What’s New in PET and SPECT ?

62nd Southwest Chapter SNMMI Dallas, TX April 1, 2016

Sally W. Schwarz, MS, BCNP Co-Director Cyclotron Facility Washington University School of Medicine St. Louis, MO 1) Overview of PET and SPECT agents used in neuroimaging including agents used to evaluate Alzheimer’s disease and movement disorders such as Parkinson’s, also a brief description of the IDEAS study

2) Overview of FDA approved PET agents used in the diagnosis of including a C-11 and F-18 FACBC.

3) Overview of Tc-99m tilmanocept for use in lymphoscintigraphpy

4) Brief description of neuroendocrine tumor imaging using Ga-68 DOTATATE compared to In-111 octreotide

5) Therapeutic radiopharmaceuticals, both FDA approved and in the pipeline. v C-11 PIB v ® Neuroimaging Amyvid v Vizamyl® Alzheimer’s: vNeuraceq®

• Progressive, degenerative disease

• Disease is associated with beta-amyloid plaques and neurofibrillary tangles in the brain

• Most common cause of dementia in people 65 years and older and the 6th leading cause of death in the US

• Proper diagnosis of Alzheimer's Disease is key

• More than 5 million Americans have the disease

FDG PET ü Available ü Reimbursed ü Not specific in early dementia Normal pattern AD pattern 100%

FTD pattern DLB pattern

Courtesy J. McConathy 0 [18F] 2012 [18F] 2013 Thioflavin T -

18F HO S NHCH3 N [11C]PiB 18 () [ F] 2014 [18F]AZD4694

HO S NHCH3 HO 18F O N H 3C NHCH3 N O N H O O 18F

Rowe CC et al., 2011. Brain Amyloid Imaging, J Nucl Med. Cselenyi Z et al., 2012. Clinical validation of 18F-AZD4694, an amyloid-beta-specific PET radioligand, J Nucl Med. • SNMMI and the Alzheimer’s Association developed Appropriate Use Criteria (AUC) to aid in the diagnosis of people with suspected Alzheimer’s disease. Ø Amyloid AUC published in J Nuc Med in 2013 • CMS Non Coverage Decision (NCD) on amyloid brain imaging – Sept 2013 – allows one PET amyloid scan per patient through Coverage with Evidence Development (CED). • CED study for PET amyloid imaging (AA, WMIC, ACRIN, SNMMI) Ø Amyloid Imaging CED workgroup submitted a draft protocol to CMS for PET amyloid imaging in patients satisfying the AUC. Ø Revised protocol for Imaging Dementia – Evidence for Amyloid Scanning “IDEAS” Study

7

• IDEAS Study was developed in response to the 2013 CMS National Coverage Decision • Medicare beneficiary, age 65 and older • Diagnosis of Mild Cognitive Impairment (MCI) or dementia verified by a dementia specialist • Meets Appropriate Use Criteria (AUC): 1. Cognitive complaint verified by objectively confirmed cognitive impairment 2. The cause of cognitive impairment is uncertain after a comprehensive evaluation by a dementia specialist 3. Knowledge of amyloid PET status is expected to alter diagnosis and management

• Must use one of the three radiopharmaceuticals approved for clinical use by the FDA: ü [F-18]florbetapir ü [F-18]florbetaben ü [F-18]flutemetamol • Cannot use a non-FDA approved amyloid PET e.g. C-11 PiB • Choice is decided by the PET Facility, which must be accredited ACR or IAC or RadSite • Physician must be Board Certified, ABNM, ABR, AOBR or AOBNM

Neuroimaging vF-18 FDOPA (FDOPA)

Parkinson’s: v DaTscan®

• Progressive degenerative disease • Loss of the nigrostriatal dopaminergic system-- underlies major motor manifestations of PD • Symptoms emerge when depletion exceeds 80-90% • Image dopaminergic terminals: ü FDOPA (PET) ü I-123 (SPECT)

Parkinson’s Disease (PD):

• Decrease in dopaminergic neurons located in the basal ganglia, specifically in the substantia nigra (area which controls movement)

• FDOPA & ioflupane selectively localizes in dopaminergic neurons

• As PD progresses FDOPA & ioflupane accumulation decreases, which correlates with severity of PD

• Need a means to assess neurotramsmission • Involves synthesis & release of neurotransmitters e.g. dopamine • Transmitters diffuse across the synapse to bind receptors located on post synaptic nerve cell • Produced by GE • Approved January 2011 • Indication: for striatal dopamine transporter visualization using SPECT in the evaluation of suspected Parkinsonian syndromes. It may be used to differentiate essential tremor from tremor due to PD. • It is an adjunct to other diagnostic evaluations Targets for dopaminergic ligands—FDOPA and Ioflupane I-123

Dopamine synthesis Tyrosine

FDOPA L-DOPA

DA Dopamine

This image cannot currently be displayed.

