PET: Positron Emission Tomography

Transcription

1 PET: Positron Emission Tomography

2 Standard PET Radioisotopes Positron- emi4ng Radioisotopes Isotope Half-life E β+max (MeV) Mode of Decay (β + %) Nuclear Reaction Target Media 15 O 2 min N(d,n) 15 O N %O 2 13 N 10 min O(p,α) 13 N [ 16 O]H 2 O/EtOH C 20.3 min N(p,α) C [ C]CO 2 : N %O 2 [ C]CH 4 : N %H 2 F 0 min O(p,n) F [ F]F - : O-enriched H 2 O [ F]F 2 : O-enriched O 2 + O 2 /Ar Non- Standard PET Radioisotopes Isotope Half-life E β+max (MeV) Mode of Decay (β + %) Nuclear Reaction Target Media 64 Cu 12.7 h Ni(p,n) 64 Cu Electroplated 64 Ni Metal 55 Co 17.5 h % 58 Ni(p,α) 55 Co Electroplated 58 Ni Metal 89 Zr 3.27 d % 89 Y(p,n) 89 Zr Yttrium foil 86 Y h % 86 Sr(p,n) 86 Y 86 SrCO 3 / 86 SrO powder

3 Strategic Si<ng of the Cyclotron Facility Moncrief Radia<on Oncology Building (NF) Clements Imaging Building (NE)

4 Quality Control (QC) Lab Clinical Produc<on Lab Research Radiochemistry Lab SOPs Cyclotron 15 O, 13 N C, F Solid Target Lab 64 Cu, 55 Co 89 Zr, 86 Y Cyclotron and Radiochemistry Opera<on Flow Chart

5 Toward the FDA s Regulatory Approvals of PET Drugs & Radiotracers Regulatory Requirements prior to Clinical Produc<on Equipment Installa3on & Valida3on Facility Valida3on Produc3on Valida3on cgmp non- cgmp Cri3cal Areas Non- Cri3cal Areas Regulatory Filings to FDA for Clinical use of PET Drugs QC equipment Radiosynthesis modules Cyclotron Clean Room for produc3on Ante room Non- Clinical Produc3on Areas F- FDG F- NaF 13 N- NH 3 C- Choline PET: Positron Emission Tomography

6 Preclinical Radiotracer Produc<on F tracer Applica<on/ Target Precursor C tracer Applica<on/ Target Precursor F- FLT Cellular prolifera3on imaging via Thymidine kinase- 1 C- acetate TCA cycle, fauy acid synthetase F- FMISO Hypoxia imaging C- choline Cancer imaging via the choline kinase F- FHBG Herpes simplex virus thymidine kinase (HSV- tk) C- methionine Cancer imaging via amino acid uptake and protein synthesis F- FDOPA Neuroimaging via dopamine receptor; cancer imaging via amino acid uptake and metabolism C- PIB (+)- C- DTBZ AD imaging via binding to amyloid plagues F- FET Cancer imaging via amino acid transport system Neuroimaging via targe3ng VMAT2 F- FES Cancer imaging via estrogen receptor C- ACBC Cancer imaging via amino acid uptake H- CN F- FDHT Cancer imaging via androgen receptor C- Lacta<c acid Lactate metabolism F- FACBC Cancer imaging via L- type amino acid transporter C- Pyruvic acid Pyruvate metabolism Goal: Five preclinical radiotracers per year star3ng in 2015 Validated tracers not included: [ F]FDG, [ 15 O]H 2 O, and [ 13 N]NH 3

7 FDA Regula<ons on PET Drugs & Regulatory Filings Preclinical R&D RDRC/eIND/IND 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 unlimited Phase I III ANDA: Abbreviated New Drug Applica3on unlimited FDA- approved ANDA is required for commercial dose distribu3on of [ F]FDG, [ F]NaF, [ 13 N]NH 3, and [ C]Choline. Goal: To file one RDRC and one IND applica3ons in 2015

8 Planned Radiotracer Produc<on (Clinical) Radiotracer Precursor Target Radiotracer Precursor Target F- Fluorothymidine ( F- FLT) F- Fluoromisonidazole ( F- FMISO) Cellular prolifera3on/ Thymidine kinase 1 Tumor hypoxia/ Tissue oxygena3on C- Acetate Acetate metabolism C- Choline Synthesis of phospholipids in recurrent prostate cancer F- ISO- 1 Cellular prolifera3on (Ki- 67) σ2 receptor C- Methionine Amino acid transporters [ ]fluoroestradiol ( F- FES) Estrogen receptor C- Palmi<c acid FaUy acid Metabolism F- Fluorodihydrotestosterone ( F- FDHT) Androgen receptor α- C- methyl- L- tryptophan ( C- AMT) Tryptophan metabolism Goal: Two clinical radiotracers per year star3ng in 2015 Validated tracers not included: [ F]FDG, [ 15 O]H 2 O, and [ 13 N]NH 3

9 CRP: Governance and Opera<on First- in- Human & Human Clinical Trials 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 Steering CommiUee Clinical Advisory CommiUee Dean s Office Governance CommiUee Affiliated En33es External Consultants Business Partner Clinical PET Facility Radiology, Nuclear Medicine Division UTSW Small Animal Imaging Resources Regulatory Affairs Officer Facility Records & Maintenance CRP s Responsibility CRP Facility Manager Radiochemistry & QC Specialist GMP Produc3on Clinical Tracers CRP - Director CRP Chief Radiochemist Produc3on Radiochemist Research with Radiotracers Administra3ve assistant Production & delivery of radiotracers for clinical or research use Novel imaging probe development Postdocs & Students Collaborative research (academic or industry) CRP Research Radiochemist FDA regulatory filings as the sponsor or a participant Radiotracer & Isotopes R&D Budget & Accoun3ng Radia3on Safety Physics & Engineering

10 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

11 Requests for Unlisted Clinical Radiotracers [ C]Raclopride Inquired by Psychiatry [ C]PK195 [ F]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?

12 Tryptophan Metabolism/Kynurenine Pathway Trp hydroxylase Protein Syn. IDO/ TDO α-[ C]methyl-L-tryptophan [ C]AMT [ C]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

13 Examples of [ C]- AMT PET Imaging FDG AMT AMT-PET/CT of Breast Cancers AMT Epileptogenic lesion in Tuberous sclerosis SR 60 yo. SA 50 yo. VS 59 yo. AMT MRI+FDG Non-small cell lung cancer AMT PET AMT-PET in patients with failed epilepsy surgery AMT-PET image of Brain Tumor Biomark Med. 20,5: ; J Nucl Med. 2009;50: Molecular Imaging, 2014, 13; 1 16; Cancer Biol Ther. 2013; 14:

14 Imaging Depression with [ C]AMT? Cell 2014, 159:33-45; N Engl J Med 2014, 371:

15 Acknowledgements The Cyclotron & Radiochemistry Team Neil Rofsky, MD Dean Sherry, PhD Robert Lenkinski, PhD Dana Mathews, PhD, MD Orhan K. Öz, MD, PhD Cyclotron Working Group 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

16 Acknowledgements Financial Support CPRIT RP0771 UT Southwestern Dr. Fitz Department of Radiology Dr. Rofsky Simmons Cancer Center Dr. Willson For more informa<on: hup:// Contact us: Cyclotron Pilot Awards (RFP issued on 2/19/2015): $50K each year for three years Submission deadline: April 1, annually Submission to: