PET: Positron Emission Tomography Positron-­‐emi4ng Radioisotopes Standard PET Radioisotopes Isotope
Half-life
Eβ+max
(MeV)
Mode of
Decay (β+%)
Nuclear
Reaction
Target Media
15O
2 min
1.74
100
14N(d,n)15O
N2 + 1 %O2
13N
10 min
1.19
100
16O(p,α)13N
[16O]H2O/EtOH
11C
20.3 min
0.96
99
14N(p,α)11C
[11C]CO2: N2 + 0.5 %O2
[11C]CH4: N2 + 10 %H2
18F
110 min
0.64
97
18O(p,n)18F
[18F]F-: 18O-enriched H2O
[18F]F2: 18O-enriched O2 + O2/Ar
Non-­‐Standard PET Radioisotopes Isotope
Half-life
Eβ+max
(MeV)
Mode of
Decay (β+%)
Nuclear
Reaction
Target Media
64Cu
12.7 h
0.653
17.6
64Ni(p,n)64Cu
Electroplated 64Ni Metal
55Co
17.5 h
1.598
76%
58Ni(p,α)55Co
Electroplated 58Ni Metal
89Zr
3.27 d
0.902
22.7%
89Y(p,n)89Zr
Yttrium foil
86Y
14.74 h
3.141
31.9%
86Sr(p,n)86Y
86SrCO /86SrO
3
powder
Strategic Si<ng of the Cyclotron Facility Moncrief Radia<on Oncology Building (NF) Clements Imaging Building (NE) Quality Control (QC) Lab Clinical Produc<on Lab Research Radiochemistry Lab SOPs 15O, 13N Cyclotron 11C, 18F Solid Target Lab 64Cu, 55Co 89Zr, 86Y Cyclotron and Radiochemistry Opera<on Flow Chart Toward the FDA’s Regulatory Approvals of PET Drugs & Radiotracers Regulatory Requirements prior to Clinical Produc<on Equipment Installa3on & Valida3on cGMP •
•
QC equipment Radiosynthesis modules Cri3cal Areas non-­‐cGMP Cyclotron Produc3on Valida3on Facility Valida3on •
•
PET: Positron Emission Tomography Clean Room for produc3on Ante room Non-­‐Cri3cal Areas Non-­‐Clinical Produc3on Areas Regulatory Filings to FDA for Clinical use of PET Drugs •
•
•
•
18F-­‐FDG 18F-­‐NaF 13N-­‐NH
3 11C-­‐Choline
Preclinical Radiotracer Produc<on 18F tracer 18F-­‐FLT Applica<on/
Target Cellular prolifera3on imaging via Thymidine kinase-­‐1 18F-­‐FMISO Precursor 11C tracer 11C-­‐acetate 11C-­‐choline Hypoxia imaging 18F-­‐FHBG 11C-­‐methionine Herpes simplex virus thymidine kinase (HSV-­‐tk) 18F-­‐FDOPA 18F-­‐FET 18F-­‐FES 18F-­‐FDHT 18F-­‐FACBC 11C-­‐PIB Neuroimaging via dopamine receptor; cancer imaging via amino acid uptake and metabolism Cancer imaging via androgen receptor Cancer imaging via L-­‐type amino acid transporter Precursor TCA cycle, faUy acid synthetase Cancer imaging via the choline kinase Cancer imaging via amino acid uptake and protein synthesis AD imaging via binding to amyloid plagues (+)-­‐11C-­‐DTBZ Neuroimaging via targe3ng VMAT2 Cancer imaging via amino acid transport system Cancer imaging via estrogen receptor Applica<on/
Target 11C-­‐ACBC Cancer imaging via amino acid uptake 11C-­‐Lacta<c acid Lactate metabolism 11C-­‐Pyruvic acid Goal: Five preclinical radiotracers per year star3ng in 2015 Validated tracers not included: [18F]FDG, [15O]H2O, and [13N]NH3 Pyruvate metabolism H-­‐11CN FDA Regula<ons on PET Drugs & Regulatory Filings RDRC/eIND/IND Preclinical R&D Clinical Research ANDA/NDA New Drug Applica3on Timeliness # pa<ents Scope Clinical Trial RDRC: Radioac3ve Drug Research CommiUee √ √ √ 30 √ Phase 0 eIND: Exploratory Inves3ga3onal New Drug √ √ 30 √ Phase 0 – I IND: Inves3ga3onal New Drug
ANDA: Abbreviated New Drug Applica3on √ √ unlimited √ √ Phase I – III √ unlimited √ √ √ FDA-­‐approved ANDA is required for commercial dose distribu3on of [18F]FDG, [18F]NaF, [13N]NH3, and [11C]Choline. Goal: To file one RDRC and one IND applica3ons in 2015 Planned Radiotracer Produc<on (Clinical) Radiotracer
Precursor
Target
Radiotracer
Precursor
Target
18F-­‐Fluorothymidine Cellular prolifera3on/ Thymidine kinase 1 11C-­‐Acetate Acetate metabolism
18F-­‐ Fluoromisonidazole Tumor hypoxia/ Tissue oxygena3on 11C-­‐Choline Synthesis of phospholipids in recurrent prostate cancer 18F-­‐ISO-­‐1 Cellular prolifera3on (Ki-­‐67) σ2 receptor
11C-­‐Methionine Amino acid transporters
[18]fluoroestradiol (18F-­‐FES) Estrogen receptor
11C-­‐Palmi<c acid FaUy acid Metabolism
18F-­‐Fluorodihydrotestosterone Androgen receptor
α-­‐11C-­‐methyl-­‐L-­‐tryptophan (11C-­‐AMT) Tryptophan metabolism
