Dataset Information

Determination of receptor occupancy in the presence of mass dose: [¹¹C]GSK189254 PET imaging of histamine H₃ receptor occupancy by PF-03654746.

ABSTRACT: Measurements of drug occupancies using positron emission tomography (PET) can be biased if the radioligand concentration exceeds "tracer" levels. Negative bias would also arise in successive PET scans if clearance of the radioligand is slow, resulting in a carryover effect. We developed a method to (1) estimate the in vivo dissociation constant K_d of a radioligand from PET studies displaying a non-tracer carryover (NTCO) effect and (2) correct the NTCO bias in occupancy studies taking into account the plasma concentration of the radioligand and its in vivo K_d. This method was applied in a study of healthy human subjects with the histamine H₃ receptor radioligand [¹¹C]GSK189254 to measure the PK-occupancy relationship of the H₃ antagonist PF-03654746. From three test/retest studies, [¹¹C]GSK189254 K_d was estimated to be 9.5?±?5.9?pM. Oral administration of 0.1 to 4?mg of PF-03654746 resulted in occupancy estimates of 71%-97% and 30%-93% at 3 and 24?h post-drug, respectively. NTCO correction adjusted the occupancy estimates by 0%-15%. Analysis of the relationship between corrected occupancies and PF-03654746 plasma levels indicated that PF-03654746 can fully occupy H₃ binding sites ( RO_max?=?100%), and its IC₅₀ was estimated to be 0.144?±?0.010?ng/mL. The uncorrected IC₅₀ was 26% higher.

SUBMITTER: Gallezot JD

PROVIDER: S-EPMC5363483 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Publications

Determination of receptor occupancy in the presence of mass dose: [11C]GSK189254 PET imaging of histamine H3 receptor occupancy by PF-03654746.

Gallezot Jean-Dominique JD Planeta Beata B Nabulsi Nabeel N Palumbo Donna D Li Xiaoxi X Liu Jing J Rowinski Carolyn C Chidsey Kristin K Labaree David D Ropchan Jim J Lin Shu-Fei SF Sawant-Basak Aarti A McCarthy Timothy J TJ Schmidt Anne W AW Huang Yiyun Y Carson Richard E RE

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20160720 3

Measurements of drug occupancies using positron emission tomography (PET) can be biased if the radioligand concentration exceeds "tracer" levels. Negative bias would also arise in successive PET scans if clearance of the radioligand is slow, resulting in a carryover effect. We developed a method to (1) estimate the in vivo dissociation constant Kd of a radioligand from PET studies displaying a non-tracer carryover (NTCO) effect and (2) correct the NTCO bias in occupancy studies taking ...[more]

PMID: 27207170

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Project description:Type 1 diabetes mellitus (T1DM) has traditionally been characterized by a complete destruction of β-cell mass (BCM); however, there is growing evidence of possible residual BCM present in T1DM. Given the absence of in vivo tools to measure BCM, routine clinical measures of β-cell function (e.g., C-peptide release) may not reflect BCM. We previously demonstrated the potential utility of PET imaging with the dopamine D2 and D3 receptor agonist 3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol (11C-(+)-PHNO) to differentiate between healthy control (HC) and T1DM individuals. Methods: Sixteen individuals participated (10 men, 6 women; 9 HCs, 7 T1DMs). The average duration of diabetes was 18 ± 6 y (range, 14-30 y). Individuals underwent PET/CT scanning with a 120-min dynamic PET scan centered on the pancreas. One- and 2-tissue-compartment models were used to estimate pancreas and spleen distribution volume. Reference region approaches (spleen as reference) were also investigated. Quantitative PET measures were correlated with clinical outcome measures. Immunohistochemistry was performed to examine colocalization of dopamine receptors with endocrine hormones in HC and T1DM pancreatic tissue. Results: C-peptide release was not detectable in any T1DM individuals, whereas proinsulin was detectable in 3 of 5 T1DM individuals. Pancreas SUV ratio minus 1 (SUVR-1) (20-30 min; spleen as reference region) demonstrated a statistically significant reduction (-36.2%) in radioligand binding (HCs, 5.6; T1DMs, 3.6; P = 0.03). Age at diagnosis correlated significantly with pancreas SUVR-1 (20-30 min) (R 2 = 0.67, P = 0.025). Duration of diabetes did not significantly correlate with pancreas SUVR-1 (20-30 min) (R 2 = 0.36, P = 0.16). Mean acute C-peptide response to arginine at maximal glycemic potentiation did not significantly correlate with SUVR-1 (20-30 min) (R 2 = 0.57, P = 0.05), nor did mean baseline proinsulin (R 2 = 0.45, P = 0.10). Immunohistochemistry demonstrated colocalization of dopamine D3 receptor and dopamine D2 receptor in HCs. No colocalization of the dopamine D3 receptor or dopamine D2 receptor was seen with somatostatin, glucagon, or polypeptide Y. In a separate T1DM individual, no immunostaining was seen with dopamine D3 receptor, dopamine D2 receptor, or insulin antibodies, suggesting that loss of endocrine dopamine D3 receptor and dopamine D2 receptor expression accompanies loss of β-cell functional insulin secretory capacity. Conclusion: Thirty-minute scan durations and SUVR-1 provide quantitative outcome measures for 11C-(+)-PHNO, a dopamine D3 receptor-preferring agonist PET radioligand, to differentiate BCM in T1DM and HCs.

Dataset Information

Determination of receptor occupancy in the presence of mass dose: [¹¹C]GSK189254 PET imaging of histamine H₃ receptor occupancy by PF-03654746.

Publications

Determination of receptor occupancy in the presence of mass dose: [<sup>11</sup>C]GSK189254 PET imaging of histamine H<sub>3</sub> receptor occupancy by PF-03654746.

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