First-in-human Imaging Using [C]MDTC: a Radiotracer Targeting the Cannabinoid Receptor Type 2

Overview

Journal Eur J Nucl Med Mol Imaging

Specialties Biophysics
Nuclear Medicine
Radiology

Date 2023 Mar 6

PMID 36877235

Authors

Yong Du

Jennifer M Coughlin

Mary Katherine Brosnan

Allen Chen

Laura K Shinehouse

Rehab Abdallah

Martin A Lodge

William B Mathews

Chen Liu

Yunkou Wu

Il Minn

Paige Finley

Andrew W Hall

Wojciech G Lesniak

Robert F Dannals

Andrew G Horti

Martin G Pomper

Affiliations

Soon will be listed here.

Abstract

Purpose: We report findings from the first-in-human study of [C]MDTC, a radiotracer developed to image the cannabinoid receptor type 2 (CB2R) with positron emission tomography (PET).

Methods: Ten healthy adults were imaged according to a 90-min dynamic PET protocol after bolus intravenous injection of [C]MDTC. Five participants also completed a second [C]MDTC PET scan to assess test-retest reproducibility of receptor-binding outcomes. The kinetic behavior of [C]MDTC in human brain was evaluated using tissue compartmental modeling. Four additional healthy adults completed whole-body [C]MDTC PET/CT to calculate organ doses and the whole-body effective dose.

Results: [C]MDTC brain PET and [C]MDTC whole-body PET/CT was well-tolerated. A murine study found evidence of brain-penetrant radiometabolites. The model of choice for fitting the time activity curves (TACs) across brain regions of interest was a three-tissue compartment model that includes a separate input function and compartment for the brain-penetrant metabolites. Regional distribution volume (V) values were low, indicating low CB2R expression in the brain. Test-retest reliability of V demonstrated a mean absolute variability of 9.91%. The measured effective dose of [C]MDTC was 5.29 μSv/MBq.

Conclusion: These data demonstrate the safety and pharmacokinetic behavior of [C]MDTC with PET in healthy human brain. Future studies identifying radiometabolites of [C]MDTC are recommended before applying [C]MDTC PET to assess the high expression of the CB2R by activated microglia in human brain.

Citing Articles

Development and evaluation of deuterated [F]JHU94620 isotopologues for the non-invasive assessment of the cannabinoid type 2 receptor in brain.

Gundel D, Maqbool M, Teodoro R, Ludwig F, Heerklotz A, Toussaint M EJNMMI Radiopharm Chem. 2024; 9(1):91.

PMID: 39714717 PMC: 11666850. DOI: 10.1186/s41181-024-00319-2.

"Neuroinflammation": does it have a role in chronic pain? Evidence from human imaging.

Loggia M Pain. 2024; 165(11S):S58-S67.

PMID: 39560416 PMC: 11729497. DOI: 10.1097/j.pain.0000000000003342.

Translational Preclinical PET Imaging and Metabolic Evaluation of a New Cannabinoid 2 Receptor (CBR) Radioligand, ()--(3-(2-(2-[F]Fluoroethoxy)ethyl)-4,5-dimethylthiazol-2(3)-ylidene)-2,2,3,3-tetramethylcyclopropane-1-carboxamide.

Auvity S, Attili B, Caille F, Goislard M, Cayla J, Hinnen F ACS Pharmacol Transl Sci. 2024; 7(10):3144-3154.

PMID: 39421654 PMC: 11480890. DOI: 10.1021/acsptsci.4c00348.

Recent advancements in new tracers from first-in-human studies.

Nakamoto Y, Inui Y, Hotta M, Wakabayashi H, Hanaoka H Ann Nucl Med. 2024; 38(11):877-883.

PMID: 39325320 PMC: 11489164. DOI: 10.1007/s12149-024-01979-5.

PET imaging of neuroinflammation: any credible alternatives to TSPO yet?.

Chauveau F, Winkeler A, Chalon S, Boutin H, Becker G Mol Psychiatry. 2024; 30(1):213-228.

PMID: 38997465 DOI: 10.1038/s41380-024-02656-9.

References

Xin Q, Xu F, Taylor D, Zhao J, Wu J . The impact of cannabinoid type 2 receptors (CB2Rs) in neuroprotection against neurological disorders. Acta Pharmacol Sin. 2020; 41(12):1507-1518. PMC: 7921135. DOI: 10.1038/s41401-020-00530-2. View

Basavarajappa B, Shivakumar M, Joshi V, Subbanna S . Endocannabinoid system in neurodegenerative disorders. J Neurochem. 2017; 142(5):624-648. PMC: 5669051. DOI: 10.1111/jnc.14098. View

Solas M, Francis P, Franco R, Ramirez M . CB2 receptor and amyloid pathology in frontal cortex of Alzheimer's disease patients. Neurobiol Aging. 2012; 34(3):805-8. DOI: 10.1016/j.neurobiolaging.2012.06.005. View

Gomez-Galvez Y, Palomo-Garo C, Fernandez-Ruiz J, Garcia C . Potential of the cannabinoid CB(2) receptor as a pharmacological target against inflammation in Parkinson's disease. Prog Neuropsychopharmacol Biol Psychiatry. 2015; 64:200-8. DOI: 10.1016/j.pnpbp.2015.03.017. View