(18F-­‐FLT) (18F-­‐FMISO) (18F-­‐FDHT) Goal: Two clinical radiotracers per year star3ng in 2015 Validated tracers not included: [18F]FDG, [15O]H2O, and [13N]NH3 CRP: Governance and Opera<on First-­‐in-­‐Human & Human Clinical Trials Dean’s Office •  Toxicology & Pharmacology •  IRB Applica3ons •  RDRC/eIND/IND/ANDA Filings •  Subject Enrollment •  Clinical coordina3on •  Clinical Imaging Protocols •  Medical Imaging Physics •  Diagnos3c Radiology •  Biosta3s3cs •  Clinical Trial Outcome •  Technology Dissemina3on Affiliated En33es Steering CommiUee Clinical Advisory CommiUee External Consultants Governance CommiUee Business Partner CRP’s Responsibility
Administra3ve CRP -­‐ Director assistant •  Production & delivery of radiotracers for clinical or
research use
Regulatory CRP Facility CRP Chief CRP Research Affairs Officer Clinical PET Facility Radiology, Nuclear Medicine Division UTSW Small Animal Imaging Resources Manager Radiochemist Radiochemist •  Novel imaging probe development
Radiochemistry Produc3on Physics & Engineering •  FDAFacility regulatory
the sponsor
or a
participant
Records filings
GMP Pas
roduc3on Research with Radiotracer & Clinical Tracers Radia3on Safety Postdocs & •  Collaborative
(academic
& QC research
Specialist Radiochemist or industry)
Students & Maintenance Budget & Accoun3ng Radiotracers Isotopes R&D Industry-­‐sponsored Clinical Trial Consor<um PET Companion Diagnos<cs for Hypoxia-­‐Targeted Lung Cancer Therapy Industry Sponsor: Threshold Pharmaceu3cals Par3cipant Physicians: David Gerber and Orhan K. Öz cGMP Produc3on of Radiotracers:
The Cyclotron Team TH-­‐302, an an<-­‐cancer prodrug HX-­‐4, a hypoxia imaging agent Hypoxia-­‐triggered Drug release Requests for Unlisted Clinical Radiotracers [11C]Raclopride Inquired by Psychiatry [11C]PK11195
[18F]FEPPA Inquired by Comprehensive Center for Depression Technically, the radiochemical synthesis of the radiotracers is not an issue. However, how should we handle such requests of preliminary experiments for future grant opportuni3es? 1)  Impact on the current work priority of the cyclotron team? 2)  Impact on the current work load of the Clinical PET Facility? 3)  Regulatory workload sharing? 4)  Upfront cost sharing with the PI and/or the PI’s department or center? Tryptophan Metabolism/Kynurenine Pathway Trp hydroxylase IDO/ TDO Protein Syn. α-[11C]methyl-L-tryptophan – [11C]AMT
[11C]AMT was developed initially as a radiotracer
for noninvasive assessment of brain serotonin
synthesis. To date, clinical studies have shown that
it can be used to trace the kynurenine pathway.
NAD+ kynurenine pathway Examples of [11C]-­‐AMT PET Imaging FDG
AMT-PET/CT of Breast Cancers
AMT
AMT
SR 60 yo.
SA 50 yo.
Epileptogenic lesion in Tuberous sclerosis
AMT
MRI+FDG
Non-small cell lung cancer AMT PET
AMT-PET in patients with failed epilepsy surgery
Biomark Med. 2011,5: 577-84; J Nucl Med. 2009;50:356-363
Molecular Imaging, 2014, 13; 1–16; Cancer Biol Ther. 2013; 14: 333–339.
AMT-PET image of Brain Tumor
VS 59 yo.
Imaging Depression with [11C]AMT? Cell 2014, 159:33-45; N Engl J Med 2014, 371:2333-2334 Acknowledgements
The Cyclotron & Radiochemistry Team Cyclotron Working Group
Neil Rofsky, MD
Dean Sherry, PhD
Robert Lenkinski, PhD
Dana Mathews, PhD, MD
Orhan K. Öz, MD, PhD
Jon Anderson, PhD
Dan Crawley, MBA
Michael Medina, MBA
Randy Kirchmeier, MBA
Sylvia Revell, RSO
Administrative Support
Sonia Hill
Jocelyn Chafouleas
Emily Mayer
Dan Crawley
Acknowledgements
Financial Support CPRIT RP110771 UT Southwestern – Dr. Fitz Department of Radiology – Dr. Rofsky Simmons Cancer Center– Dr. Willson For more informa<on: hUp://www.utsouthwestern.edu/research/cyclotron/index.html Contact us: Cyclotron@UTSouthwestern.edu Cyclotron Pilot Awards (RFP issued on 2/19/2015): $50K each year for three years Submission deadline: April 1, annually Submission to: Sonia.Hill@UTSouthwestern.edu