Dopamine D1 Receptor Agonist PET Tracer Development: Assessment in Nonhuman Primates

Abstract

Non-catechol-based high-affinity selective dopamine D₁ receptor (D1R) agonists were recently described, and candidate PET ligands were selected on the basis of favorable properties. The objective of this study was to characterize in vivo in nonhuman primates 2 novel D1R agonist PET radiotracers, racemic ¹⁸F-MNI-800 and its more active atropisomeric (-)-enantiomer, ¹⁸F-MNI-968. Methods: Ten brain PET experiments were conducted with ¹⁸F-MNI-800 on 2 adult rhesus macaques and 2 adult cynomolgus macaques, and 8 brain PET experiments were conducted with ¹⁸F-MNI-968 on 2 adult rhesus macaques and 2 adult cynomolgus macaques. PET data were analyzed with both plasma-input-based methods and reference-region-based methods. Whole-body PET images were acquired with ¹⁸F-MNI-800 from 2 adult rhesus macaques for radiation dosimetry estimates. Results:¹⁸F-MNI-800 and ¹⁸F-MNI-968 exhibited regional uptake consistent with D1R distribution. Specificity and selectivity were demonstrated by dose-dependent blocking with the D₁ antagonist SCH-23390. ¹⁸F-MNI-968 showed a 30% higher specific signal than ¹⁸F-MNI-800, with a nondisplaceable binding potential of approximately 0.3 in the cortex and approximately 1.1 in the striatum. Dosimetry radiation exposure was favorable, with an effective dose of about 0.023 mSv/MBq. Conclusion:¹⁸F-MNI-968 has significant potential as a D1R agonist PET radiotracer, and further characterization in human subjects is warranted.

Keywords: D1 receptor; PET imaging; Parkinson disease; agonist; schizophrenia.

Graphical abstract

FIGURE 1.

Profile of D1R agonist PET ligand lead MNI-968. AB = apical to basolateral; BA = basolateral to apical; CNS = central nervous system; cFu_b = fraction unbound in brain; EC₅₀ = half-maximal effective concentration; Emax = maximal effect; hD1 = human D₁; hD2 = human D₂; IC₅₀ = half-maximal inhibitory concentration; Ki = inhibition constant; MDR1 = multi-drug resistance 1; MPO = multiparameter optimization; rD1 = rat D₁; P_app = apparent permeability; RRCK = Ralph Russ canine kidney assay.

FIGURE 2.

Radiosynthesis of ¹⁸F-MNI-800 and ¹⁸F-MNI-968.

FIGURE 3.

Parent fraction profile in arterial plasma after intravenous administration of ¹⁸F-MNI-800 (mean ± SD, n = 4) or ¹⁸F-MNI-968 (mean ± SD, n = 4).

FIGURE 4.

(Left) Average PET images from 30 to 90 min after injection for rhesus macaque (NHP A) in transverse plane of ¹⁸F-MNI-800 at baseline and after dosing with SCH-23390 at 0.5 mg/kg (occupancy of ∼85%) and of ¹⁸F-MNI-968 at baseline and after dosing with PF-2562 at 1.2 mg/kg (occupancy of ∼40%). (Right) Time–activity curves in some brain regions for same rhesus macaque for studies with ¹⁸F-MNI-800 and ¹⁸F-MNI-968. Caud. Nucl. = caudate nucleus; Glob. Pall. = globus pallidus; Nucl. Acc. = nucleus accumbens.

FIGURE 5.

(A and C) Representative time–activity curves at baseline for rhesus macaque (NHP B) in some brain regions after bolus injection of ¹⁸F-MNI-968, showing 2T compartment model fits (A) and SRTM fits (C). (B and D) Graphical analysis with LGA with plasma input function (t* = 15 min) (B) and NI-LGA with reference region input function (t* = 10 min) (D). Caud. Nucl. = caudate nucleus; C_p = activity concentration in plasma; C_ref = activity concentration in reference region; C_t = activity concentration in region of interest; Glob. Pall. = globus pallidus; Nucl. Acc. = nucleus accumbens; Thal. = thalamus.

FIGURE 6.

(A) Within-animal comparison (n = 2) of ¹⁸F-MNI-800 and ¹⁸F-MNI-968 2T V_T estimates. (B) Comparison of ¹⁸F-MNI-968 V_T estimates across models (n = 3). (C) Comparison of ¹⁸F-MNI-968 BP_ND estimates across models (n = 3). 1T = 1 tissue compartment.

FIGURE 7.

(A) SCH-23390 plasma levels for 4 doses, with ¹⁸F-MNI-800 injection at 25 min after drug administration. (B) Striatal D1R occupancy against average plasma levels between 25 and 145 min after administration of SCH-23390. EC₅₀ = half-maximal effective concentration.