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"Pseudo-reference-based Input Function Shape" (pRef-IFS): Towards a True image-derived input function for PET kinetic

Tommaso Volpi1,2, Mika Naganawa1,2, Richard E Carson1,2

  • 1Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, USA.

Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism
|January 16, 2026
PubMed
Summary
This summary is machine-generated.

This study introduces a novel non-invasive method, pseudo-Reference-based Input Function Shape (pRef-IFS), to estimate plasma input functions for PET imaging. pRef-IFS shows promise for accurate quantification with one-tissue kinetics, even with imperfect reference regions.

Keywords:
Metabolite-corrected plasma input functionclearance rate constant k2′one-tissue compartment modelpseudo-reference regionsimplified reference tissue models

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Area of Science:

  • Nuclear Medicine
  • Radiochemistry
  • Pharmacokinetics

Background:

  • Absolute quantification in Positron Emission Tomography (PET) relies on accurate metabolite-corrected plasma input function (CP).
  • Obtaining CP non-invasively is challenging, especially when ideal reference regions are unavailable for PET imaging.
  • Existing methods often require invasive procedures or ideal reference regions, limiting broad applicability.

Purpose of the Study:

  • To introduce and evaluate a novel non-invasive method, pseudo-Reference-based Input Function Shape (pRef-IFS), for estimating CP in PET.
  • To assess the performance of pRef-IFS under varying kinetic models and reference region properties.
  • To determine the impact of inaccurate kinetic parameter estimates on the accuracy of pRef-IFS.

Main Methods:

  • pRef-IFS estimates CP shape from a pseudo-reference region (pRef) using a one-tissue (1T) compartment model.
  • The pRef clearance rate (k'2) was estimated using simplified reference tissue models (SRTM) or assumed.
  • The unscaled CP shape was subsequently scaled using an early image-derived blood time-activity curve (ID-BTAC).

Main Results:

  • Under 1T kinetics, SRTM-estimated k'2 was unbiased, and pRef-IFS yielded small distribution volume (VT) bias in human data (e.g., 11C-LSN3172176: -2±5% to 11±8%).
  • pRef-IFS performance degraded with two-tissue kinetics, particularly for tracers like 18F-FPEB, though some tracers (18F-ASEM) showed minimal bias (-4±10%).
  • The accuracy of pRef-IFS was dependent on the adherence to 1T kinetic assumptions and the quality of ID-BTAC scaling.

Conclusions:

  • pRef-IFS offers a promising fully non-invasive approach for PET absolute quantification when radiotracers exhibit one-tissue kinetics.
  • The method is robust even with modest specific binding in the pseudo-reference region, provided accurate ID-BTAC scaling is achieved.
  • Further validation is needed for tracers with complex (two-tissue) kinetics or when reference region assumptions are significantly violated.