Quantification of μ-opioid receptors with[11C]carfentanil-PET

Published analysis methods

Tissue ratio method has been shown to provide binding estimates that are highly correlated with specific binding estimates obtained using blood-input (Frost et al. 1989). Even recently, for SPM analysis, "μ-opioid receptor binding" images have been calculated by the same group with ratio method: time frames 34-82 min have been summed and the sum image is divided by the value in occipital cortex, and 1 is subtracted from the ratio image (Bencherif et al. 2004a; Bencherif et al. 2004b). Partial volume correction reduces the variance and reveals an age-dependent increase in binding (Bencherif et al. 2004b).

Logan plot analysis with occipital cortex input has also been validated as an analysis method (Endres et al. 2003). However, choosing the start time for linear fit was found to be problematic. A later time value (30 min) gave less bias than an earlier time (10 min), but increased the noise level (Endres et al. 2003). This may be acceptable for regional analysis, but not for calculation of parametric images. Investigation of the performance of simplified reference tissue method (SRTM) was suggested by these authors. Problems withLogan plot with occipital cortex input can be partly avoided by correcting for the washout rate from the occipital cortex (k2'); Heinz et al. (2005) used this method, assuming k2' =0.1 min-1, based on Endres et al. 2003.

Logan plot analysis with plasma input has been used in regional analysis of myocardium, skeletal muscle and lung (Villemagne et al. 2002). Skeletal muscle was used as a reference tissue to achieve an estimate of binding potential as BP = DV in myocardium / DV in muscle - 1.

A bolus + infusion protocol has been frequently used in [11C]carfentanil studies to achieve steady-state tracer levels. It is possible that this approach solves the non-linearity problem withreference input Logan plot analysis. Bmax/Kd (DVR-1) images were produced with this technique and used in SPM analysis (Zubieta et al. 2001; Liberzon et al. 2002).

Simulation on the different analysis methods

Report on the simulation is available in http://users.utu.fi/vesoik/pdf/carfentanil_sim.pdf. In short, SRTM was found to provide similar results as Logan plot with reference region input, but without the problem of non-linearity. However, the reference tissue methods do not provide quantitative BP values. To achieve those, plasma input methods must be used.

Suggested analysis method for Turku

BP images are calculated with SRTM using occipital cortex as reference region. Use software that applies basis function method in calculation of BP maps, either Roger Gunn's RPM, or imgbfbp. (Ingman et al., 2005).


References:

Bencherif B, Wand GS, McGaul ME, Kim YK, Ilgin N, Dannals RF, Frost JJ. Mu-opioid receptor binding measured by [11C]carfentanil positron emission tomography is related to craving and mood in alcohol dependence. Biol. Psychiatry 2004a; 55: 255-262.

Bencherif B, Stumpf MJ, Links JM, Frost JJ. Application of MRI-based partial-volume correction to the analysis of PET images of μ-opioid receptors using statistical parametric mapping. J. Nucl. Med. 2004b; 45: 402-408.

Endres CJ, Bencherif B, Hilton J, Madar I, Frost JJ. Quantification of brain μ-opioid receptors with [11C]carfentanil: reference-tissue methods. Nucl. Med. Biol. 2003; 30: 177-186.

Frost JJ, Douglass KH, Mayberg HS, Dannals RF, Links JM, Wilson AA, Ravert HT, Crozier WC, Wagner HN Jr. Multicompartmental analysis of [11C]-carfentanil binding to opiate receptors in humans measured by positron emission tomography. J. Cereb. Blood Flow Metabol. 1989; 9: 398-409.

Heinz A, Reimold M, Wrase J, Hermann D, Croissant B, Mundle G, Dohmen BM, Braus DH, Schumann G, Machulla H-J, Bares R, Mann K. Correlation of stable elevations in striatal μ-opioid receptor availability in detoxified alcoholic patients with alcohol craving. Arch. Gen. Psychiatry 2005; 62: 57-64.

Ingman K, Hagelberg N, Aalto S, Någren K, Juhakoski A, Karhuvaara S, Kallio A, Oikonen V, Hietala J, Scheinin H. Prolonged central μ-opioid receptor occupancy after single and repeated nalmefene dosing. Neuropsychopharmacology 2005; 30(12): 2245-2253.

Liberzon I, Zubieta JK, Fig LM, Koeppe RA, Taylor SF. μ-Opioid receptors and limbic responses to aversive emotional stimuli. Proc. Natl. Acad. Sci. USA 2002; 99(10): 7084-7089.

Villemagne PSR, Dannals RF, Ravert HT, Frost JJ. PET imaging of human cardiac opioid receptors. Eur. J. Nucl. Med. 2002; 29: 1385-1388.

Zubieta J-K, Smith YR, Bueller JA, Xu Y, Kilbourn MR, Jewett DM, Meyer CR, Koeppe RA, Stohler CS. Regional mu opioid receptor regulation of sensory and affective dimensions of pain. Science 2001; 293:311-315.


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