This image cannot currently be displayed. x Transporter x This image cannot currently be displayed. Vesicles X = dopamine Pre-synaptic terminal This image cannot currently be displayed. x FDOPA(mine) x x x x x x

D2 Receptors I-123 Ioflupane

Post-synaptic cell Binds reversibly to pre-synaptic dopamine transporter (DAT) Head of Caudate Body of Caudate

MRI

Putamen

Ioflupane I-123 SPECT Medial part of SN projects to caudate Lateral part of SN projects to putamen

In PD the lateral part of SN always degenerates first

preferential loss in putamen relative to caudate FDOPA in PD

Normal Mild PD

Severe PD • Glioblastoma multiforme (GMB): Most common form of primary brain tumor • Diagnosis: MRI, CT and PET • FDOPA PET: useful in detection and recurrence of glioma glioblastoma

grade II oligodendro glioma

18 MR [ F]FDG [18F]FDOPA Sensitivity = 61% Sensitivity = 96% (78% for high grade) Chen, W., 2007. Clinical applications of PET in brain tumors, J Nucl Med. 48: 1468. Image at 15-20 min after FDOPA injection

• Joint project, SNMMI/NCI • Submit for single indication: hyperinsulinemic hypoglycemia (HHI) • CMC: nucleophilic and electrophilic chemistry üNeed to determine if both should be submitted • Clinical data from 3 potential sites • Application for orphan drug status is in progress

• Persistent HHI is relatively rare. Also known as nesidioblastosis • Most common cause of persistent hypoglycemia in infants and children • 1:50,000 • Due to excessive pancreatic insulin secretion • Two clinically indistinguishable forms: focal – may have surgical option for cure diffuse – not surgically resectable

Slide compliments of Helen Nadel, MD, UBC, Vanc Two newborns with hyperinsulinemic hypoglycemia of infancy using FDOPA

Focal

Diffuse

Slide compliments of Helen Nadel, MD, UBC, Vancouver Prostate Cancer Imaging v C-11 v C-11 Choline vF-18

And Therapy v Ra-223 Chloride

} Most common malignancy in men } Lifetime risk of 1 in 6 men } >20% of men will die from their disease

Siegel et al. CA Cancer 2014 C-11 Acetate F-18 FDG

pancreas Ureter

Bladder

ANT POST ANT POST No renal excretion of C-11 Acetate • FDA approved NDA for Mayo Clinic Rochester production: September 12, 2012 • Indication: Diagnostic agent for prostate cancer recurrence and non-informative bone , CT or MR. • C-11 choline transport and metabolism is increased in prostate cancer--marker of cell membrane synthesis • Mayo clinical volume ~150 patients/month in April 2014 • Local CMS provider approved reimbursement beginning: October 1, 2013

Slide courtesy of Pat Peller, M.D., Mayo Clinic Radiosynthesis:

11 CH3 11 + N [ C]CH3I N HO HO 11 2-dimethylaminoethanol [ C]Choline

1. Target 0.5% O2 in N2 gas mixture is irradiated with protons for up to 100 minutes in the cyclotron

2. The resultant C-11 CO2 is shunted to MeI box, which converts C-11 CO to C-11 MeI

3. C-11 MeI gas is shunted through a NaOH column to scavenge free iodide or HI (hydrogen iodide), and transferred to the C-11 choline synthesis module

A 61-year-old man presented with a PSA of 5.4 originally and is status post radical prostatectomy for Gleason 7 prostate cancer felt to be confined to the gland.

Two years later, patient had a measurable PSA of 5.75 and recently rose to 6.9.

C-11 Choline PET/CT shows multiple bony metastases which have minimal sclerotic Slide courtesy of Pat Peller, M.D., Mayo Clinic changes on CT images. Bone scan negative

• Probable peripheral nerve sheath tumor (not prostate cancer), but not biopsy proven at the time or imaging. • Image does show abnormal uptake in the prostate gland.

Image compliments of BA Siegel, MD Washington University in St. Louis • analogue

• Synthetic L-leucine analog taken up in prostate cancer cells but not further metabolized } Dose 10 mCi

F-18 Fluciclovine Physiological Distribution

Biology: • F-18 Fluciclovine: not metabolized; (A) transporters ubiquitous throughout body • Pancreas and liver: AA metabolism & synthesis of plasma proteins

• Muscle hosts majority glutamine pool 5-16 min- 17-28 min: 29-40 min: Pancreas > Liver Pancreas = Liver Pancreas < Liver Whole body: • Most intense physiologic uptake: liver and pancreas

• Moderate: salivary gland, pituitary

– Muscle: • with time – Marrow: heterogeneous and ¯ with time • Mild to none: brain and lung

