibrium method is needed and tracers that equilibrate faster are better. Seems not to know about Mintun model – which does not require equilibrium.