Garcia M, Cinquina V, Palomo-Garo C, Rabano A, Fernandez-Ruiz J . Identification of CB₂ receptors in human nigral neurons that degenerate in Parkinson's disease. Neurosci Lett. 2014; 587:1-4. DOI: 10.1016/j.neulet.2014.12.003. View

Cristino L, Bisogno T, Di Marzo V . Cannabinoids and the expanded endocannabinoid system in neurological disorders. Nat Rev Neurol. 2019; 16(1):9-29. DOI: 10.1038/s41582-019-0284-z. View

Horti A, Gao Y, Ravert H, Finley P, Valentine H, Wong D . Synthesis and biodistribution of [11C]A-836339, a new potential radioligand for PET imaging of cannabinoid type 2 receptors (CB2). Bioorg Med Chem. 2010; 18(14):5202-7. PMC: 2903661. DOI: 10.1016/j.bmc.2010.05.058. View

Yao B, Hsieh G, Daza A, Fan Y, Grayson G, Garrison T . Characterization of a cannabinoid CB2 receptor-selective agonist, A-836339 [2,2,3,3-tetramethyl-cyclopropanecarboxylic acid [3-(2-methoxy-ethyl)-4,5-dimethyl-3H-thiazol-(2Z)-ylidene]-amide], using in vitro pharmacological assays, in vivo pain.... J Pharmacol Exp Ther. 2008; 328(1):141-51. DOI: 10.1124/jpet.108.145011. View

Rahmim A, Cheng J, Blinder S, Camborde M, Sossi V . Statistical dynamic image reconstruction in state-of-the-art high-resolution PET. Phys Med Biol. 2005; 50(20):4887-912. DOI: 10.1088/0031-9155/50/20/010. View

10.

Hilton J, Yokoi F, Dannals R, Ravert H, Szabo Z, Wong D . Column-switching HPLC for the analysis of plasma in PET imaging studies. Nucl Med Biol. 2000; 27(6):627-30. DOI: 10.1016/s0969-8051(00)00125-6. View

11.

Coughlin J, Du Y, Rosenthal H, Slania S, Koo S, Park A . The distribution of the alpha7 nicotinic acetylcholine receptor in healthy aging: An in vivo positron emission tomography study with [F]ASEM. Neuroimage. 2017; 165:118-124. PMC: 5738927. DOI: 10.1016/j.neuroimage.2017.10.009. View

12.

Innis R, Cunningham V, Delforge J, Fujita M, Gjedde A, Gunn R . Consensus nomenclature for in vivo imaging of reversibly binding radioligands. J Cereb Blood Flow Metab. 2007; 27(9):1533-9. DOI: 10.1038/sj.jcbfm.9600493. View

13.

Fujita M, Seibyl J, Verhoeff N, Ichise M, Baldwin R, Zoghbi S . Kinetic and equilibrium analyses of [(123)I]epidepride binding to striatal and extrastriatal dopamine D(2) receptors. Synapse. 1999; 34(4):290-304. DOI: 10.1002/(SICI)1098-2396(19991215)34:4<290::AID-SYN5>3.0.CO;2-B. View

14.

Stabin M, Sparks R, Crowe E . OLINDA/EXM: the second-generation personal computer software for internal dose assessment in nuclear medicine. J Nucl Med. 2005; 46(6):1023-7. View

15.

Glatting G, Kletting P, Reske S, Hohl K, Ring C . Choosing the optimal fit function: comparison of the Akaike information criterion and the F-test. Med Phys. 2007; 34(11):4285-92. DOI: 10.1118/1.2794176. View

16.

Scheinin N, Tolvanen T, Wilson I, Arponen E, Nagren K, Rinne J . Biodistribution and radiation dosimetry of the amyloid imaging agent 11C-PIB in humans. J Nucl Med. 2007; 48(1):128-33. View

17.

Van der Aart J, Hallett W, Rabiner E, Passchier J, Comley R . Radiation dose estimates for carbon-11-labelled PET tracers. Nucl Med Biol. 2011; 39(2):305-14. DOI: 10.1016/j.nucmedbio.2011.08.005. View

18.

Dishino D, Welch M, Kilbourn M, Raichle M . Relationship between lipophilicity and brain extraction of C-11-labeled radiopharmaceuticals. J Nucl Med. 1983; 24(11):1030-8. View

19.

Kao C, Waki A, Sassaman M, Jagoda E, Szajek L, Ravasi L . Evaluation of [76Br]FBAU 3',5'-dibenzoate as a lipophilic prodrug for brain imaging. Nucl Med Biol. 2002; 29(5):527-35. DOI: 10.1016/s0969-8051(02)00324-4. View

20.

Welch M, Chi D, Mathias C, Kilbourn M, Brodack J, Katzenellenbogen J . Biodistribution of N-alkyl and N-fluoroalkyl derivatives of spiroperidol; radiopharmaceuticals for PET studies of dopamine receptors. Int J Rad Appl Instrum B. 1986; 13(5):523-6. DOI: 10.1016/0883-2897(86)90132-7. View