• Variable: bowel 34 • Bladder absent or mild on early imaging

and • with time 1. Schuster, et al. J Nucl Med 2014 } FDA Approval, June 2016 } Manufactured by PETNET (under 21 CFR Part 212) } Indication: for positron emission tomography (PET) imaging in men with suspected prostate cancer recurrence based on elevated blood prostate specific antigen (PSA) levels following prior treatment } U.S. FDA review based on data from >700 prostate cancer patients imaged in the US, Norway and Italy1 ◦ Granted Orphan Drug Status diagnosis of glioma2 1. Press Release December 2015: http://www.blueearthdiagnostics.com/news/ 2. Press Release April 2015: http://www.blueearthdiagnostics.com/news/

1. Focal radiotracer uptake in the right peripheral zone of the prostate most consistent with recurrent disease. 2. More subtle focal radiotracer uptake in the left mid gland is also suspicious for disease. 3. No metastatic disease identified. Specifically, there is no increased tracer activity in the right iliac bone.

Image compliments of BA Siegel, MD Washington University in St. Louis • About 4% of prostate cancer have distant metastases at diagnosis • Bone metastases are most common • Metastatic disease is virtually incurable • The aim of therapy is to control the disease while maintaining quality of life

Radium-223 • Bone – targeting radiopharmaceutical • High energy alpha-particles with short range (<100µm) hence less bone marrow toxicity üAlpha 5.78 MeV

üT½ 11.4 days üFDA approved-- metastatic bone disease

• Indication: alpha particle-emitting radio-therapeutic for treatment of castrate-resistant prostate cancer (CRPC), symptomatic bone metastases & no known visceral metastatic disease • Dose: 50 kBq (1.35 µCi)/kg body weight given at 4 week entervals for 6 injections • Warnings & Precautions: bone marrow supression, Monitor blood counts prior to treatment initiation and before every dose of Ra-223 • Adverse Reactions: Most common, were nausea, diarrhea, vomiting & peripheral edema and anemia, lymphocytopenia, leukopenia, thrombocytopenia & neutropenia. • Contraindications: pregnancy • Contamination removal: 0.01 EDTA solution recommended

Lymphoscintigraphy vTc-99m Tilmanocept

• Most common type of cancer among American women, but is also affects men as well. • Second leading cause of death in women following lung cancer. • ACS estimates for 2015 (women) Cancer.Net for 2016 (men) ü New cases of invasive breast cancer diagnosed in women– 231,840 New cases in men– 2,600 ü New cases of non-invasive breast cancer, women– 60,290 ü Deaths − 40,290 women − 440 men

• Skin cancer-most common of all cancers • Melanoma only accounts for less than 5% of skin cancer cases, but is responsible for the large majority of skin cancer deaths • ACS projected for 2017:

ü New melanomas diagnosed: 87,110 Men: 52,170; Women: 34,940 ü Deaths: 9,730 Men 6,380; Women: 3,350; Sentinel Lymph Node Schematic First node encountered by lymph draining from primary tumor, sentinel lymph node, should be site where clusters of tumor cells migrating through lymphatic channels are most likely to be entrapped and possibly proliferate before widespread tumor dissemination in body. • Indication: Lymphatic mapping with or without imaging ü Assist in the localization of lymph nodes draining a primary tumor site in patients with breast cancer or melanoma using a hand-held gamma counter ü Guide sentinel lymph node mapping with hand-held gamma counter • First receptor targeted lymphatic mapping agent: Mannose receptor (CD-206) • Dose: 0.5 mCi (50 µg) • Kit expires 6 hours post preparation

Injection Site Axillary Node

ANT IMMED LAO LLAT ANT 20 MIN Lymphatic Channel ü Sentinal LN: Axillary Node visualized at 20 min observed at 24 h ü Activity also visualized

LT LAT 24 HR in the lymphatic channels of the upper arm

Sondak VK, et al. Ann Surg Oncol. 2013;20(2):680-688. • Rapid and consistent injection site clearance • Detectable within 10 min, up to 30 hrs • Targets and tightly binds receptors within lymph nodes • Primary sentinel node uptake of Tilmanocept does not significantly differ from sulfur colloid • Clearance half-time is reduced to 2.72 ± 1.57 hours compared to 49.5 ± 38.5 hours for sulfur colloid

Ann Surg Oncol. 2013;20:680-8 Neuroendocrine Tumors Imaging v Ga-68 dotatate

And Therapy v Lu-177 dotatate

• Arise from cells of the endocrine system rather than from cells specific to a certain organ or tissue • NETS produce hormones and bioactive substances that control critical body functions • NETs are capable of over secreting these substances, which can result in a broad spectrum of symptoms and clinical syndromes • Three broadly defined types: GI, pancreatic, lung

