Reply: ¹¹C-(+)-PHNO Trapping Reversibility for Quantitative PET Imaging of β-Cell Mass in Patients with Type 1 Diabetes

REPLY: We would like to address several assumptions recently posited by Laffon and Marthan in their letter to the editor that was prompted by our recently published study examining the use of ¹¹C-(+)-PHNO (3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol) to assess β-cell mass in healthy controls and type 1 diabetics (1). Laffon and Marthan put forth several contentions as the basis for use of their method to exploit “trapping reversibility” of ¹¹C-(+)-PHNO; we have significant concerns with their viewpoint.

The first statement in question is that we did not exploit the reversible nature of ¹¹C-(+)-PHNO. In fact, our method depends explicitly on the reversible binding nature of this tracer. For reversible radioligands, the uptake is conventionally described by either 1- or 2-tissue-compartment models (1TC and 2TC, respectively) (2). For 1TC models, the rate constants K₁ and k₂ describe the kinetics in and out of the tissue from plasma, respectively. For a 2TC model, there are additional rate constants, k₃ and k₄, defining the rate of receptor binding and disassociation, respectively. The 1TC and 2TC models were both assessed as the gold standard in our recent publication, with a metabolite-corrected arterial input function to estimate the distribution volume (V_T), the ratio of the radioligand concentrations in the target tissue to that in plasma at equilibrium (e.g., V_T = K₁/k₂ for 1TC). V_T cannot be estimated reliably unless the tracer clearance constant (k₂ for the 1TC) is large enough so that there is significant clearance from the target organ during the imaging period. Thus, our modeling explicitly does take into the account reversibility of ¹¹C-(+)-PHNO. Laffon and Marthan go on to suggest that a monoexponential fit should be applied to the tail portion of the time–activity curve yielding the parameter k_B. If the plasma activity was truly 0, then this parameter would be equal to k₂ in our 1TC model. However, although the ratio of blood to tissue activity is low, it is not 0, and is consistent with the model estimate of V_T of 20–30 mL/cm³. The fact that the time–activity curves out to 120 min “do not reach a plateau at late imaging” is fully consistent with the reversible model we used.

We also consider it important to address the issue of radiolabeled metabolites, especially in the context of imaging outside a functioning blood–brain barrier. Given the low parent fraction in the plasma (<20%), extra caution must be taken to minimize the effects of radiolabeled metabolites in both the pancreas and the spleen. Ex vivo animal well counting studies in both pancreas and spleen tissue would need to be performed at multiple time points after injection of ¹¹C-(+)-PHNO to determine the amount of radiolabeled metabolites present in both organs. As we stated in the original publication, our group previously demonstrated radiolabeled metabolites may be accumulating in the pancreas and spleen at similar levels, as was seen in a previous study with ¹⁸F-FP-(+)-DTBZ (3); however, this has yet to be proven with ¹¹C-(+)-PHNO and is technically challenging given the shorter half-life of this tracer (∼20 min). This uncertainty of radiolabeled metabolites encouraged us to develop quantitative measures based on early time points (e.g., 30 min).

To conclude, 1TC and 2TC modeling intrinsically exploits the reversible nature of radioligands. Such reversible tracers are preferred for quantitative assays of protein targets in the molecular imaging field (2).

• © 2020 by the Society of Nuclear Medicine and Molecular Imaging.