Ga-68 dotatate

} FDA approved: June 2016 } Ga-68 dotatate is prepared under pharmacy practice according to the package insert } Similar to Tc-99m kit preparation Ge-68 } ® E.C. Prepared using the GalliaPharm T1/2 = 275 d Ge-68/Ga-68 generator which is not FDA approved except for use in Ga-68 the preparation of Ga-68 dotatate β+ (88%) } Ge-68 parent is cyclotron produced E.C. (12%)

üZn-66 (α,2n) Ge-68 T1/2 = 68 min üGe-69 (p,2n) Ge-68 Zn-68 (stable)

GalliaPharm® Ge-68/Ga-68 Generator Elution in ISO5 LFH

0.1 M HCl Formate buffer

Preparation regulated under Practice of Pharmacy USP Chapter 797 A) 111In Octreotide SPECT/CT false-negative B) 68Ga dotatate true positive C) Contrast CT D) PET/CT A. JNM. Deppen SA, Liu E, Blume JD, Clanton J, et al. Safety & Efficacy of 68Ga dotatate for Diagnosis, Staging & Treatment of Neuroendocrine Tumors. J Nucl Med. 2016.115:163865. • Lu-177 dotatate üBeta: 490 keV üGamma & X-rays: 113 keV (3%), 210 keV (11%)

ü T½: 6.7 days

• Under FDA review

• Response to 177Lu dotatate – PRRT in a rectal NET with a massive (21.5-cm diameter) inoperable right lobe liver metastasis • Treatment with 177Lu dotatate every 8 weeks • 68Ga dotatate Images are immediate post initial treatment, and every 8 weeks • Last image, on right, liver lesion has shrunk to 1.5 cm. (43 GBq cumulative activity) } Ra-223 Chloride ü Alpha 5.78 MeV

ü T½ 11.4 days ü FDA approved-- metastatic bone disease } Lu-177 dotatate ü Beta: 490 keV ü Gamma & X-rays: 113 keV (3%), 210 keV (11%)

ü T½: 6.7 days ü under FDA review } Ac-225 Lintuzemab (Actimab-A®) ü Alpha - 8.38 MeV ü Beta - 1.42 MeV

ü T½: 10 days ü FDA Orphan Drug status-- myeloid leukemia ü Humanized MAb targets CD33 found on myeloid leukemia cells Produced under FDA 21 CFR Part 211

1. Medicare beneficiary, age 65 and older 2. Diagnosis of mild cognitive impairment (MCI) or dementia verified by a dementia specialist 3. Meets AUC 4. Must use one of the three radiopharmaceuticals approved for clinical use by the FDA 5. All the above

1. Medicare beneficiary, age 65 and older 2. Diagnosis of mild cognitive impairment (MCI) or dementia verified by a dementia specialist 3. Meets AUC 4. Must use one of the three radiopharmaceuticals approved for clinical use by the FDA 5. All the above

Reference: 1. Ckliinical Trials.gov https://clinicaltrials.gov/ct2/show/NCT02420756 2. IDEAS https://www.snmmi.org/files/Outreach/IDEAS_Flyer%20cbc%20edits.28Aug15.pdf

1. Flurodopa 2. FACBC 3. Ioflupane 4. Tilmanocept

1. Flurodopa 2. FACBC 3. Ioflupane 4. Tilmanocept

Referemce: Package Insert file:///C:/Users/sschwa01/Downloads/GEHealthcare_Da Tscan-Prescribing-Information.pdf

A. C-11 choline B. Ga-68 dotatate C. F-18 fluciclovine D. C-11 acetate E. A and D F. A and C

A. C-11 choline B. Ga-68 dotatate C. F-18 fluciclovine D. C-11 acetate E. A and D F. A and C

Package Insert Choline http://www.accessdata.fda.gov/drugsatfda_ docs/label/2012/203155s000lbl.pdf

Package Insert Flucilovine: http://www.accessdata.fda.gov/drugsatfda_do cs/label/2016/208054s000lbl.pdf

1. Diagnostic agent for prostate cancer recurrence 2. Localization of somatostatin receptor positive neuroendocrine tumors 3. Assist in the localization of lymph node metastases 4. Radiotherapeutic for bone metastases

1. Diagnostic agent for prostate cancer recurrence 2. Localization of somatostatin receptor positive neuroendocrine tumors 3. Assist in the localization of lymph node metastases 4. Radiotherapeutic for bone metastases

Reference: package insert http://www.accessdata.fda.gov/drugsatfda_docs/label/201 6/208547s000lbl.pdf A. Ra-223 B. Lu-177 dotatate C. Ga-68 dotatate D. F-18 Fluciclovine

A. Ra-223 B. Lu-177 dotatate C. Ga-68 dotatate D. F-18 Fluciclovine

Reference: Package Insert http://www.accessdata.fda.gov/drugsatfda_docs/ label/2013/203971lbl.pdf